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ARTICLE
Age and sex-specific risks of myocarditis and
pericarditis following Covid-19 messenger RNA
vaccines
Stéphane Le Vu 1✉, Marion Bertrand1, Marie-Joelle Jabagi 1, Jérémie Botton 1,2, Jérôme Drouin1,
Bérangère Baricault1, Alain Weill 1, Rosemary Dray-Spira 1& Mahmoud Zureik1,3
Cases of myocarditis and pericarditis have been reported following the receipt of Covid-19
mRNA vaccines. As vaccination campaigns are still to be extended, we aimed to provide a
comprehensive assessment of the association, by vaccine and across sex and age groups.
Using nationwide hospital discharge and vaccine data, we analysed all 1612 cases of myo-
carditis and 1613 cases of pericarditis that occurred in France in the period from May 12, 2021
to October 31, 2021. We perform matched case-control studies and find increased risks of
myocarditis and pericarditis during the first week following vaccination, and particularly after
the second dose, with adjusted odds ratios of myocarditis of 8.1 (95% confidence interval
[CI], 6.7 to 9.9) for the BNT162b2 and 30 (95% CI, 21 to 43) for the mRNA-1273 vaccine.
The largest associations are observed for myocarditis following mRNA-1273 vaccination in
persons aged 18 to 24 years. Estimates of excess cases attributable to vaccination also reveal
a substantial burden of both myocarditis and pericarditis across other age groups and in both
males and females.
https://doi.org/10.1038/s41467-022-31401-5 OPEN
1EPIPHARE Scientific Interest Group in Epidemiology of Health Products, (French National Agency for the Safety of Medicines and Health Products - ANSM,
French National Health Insurance - CNAM), Saint-Denis, France. 2Faculté de Pharmacie, Université Paris-Saclay, 92296 Châtenay-Malabry, France.
3University Paris-Saclay, UVSQ, University Paris-Sud, Inserm, Anti-infective evasion and pharmacoepidemiology, CESP Montigny le Bretonneux, France.
✉email: stephane.le-vu@ansm.sante.fr
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On July 19, 2021 the European Medicines Agency advised
that myocarditis and pericarditis be added to the list of
adverse effects of both messenger RNA (mRNA) based
vaccines (BNT162b2 [Pfizer–BioNTech] and mRNA-1273
[Moderna]) against coronavirus disease 2019 (Covid-19)1. This
statement followed pharmacovigilance reports of an increased
risk of myocarditis among recipients of mRNA vaccines that
showed certain common patterns2,3. Several reports indicate that
adverse events typically occur within a week after injection,
mostly after the second dose of vaccine, cluster in young males,
and result in a mild clinical course and short duration of
hospitalization4–6. However, the predominance of a vaccine-
associated risk in males7and its extent regarding pericarditis, as a
specific condition, remains uncertain8–11. Population-based risks
estimates for each condition and across sex and age groups and
by vaccine type remains crucial as vaccination campaigns are still
to be extended especially towards the youngest and with sub-
sequent doses. The Covid-19 vaccination campaign began in
France in late 2020 with the gradual roll-out of the two mRNA
vaccines, BNT162b2 and mRNA-1273 alongside viral vector-
based vaccines. Initially reserved for the oldest and most vul-
nerable groups, as well as healthcare professionals, vaccination
was opened up to the entire population over the age of 18 years as
of May 12, 2021, and to all over 12 years old as of June 15, 2021.
As of October 31, 2021 approximately 50 million people (88% of
the eligible population, i.e. over 12 years old) in France had
received a full vaccination schedule12. Here, we aimed to estimate
the age and sex-specific associations between each mRNA Covid-
19 vaccine and the risk of myocarditis and pericarditis, using
nationwide hospital discharge and vaccine data for France.
