Age- and gender-specific risks of myocarditis and pericarditis following Covid-19 messenger RNA vaccines – Nature Communications

Characteristics of the study population

Between May 12, 2021 and October 31, 2021, in a population of 32 million people aged 12 to 50, 21.2 million first (19.3 million second) doses of the BNT162b2 and 2 vaccine, 86 million first (2.58 million second) doses of mRNA -1273 vaccines were received (Table S1). In the same period, 1612 cases of myocarditis (including 87 [5.4%] also had pericarditis as an associated diagnosis) and 1613 cases of pericarditis (37 [2.3%] with myocarditis as an associated diagnosis) have been registered in France. We matched these cases to 16,120 and 16,130 control subjects, respectively. The characteristics of the cases and their matched controls are shown in Table 1. For myocarditis and pericarditis, the main differences between cases and controls included a higher proportion among cases with a history of myocarditis or pericarditis, d history of SARS-CoV-2 infection, and receipt of a Covid-19 mRNA vaccine. Mean age and proportion of women were lower in patients with myocarditis than in those with pericarditis.

Table 1 Characteristics of case and control studies.

Risk of myocarditis and pericarditis associated with vaccination

For both vaccines, the risk of myocarditis was increased in the seven days post-vaccination (Table 2; in the rest of the text, we will speak of multivariate odds ratios). For the BNT162b2 vaccine, the odds ratios were 1.8 (95% confidence interval [CI]: 1.3–2.5) for the first dose and 8.1 (95% CI, 6.7–9.9) for the second. The association was stronger for the mRNA-1273 vaccine with odds ratios of 3.0 (95% CI, 1.4 to 6.2) for the first dose and 30 (95% CI, 21 to 43) for the second. The risk of pericarditis was increased within seven days of the second dose of both vaccines, with odds ratios of 2.9 (95% CI, 2.3 to 3.8) for the BNT162b2 vaccine and 5. 5 (95% CI, 3.3-9.0) for mRNA -1273 vaccine. Vaccination within the previous 8-21 days with BNT162b2 or mRNA-1273 vaccine was not associated with risk of myocarditis or pericarditis. Regardless of vaccination status, a history of myocarditis was strongly associated with a risk of acquiring myocarditis during the study period, with an odds ratio of 160 (95% CI, 83–330). The same was true for pericarditis, with an odds ratio of 250 (95% CI, 120–540). No interaction was found between a history of myocarditis or pericarditis and exposure to the vaccine. SARS-CoV-2 infection in the previous month was also associated with risk of myocarditis (odds ratio, 9.0 [95% CI, 6.4–13]) or pericarditis (odds ratio, 4.0 [95% CI, 2.7–5.9]).

Table 2 Association between myocarditis and pericarditis and exposure to mRNA vaccines within 1 to 7 days and 8 to 21 days.

Estimates of subgroups by sex and age groups

The risk of myocarditis was significantly increased during the first week after vaccination in both males and females (Fig. 1 and Table S2). The odds ratios associated with the second dose of the mRNA-1273 vaccine were consistently the highest, with values ​​up to 44 (95% CI, 22-88) and 41 (95% CI, 12-140) , respectively in men and women aged 18 to 24 but remaining high in the upper age groups. The odds ratios for the second dose of the BNT162b2 vaccine tended to decrease with age, from 18 (95% CI, 9 to 35) and 7.1 (95% CI, 1.5 to 33), in males and females aged 12 to 17, respectively, down to 3.0 (95% CI, 1.5 to 5.9) and 1.9 (95% CI, 0.39 to 9, 3), respectively in men and women aged 40 to 51 years.

Fig. 1: Association between myocarditis and exposure to mRNA vaccines within 7 days, by sex and age group.

The adjusted odds ratios (aOR) of the multivariable model are represented in logarithmic scale base 10 according to the age groups (X-axis), by sex (columns) and classification of vaccine doses (rows). The colors indicate the type of vaccine. Center values ​​are aOR point estimates and error bars represent 95% confidence intervals. The number of cases (N) by age groups (12–17, 18–24, 25–29, 30–39, 40–50 and 12–50 years) are respectively as follows: NOT= 137, 480, 210, 273, 181 and 1281 for men, and NOT= 29, 106, 40, 88, 68 and 331 for women. The aOR could not be calculated in categories where no vaccine-exposed cases were recorded, for example for males and females aged 12-17 who received the mRNA-1273 vaccine.

An increased risk of pericarditis was also found during the first week after the second dose of one of the mRNA vaccines in both males and females (Fig. 2 and Table S3). The odds ratios for the second dose of the BNT162b2 vaccine showed a decreasing trend in all age groups with values ​​up to 6.8 (95% CI, 2.3 to 20) and 10 ( 95% CI, 2.5 to 41), respectively in men and women aged 12 to 17 years. The second dose of the mRNA-1273 vaccine was associated with pericarditis in men and only in women between 30 and 39 years of age (odds-ratio 20 [95% CI, 3.5–110]) and aged between 40 and 50 (odds-ratio 13 [95% CI, 3.5–49]).

Fig. 2: Association between pericarditis and exposure to mRNA vaccines within 7 days, by sex and age group.
Figure 2

The adjusted odds ratios (aOR) of the multivariable model are represented in logarithmic scale base 10 according to the age groups (X-axis), by sex (columns) and classification of vaccine doses (rows). The colors indicate the type of vaccine. Center values ​​are aOR point estimates and error bars represent 95% confidence intervals. The number of cases (N) by age groups (12–17, 18–24, 25–29, 30–39, 40–50 and 12–50 years) are respectively as follows: NOT= 65, 194, 106, 282, 342 and 989 for men, and NOT= 36, 118, 91, 183, 196 and 624 for women. The aOR could not be calculated in categories where no vaccine-exposed cases were recorded, for example for males and females aged 12-17 who received the mRNA-1273 vaccine.