Results
Characteristics of the study population. Between May 12, 2021
and October 31, 2021, within a population of 32 million persons
aged 12 to 50 years, 21.2 million first (19.3 million second) doses
of the BNT162b2 vaccine and 2.86 million first (2.58 million
second) doses of the mRNA-1273 vaccine were received
(Table S1). In the same period, 1612 cases of myocarditis (of
which 87 [5.4%] had also a pericarditis as associated diagnosis)
and 1613 cases of pericarditis (37 [2.3%] with myocarditis as
associated diagnosis) were recorded in France. We matched those
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 both myocarditis and pericarditis, key differences
between cases and controls included a higher proportion among
cases of a history of myocarditis or pericarditis, of history of
SARS-CoV-2 infection, and receipt of an mRNA Covid-19 vac-
cine. The mean age and proportion of women were lower among
patients with myocarditis than those with pericarditis.
Risk of myocarditis and pericarditis associated with vaccina-
tion. 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 refer to multivariable odds ratios). For the BNT162b2 vac-
cine, 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, 1.4–6.2) for the first dose and 30 (95% CI,
21–43) for the second. The risk of pericarditis was increased in
the seven days following the second dose of both vaccines, with
odds ratios of 2.9 (95% CI, 2.3–3.8) for the BNT162b2 vaccine
and 5.5 (95% CI, 3.3–9.0) for the mRNA-1273 vaccine. Vacci-
nation in the previous 8 to 21 days, with either the BNT162b2 or
mRNA-1273 vaccine was not associated with a risk of myocarditis
or pericarditis. Independently of vaccination status, a history of
myocarditis was strongly associated with a risk of contracting
myocarditis during the study period, with an odds-ratios 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 history of myocarditis or pericarditis and vaccine
exposure. Infection with SARS-CoV-2 in the preceding month
was also associated with a risk of myocarditis (odds ratio, 9.0
[95% CI, 6.4–13]) or pericarditis (odds ratio, 4.0 [95% CI,
2.7–5.9]).
Subgroup estimates by sex and age classes. The risk of myo-
carditis was substantially increased within the first week post
vaccination in both males and females (Fig. 1and Table S2).
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 males and
females aged 18 to 24 years but remaining high in older age
groups. Odds-ratios for the second dose of the BNT162b2 vaccine
tended to decrease with age, from 18 (95% CI, 9–35) and 7.1 (95%
CI, 1.5–33), respectively in males and females aged 12 to 17 years,
down to 3.0 (95% CI, 1.5–5.9) and 1.9 (95% CI, 0.39–9.3),
respectively in males and females aged 40 to 51 years.
An increased risk of pericarditis was also found in the first
week after the second dose of either of the mRNA vaccines
among both males and females (Fig. 2and Table S3). Odds-ratios
for the second dose of the BNT162b2 vaccine showed a
downward trend across age groups with values up to 6.8 (95%
CI, 2.3–20) and 10 (95% CI, 2.5–41), respectively in males and
females aged 12 to 17 years. The second dose of the mRNA-1273
vaccine was associated with pericarditis among males and among
females only within age 30 to 39 years (odds-ratio 20 [95% CI,
3.5–110]) and age 40 to 50 years (odds-ratio 13 [95% CI, 3.5–49]).
Associations between vaccination within the seven preceding
days and the risk of myocarditis or pericarditis were of the same
magnitude when the analysis was restricted to the period prior to
the warning against myocarditis and pericarditis as adverse events
sent to prescribers on July 19, 2021 (Fig. S1 and Table S4). The
results were unchanged in models excluding patients with a
history of SARS-CoV-2 infection in the past month, those with a
history of myocarditis or pericarditis within five years, those
diagnosed with both myocarditis and pericarditis, or those with a
hospitalization within a month prior to index date.
Excess events. We estimated the number of excess cases attri-
butable to vaccines by sex and age group (Fig. 3). The number of
excess cases of myocarditis per 100,000 doses administered to
adolescent males 12 to 17 years was 1.9 (95% CI, 1.4–2.6) for the
second dose of the BNT162b2 vaccine and for young adults 18 to
24 years of age reached 4.7 (95% CI, 3.8–5.8) for the second dose
of the BNT162b2 vaccine, and 17 (95% CI, 13–23) for the second
dose of the mRNA-1273 vaccine (Fig. 3). This translates into one
case of vaccine-associated myocarditis per 52,300 (95% CI,
38,200–74,100) second doses of the BNT162b2 vaccine among
12–17 years, and 21,100 (95% CI, 17,400–26,000) second doses of
the BNT162b2 vaccine and 5900 (95% CI, 4400–8000) second
doses of the mRNA-1273 vaccine among 18–24 years (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. Among females aged 18 to 24
years, the estimated number of excess cases of myocarditis per
100,000 doses reached 0.63 (95% CI, 0.34–1.1) for the second
dose of the BNT162b2 vaccine (corresponding to 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 the mRNA-1273 vaccine
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(corresponding to 1 case per 18,700 [95% CI, 11,000–33,400]
doses). The number of excess cases of pericarditis is presented in
Fig. 3. As for myocarditis, estimates for the second dose of the
mRNA-1273 vaccine were consistently higher.
Characteristics of myocarditis and pericarditis cases occurring
after vaccination. Among exposed cases, the delay between
administration of the vaccine 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 the BNT162b2
vaccine and of 3.5 days versus 9 days after the mRNA-1273
vaccine) and for pericarditis (median of 6 days versus 10 days
after the BNT162b2 vaccine and of 3 days versus 11 days after the
mRNA-1273 vaccine).
Table 3shows the characteristics of cases acquired within
7 days of vaccination (deemed post-vaccination cases) compared
to those acquired within a larger delay or in the absence of
vaccination. Post-vaccination cases were significantly younger
(predominantly in 18 to 24 years), more frequently concerned
males for myocarditis but not for pericarditis, and without a
history of myocarditis or pericarditis, respectively, or of SARS-
CoV-2 infection. The lengths of hospital stay were not
significantly different in post-vaccination cases of myocarditis
(median 4 days) and pericarditis (median 2 days) than in
unexposed cases. The frequency of admission in intensive care
unit, mechanical ventilation or death was lower for post-
vaccination cases than for unexposed cases. After a follow-up of
30 days after discharge, 4 (0.24%) deaths among cases of
Table 1 Characteristics of study cases and controls.
Myocarditis Pericarditis
Cases Controls Cases Controls
(N=1612) (N=16,120) (N=1613) (N=16,130)
Sex
Male 1281 (79.5) 12,810 (79.5) 989 (61.3) 9890 (61.3)
Female 331 (20.5) 3310 (20.5) 624 (38.7) 6240 (38.7)
Agea
Mean (sd) 27.8 (9.51) 27.8 (9.51) 33.4 (10.3) 33.4 (10.3)
Median (range) 25.0 (20.0–34.3) 25.0 (20.0–34.3) 34.0 (24.0–42.0) 34.0 (24.0–42.0)
Age distributiona
12–17 166 (10.3) 1660 (10.3) 101 (6.3) 1010 (6.3)
18–24 586 (36.4) 5860 (36.4) 312 (19.3) 3120 (19.3)
25–29 250 (15.5) 2500 (15.5) 197 (12.2) 1970 (12.2)
30–39 361 (22.4) 3610 (22.4) 465 (28.8) 4650 (28.8)
40–50 249 (15.4) 2490 (15.4) 538 (33.4) 5380 (33.4)
Deprivation Indexb
Most deprived 986 (61.2) 9567 (59.3) 1049 (65.0) 10,080 (62.5)
Least deprived 626 (38.8) 6553 (40.7) 564 (35.0) 6050 (37.5)
History of myocarditis or pericarditisc126 (7.8) 9 (0.1) 173 (10.7) 8 (0.0)
History of SARS-CoV-2 infectiond64 (4.0) 107 (0.7) 42 (2.6) 110 (0.7)
Receipt of mRNA vaccine 950 (58.9) 7837 (48.6) 906 (56.2) 8436 (52.3)
aAt index date (date of hospital admission for myocarditis for case patients and date of selection for matched control individuals).
bLeast deprived refers to the grouping of 1st and 2nd quintiles, and most deprived to the grouping of 3d to 5th quintiles of the deprivation index.
cDefined as an hospitalization with the respective condition within past 5 years.
dEither a positive RT-PCR or antigenic test for SARS-CoV-2, or hospitalization for COVID-19, within 30 days prior to index date.