Associations between vaccination in the previous seven days and the risk of myocarditis or pericarditis were of the same order of magnitude when the analysis was restricted to the period before the warning of myocarditis and pericarditis as adverse events sent to prescribers on July 19, 2021 (Fig. S1 and table S4). Results were unchanged in models excluding patients with a history of SARS-CoV-2 infection within the previous month, those with a history of myocarditis or pericarditis within five years, those diagnosed with both myocarditis and pericarditis, or those with hospitalization within one month prior to the index date.

Excess events

We estimated the number of excess cases attributable to vaccines by sex and age group (Fig. 3). The excess number of myocarditis cases per 100,000 doses given to adolescent males 12-17 years of age was 1.9 (95% CI 1.4-2.6) for the second dose of BNT162b2 vaccine and for young adults 18–24 years old, it reached 4.7 (95% CI, 3.8–5.8) for the second dose of BNT162b2 vaccine and 17 (95% CI, 13–23) for the second dose mRNA-1273 vaccine (Fig. 3). This translates to one case of vaccine-associated myocarditis per 52,300 (95% CI, 38,200 to 74,100) second doses of BNT162b2 vaccine among 12 to 17 year olds, and 21,100 (95% CI, 17,400 to 26,000) second doses of BNT162b2 vaccine and 5,900 (95% CI, 4400 to 8000) second doses of mRNA-1273 vaccine in 18-24 year olds (Table S5). Estimates of excess cases were lower for older age groups and generally for females. However, the number of excess cases of myocarditis attributable to the second dose of the mRNA-1273 vaccine was consistently higher. In women aged 18 to 24 years, the estimated number of excess cases of myocarditis per 100,000 doses reached 0.63 (95% CI, 0.34 to 1.1) for the second dose of BNT162b2 vaccine (corresponding 1 case per 159,000 [95% CI, 90,800–294,400] doses) and 5.3 (95% CI, 3.0–9.1) for the second dose of mRNA-1273 vaccine (corresponding to 1 case in 18,700 [95% CI, 11,000–33,400] doses). The number of excess cases of pericarditis is shown in Fig. 3. As with myocarditis, estimates for the second dose of mRNA-1273 vaccine were consistently higher.

Fig. 3: Excess cases of myocarditis and pericarditis attributable to mRNA vaccines by sex and age group, per 100,000 doses.
picture 3

Excess cases are based on risk within 7 days of vaccination. The colors indicate the vaccine type and the shape of the point estimate indicates the vaccine dose ranking. The central value corresponds to the point estimates of the excess cases and the error bars represent the 95% confidence intervals. The number of cases (N) by age groups (12–17, 18–24, 25–29, 30–39, 40–50 and 12–50 years) are respectively as follows: for cases of myocarditis, NOT= 137, 480, 210, 273, 181 and 1281 in men, and NOT= 29, 106, 40, 88, 68 and 331 in women; for cases of pericarditis, NOT= 65, 194, 106, 282, 342 and 989 in men, and NOT= 36, 118, 91, 183, 196 and 624 in women. Excess cases were only calculated in categories with a significantly positive association between vaccine exposure and outcome (adjusted odds ratio > 1).

Characteristics of cases of myocarditis and pericarditis occurring after vaccination

Among exposed cases, the time between vaccine administration and hospitalization (Fig. S2) was shorter after the second dose than after the first dose, both for myocarditis (median of 4 days versus 10 days after BNT162b2 vaccine and 3.5 days versus 9 days after mRNA-1273 vaccine) and for pericarditis (median 6 days versus 10 days after BNT162b2 vaccine and 3 days versus 11 days after mRNA-1273 vaccine).

Table 3 presents the characteristics of cases acquired within 7 days of vaccination (cases considered post-vaccination) compared to those acquired within a longer period or in the absence of vaccination. Post-vaccination cases were significantly younger (mainly between 18 and 24 years old), more frequently involved men for myocarditis but not pericarditis, and without a history of myocarditis or pericarditis, respectively, or SARS infection -CoV-2. Hospital stay durations were not significantly different in post-vaccination cases of myocarditis (median 4 days) and pericarditis (median 2 days) compared to unexposed cases. The frequency of ICU admission, mechanical ventilation, or death was lower for post-vaccination cases than for unexposed cases. After 30 days post-discharge follow-up, 4 (0.24%) deaths among myocarditis cases (none among those exposed to the vaccine) and 5 (0.31%) deaths among pericarditis cases (including one patient with received a vaccine 8 to 21 days before diagnosis) have been reported. Of these, 3 and 2 died while in hospital for myocarditis and pericarditis, respectively.

Table 3 Description of hospitalized patients by exposure to mRNA vaccines.

Drug treatments within 30 days of hospital discharge are shown in Figs. S3 and S4. Irrespective of the vaccination status, the therapeutic classes most frequently used during the follow-up of cases of myocarditis are beta-blockers (63% of patients), analgesics (52%) and agents acting on the renin-angiotensin system ( 46%). The corresponding treatments for cases of pericarditis were analgesics (83%), colchicine (69%) and beta-blockers (14%) (Fig. S4).

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