Table 2 Association between myocarditis and pericarditis and exposure to mRNA vaccines within 1 to 7 days and 8 to 21 days.
Myocarditis Pericarditis
Cases Controls OR (95% CI)aaOR (95% CI)bCases Controls OR (95% CI)aaOR (95% CI)b
Unexposed Daysc1078 13342 Reference Reference 1269 13398 Reference Reference
BNT162b2
Dose 1 1–7 51 370 1.7 (1.3–2.4) 1.8 (1.3–2.5) 43 398 1.1 (0.83–1.6) 1.3 (0.92–1.8)
8–21 71 855 1.1 (0.86–1.4) 1.2 (0.93–1.6) 72 824 0.94 (0.73–1.2) 0.93 (0.72–1.2)
Dose 2 1–7 211 439 6.9 (5.7–8.4) 8.1 (6.7–9.9) 93 374 2.7 (2.2–3.5) 2.9 (2.3–3.8)
8–21 72 816 1.2 (0.95–1.6) 1.3 (0.98–1.7) 80 765 1.2 (0.91–1.5) 1.3 (0.98–1.6)
mRNA-1273
Dose 1 1–7 9 48 2.4 (1.2–5) 3 (1.4–6.2) 8 78 1.1 (0.52–2.2) 1.2 (0.56–2.4)
8–21 10 109 1.2 (0.63–2.3) 1.1 (0.55–2.3) 9 146 0.65 (0.33–1.3) 0.73 (0.37–1.4)
Dose 2 1–7 106 51 27 (19–39) 30 (21–43) 26 54 5.3 (3.3–8.4) 5.5 (3.3–9)
8–21 4 89 0.68 (0.25–1.9) 0.59 (0.19–1.9) 11 89 1.4 (0.72–2.5) 1.5 (0.76–2.9)
History of myocarditis or pericarditisd
No 1486 16111 Reference Reference 1440 16122 Reference Reference
Yes 126 9 140 (71–280) 160 (83–330) 173 8 250 (120–520) 250 (120–540)
History of SARS-CoV-2 infectione
No 1548 16013 Reference Reference 1571 16020 Reference Reference
Yes 64 107 6.3 (4.6–8.6) 9 (6.4–13) 42 110 3.9 (2.7–5.7) 4 (2.7–5.9)
Deprivation Indexf
Most deprived 986 9567 Reference Reference 1049 10080 Reference Reference
Least deprived 626 6553 0.9 (0.8–1) 0.88 (0.77–1) 564 6050 0.87 (0.77–0.98) 0.87 (0.76–0.99)
aOdds-ratio (95% confidence interval) were obtained from univariable conditional logistic regression, adjusting for matching variables (sex, age and department of residence).
bAdjusted odds-ratio (95% confidence interval) were obtained from multivariable conditional logistic regression, adjusting for all covariates and matching variables.
cPeriod of vaccine receipt relative to index date.
dDefined as an hospitalization with the respective condition within past 5 years.
eEither a positive RT-PCR or antigenic test for SARS-CoV-2, or hospitalization for COVID-19, within 30 days prior to index date.
fLeast deprived refers to the grouping of 1st and 2nd quintiles, and most deprived to the grouping of 3d to 5th quintiles of the deprivation index.
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Male Female
Dose 1 Dose 2
12−17 18−24 25−29 30−39 40−50 12−50 12−17 18−24 25−29 30−39 40−50 12−50
1
10
100
1
10
100
Age
aOR
BNT162b2 mRNA−1273
Fig. 1 Association between myocarditis and exposure to mRNA vaccines within 7 days, according to sex and age group. Adjusted odds-ratio (aOR) from
multivariable model are represented in base 10 logarithmic scale according to age groups (x-axis), by sex (columns) and vaccine dose ranking (rows).
Colors denote the type of vaccine. Centre value are aOR point estimates and error bars represent 95% confidence intervals. Number of cases (N) by age
categories (12–17, 18–24, 25–29, 30–39, 40–50 and 12–50 years) are respectively as follows: N=137, 480, 210, 273, 181 and 1281 for males, and N=29,
106, 40, 88, 68 and 331 for females. aOR could not be calculated in categories where no case exposed to vaccine was recorded, for instance for males and
females aged 12 to 17 years having received the mRNA-1273 vaccine.
Male Female
Dose 1 Dose 2
12−17 18−24 25−29 30−39 40−50 12−50 12−17 18−24 25−29 30−39 40−50 12−50
1
10
1
10
100
Age
aOR
BNT162b2 mRNA−1273
Fig. 2 Association between pericarditis and exposure to mRNA vaccines within 7 days, according to sex and age group. Adjusted odds-ratio (aOR) from
multivariable model are represented in base 10 logarithmic scale according to age groups (x-axis), by sex (columns) and vaccine dose ranking (rows).
Colors denote the type of vaccine. Centre value are aOR point estimates and error bars represent 95% confidence intervals. Number of cases (N) by age
categories (12–17, 18–24, 25–29, 30–39, 40–50 and 12–50 years) are respectively as follows: N=65, 194, 106, 282, 342 and 989 for males, and N=36,
118, 91, 183, 196 and 624 for females. aOR could not be calculated in categories where no case exposed to vaccine was recorded, for instance for males and
females aged 12 to 17 years having received the mRNA-1273 vaccine.
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myocarditis (none among exposed to vaccine) and 5 (0.31%)
deaths among cases of pericarditis (including one patient having
received a vaccine 8 to 21 days prior to the diagnosis) were
reported. Of those, 3 and 2 died during their hospital stay for
myocarditis and pericarditis, respectively.
Drugs treatments within 30 days after hospital discharge are
presented in Figs. S3 and S4. Regardless of the vaccination status,
the therapeutic classes most frequently used during the follow-up
of myocarditis cases included beta blocking agents (63% of
patients), analgesics (52%) and agents acting on the renin
−angiotensin system (46%). The corresponding treatments of
pericarditis cases were analgesics (83%), colchicine (69%) and
beta blocking agents (14%) (Fig. S4).
Discussion
In this nationwide study involving a population of 32 million
people aged 12 to 50 years having received 46 million doses of
mRNA vaccines, we provide detailed estimates of the risk of
myocarditis and pericarditis by sex, age categories and vaccine
type. We find that vaccination with both mRNA vaccines was
associated with an increased risk of myocarditis and pericarditis
within the first week after vaccination. The associations were
particularly pronounced after the second dose, and were evident
in both males and females. We found a trend of increased risks
towards younger age groups but a significant risk was also found
in males over 30 years to develop myocarditis and in females over
30 years to develop a pericarditis after vaccination. Reassuringly,
these cases of myocarditis and pericarditis, although requiring
hospitalization, did not result in more severe outcomes than those
unrelated to vaccination.
Our results are generally consistent with those reported by the
pharmacovigilance systems in France and other countries8,13–16.
Several common factors in terms of the characteristics and
prognosis of cases identified, and the temporal relationship
Male Female
12−17 18−24 25−29 30−39 40−50 12−50 12−17 18−24 25−29 30−39 40−50 12−50
0.0
2.5
5.0
7.5
0
5
10
15
20
Excess cases per 100,000 doses
Myocarditis
Male Female
12−17 18−24 25−29 30−39 40−50 12−50 12−17 18−24 25−29 30−39 40−50 12−50
0
1
2
3
0
2
4
6
Age
Excess cases per 100,000 doses
Pericarditis
BNT162b2 mRNA−1273 Dose 1 Dose 2
Fig. 3 Excess cases of myocarditis and pericarditis attributable to mRNA vaccines according to sex and age group, per 100,000 doses. Excess cases
are based on the risk in the 7 days following vaccination. Colors denote the type of vaccine and the shape of point estimate denotes the ranking of dose
vaccine. Centre value are excess cases point estimates and error bars represent 95% confidence intervals. Number of cases (N) by age categories (12–17,
18–24, 25–29, 30–39, 40–50 and 12–50 years) are respectively as follows: for cases of myocarditis, N=137, 480, 210, 273, 181 and 1281 in males, and
N=29, 106, 40, 88, 68 and 331 in females; for cases of pericarditis, N=65, 194, 106, 282, 342 and 989 in males, and N=36, 118, 91, 183, 196 and 624 in
females. Excess cases was only calculated in categories with a significantly positive association between the vaccine exposure and the outcome (adjusted
odds-ratio >1).
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between vaccine exposure and the event of interest, suggest a
consistent underlying mechanism5,6,17,18. As found in our ana-
lyses, various reports indicate that the risk is more pronounced
with the mRNA-1273 vaccine7,10,19,20, even though there was no
difference in rates between the two vaccines in the passive sur-
veillance reporting in the US4.
Our findings bring new elements in showing that the risk of
acute cardiac inflammation after vaccination is not confined to
myocarditis in young men4–6,14. First, in line with results from a
cohort study in Nordic countries11, our analyses show a sig-
nificant risk and population burden of pericarditis following the
second dose of the BNT162b2 and mRNA-1273 vaccine. Often
comprised in a combined outcome of myopericarditis7,19,21,
pericarditis as specific entity has been less studied for its asso-
ciation with mRNA vaccines, and even more rarely regarding the
mRNA-12173 vaccine. For the BNT162b2 vaccine, results are
inconsistent with either reports of a positive association11,18 or an
absence of association8–10. Barda et al. and Lai et al. found a non-
significant risk ratio of 1.27 and odds ratio of 1.06, respectively,
for the combined effect of first and second dose of the BNT162b2
vaccine8,9. Patone et al. found a non-significant relative incidence
of pericarditis in the week after both doses of the BNT162b2
vaccine of approximately 0.6, while the association with mRNA-
1273 could not be quantified10. Considering that the risk of
myocarditis following the BNT162b2 vaccine is also found lower
in the later study than in others, we hypothesized that the
probably weaker association with pericarditis might be more
difficult to reveal. This discrepancy could also reflect different
diagnostic practices as pericarditis is a retrospective diagnosis of
exclusion.
Second, by differentiating the risk between adolescent (aged
12 to 17 years) and young men or women (18–25 years), we
estimate that the number of excess cases after the second dose
of BNT162b2 vaccine is lower in adolescents compared to
young adults. This is consistent with findings from surveillance
data in Israel22 but in contrast with those from the US4.There
is some support for the role of sex hormones in the increased
susceptibility for myocarditis of young men compared to
women23–25.Whilewedofind higher absolute burden of
myocarditis and pericarditis in adolescent males and men, we
also find that the female counterpart also faces a significant
risk, notably of pericarditis for women over 30 years after the
second dose of the mRNA-1273 vaccine, which has not yet
been shown.
There are several factors that support the hypothesis of a causal
relationship between exposure to mRNA vaccines and the risk of
myocarditis and pericarditis. First, the associations remained
strong, even after adjusting for a history of these conditions or
Table 3 Description of hospitalized patients according to the exposure to mRNA vaccines.
Myocarditis Pericarditis
Unexposed Vaccinated within
1 to 7 days
Vaccinated within
8 to 21 days
Unexposed Vaccinated within
1 to 7 days
Vaccinated within
8 to 21 days
(N=1077) (N=378) (N=157) (N=1267) (N=172) (N=174)
Sex
Male 829 (77.0) 324 (85.7) 128 (81.5) 778 (61.4) 101 (58.7) 110 (63.2)
Female 248 (23.0) 54 (14.3) 29 (18.5) 489 (38.6) 71 (41.3) 64 (36.8)
Agea
Mean (sd) 28.5 (9.74) 25.6 (8.44) 28.6 (9.53) 33.8 (10.3) 29.9 (10.0) 33.9 (10.0)
Median (range) 26.0 (21.0–36.0) 23.0 (19.0–30.8) 26.0 (20.0–37.0) 35.0 (25.0–43.0) 29.0 (21.0–38.0) 34.0 (26.0–42.0)
Age distributiona
12–17 114 (10.6) 40 (10.6) 12 (7.6) 80 (6.3) 12 (7.0) 9 (5.2)
18–24 356 (33.1) 171 (45.2) 59 (37.6) 228 (18.0) 56 (32.6) 28 (16.1)
25–29 168 (15.6) 60 (15.9) 22 (14.0) 152 (12.0) 22 (12.8) 23 (13.2)
30–39 248 (23.0) 74 (19.6) 39 (24.8) 361 (28.5) 47 (27.3) 57 (32.8)
40–50 191 (17.7) 33 (8.7) 25 (15.9) 446 (35.2) 35 (20.3) 57 (32.8)
Deprivation Indexb
Most deprived 654 (60.7) 237 (62.7) 95 (60.5) 820 (64.7) 115 (66.9) 114 (65.5)
Least deprived 423 (39.3) 141 (37.3) 62 (39.5) 447 (35.3) 57 (33.1) 60 (34.5)
History of myocarditis
or pericarditisc
104 (9.7) 12 (3.2) 10 (6.4) 149 (11.8) 10 (5.8) 14 (8.0)
History of SARS-CoV-2
infectiond
58 (5.4) 2 (0.5) 4 (2.5) 39 (3.1) 0 (0) 3 (1.7)
Length of hospital stay
Mean (sd) 4.56 (5.97) 3.75 (2.60) 4.18 (2.70) 2.84 (4.46) 2.36 (2.49) 2.52 (2.84)
Median (range) 4.00 (2.00–5.00) 4.00 (2.00–5.00) 4.00 (3.00–5.00) 1.00 (0–4.00) 2.00 (1.00–4.00) 2.00 (1.00–3.00)
Death up to 30 days
after discharge
4 (0.4) 0 (0) 0 (0) 4 (0.3) 0 (0) 1 (0.6)
among which
deceased during
hospital stay
3 (0.3) 0 (0) 0 (0) 1 (0.1) 0 (0) 1 (0.6)
Intensive care unit 66 (6.1) 9 (2.4) 6 (3.8) 32 (2.5) 0 (0) 2 (1.1)
Ventilation - oxygen
therapy
46 (4.3) 12 (3.2) 5 (3.2) 30 (2.4) 1 (0.6) 3 (1.7)
Pericardial drainage 3 (0.3) 0 (0) 0 (0) 38 (3.0) 1 (0.6) 2 (1.1)
aAt index date (date of hospital admission for myocarditis or pericarditis).
bLeast deprived refers to the grouping of 1st and 2nd quintiles, and most deprived to the grouping of 3d to 5th quintiles of the deprivation index.
cDefined as an hospitalization with the respective condition within past 5 years.
dEither a positive RT-PCR or antigenic test for SARS-CoV-2, or hospitalization for COVID-19, within 30 days prior to index date.
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recent SARS-CoV-2 infection, and in a period during which most
common respiratory viruses were not widely circulating26,27.
Second, the time that elapsed between exposure to the vaccine
and hospitalization was very short for both conditions, particu-
larly after the second dose. Third, in most cases, the associations
did not persist after seven days following exposure. Fourth, the
stronger risk associated with the second dose and the mRNA-
1273 vaccine, which contains a larger amount of mRNA, suggest
a dose response relationship28.
The strengths of our study include the large sample size,
population-based character and the assessment of cases and
exposure to vaccines in high-quality and comprehensive data-
bases. It allowed us to include 1612 confirmed cases of myo-
carditis and 1613 of pericarditis, occurring in a period during
which 46 million doses of the two mRNA vaccines were admi-
nistered. This study provides population estimates of vaccine
associated risk and burden at a national level, which cannot be
informed by passive case notification surveillance. Furthermore,
results were consistent after adjusting for other risk factors,
including SARS-CoV-2 infection, and different periods.
Our study has several limitations. First, the National Health
Data System provides little clinical and no laboratory information
concerning cases. The cases included in this study were identified
solely on the basis of the diagnosis codes associated with hospital
admissions. We therefore could not detect asymptomatic or mild
forms of myocarditis and pericarditis that would not require
hospitalization. Nevertheless, the incidence of myocarditis and
pericarditis before the Covid-19 pandemic, estimated using the
SNDS data, is consistent with the figures reported by other
countries14. Furthermore, the observed durations of stay and
post-discharge treatments were consistent with typical presenta-
tions of these conditions. Second, while our assessment of severity
indicators within four weeks post-discharge indicates a favourable
clinical outcome of post-vaccination carditis in their acute phase,
we could not investigate potential long-term consequences. Third,
we did not study the Covid-19 booster vaccination which was not
yet recommended for healthy younger adults in our study period.
Finally, associations across age and sex subgroups could not
always be quantified for both vaccines or only with a considerable
degree of uncertainty due to the limited time span of observation.
The extent of the risk for certain subgroups, especially among
women, for whom the incidence appears to be lower, warrants
further studies and meta-analyses26,29.
In conclusion, this study provides strong evidence of an
increased risk of myocarditis and of pericarditis in the week
following vaccination against Covid-19 with mRNA vaccines in
both males and females, in particular after the second dose of the
mRNA-1273 vaccine. Future studies based on an extended period
of observation will allow to investigate the risk related to the
booster dose of the vaccines and monitoring the long-term con-
sequences of these post vaccination acute inflammations.
Methods
Study design. We conducted a matched case-control study within the entire
French population between 12 and 50 years of age for myocarditis and pericarditis,
treating each condition separately. The study focused on the period from May 12,
2021, to October 31, 2021, during which the Covid-19 vaccination campaign was
opened to individuals under 50 years of age.
Data sources and study population. The study was based on data of the National
Health Data System (SNDS) which covers more than 99% of the French population
(67 million inhabitants)30,31. Data on hospital admission were obtained from the
French hospital discharge database (PMSI) and linked at the individual level with
the nationwide databases for Covid-19 vaccination (VAC-SI) and testing (SI-DEP).
Cases corresponded to all patients admitted to French hospitals with a diagnosis of
myocarditis or pericarditis in the study period. Diagnoses at hospital were typically
based on presenting symptoms, electrocardiography, echocardiography and cardiac
magnetic resonance imaging32,33. We used the codes for myocarditis (I40.x, I41.x,
and I51.4) and pericarditis (I30.x and I32.x) of the International Classification of
diseases, 10th revision (ICD-10) for detection. Although the data were compre-
hensive up to September 2021, at the time this study was conducted, approximately
78% of hospital stays for October 2021 had been entered into the PMSI database.
Each case was matched at the date of his/her hospital admission for myocarditis or
pericarditis (index date) to 10 control individuals. Controls were selected from
among the whole population by simple random sampling without replacement
within each stratum of age, gender and area of residence (matching criteria), with
constraint of not being diagnosed with myocarditis or pericarditis and being alive
at the index date.
Our research group (EPI-PHARE) has a regulatory permanent access to the
data from the SNDS. This permanent access is given according the French Decree
No. 2016-1871 of December 26, 2016 relating to the processing of personal data
called “National Health Data System”and French law articles Art. R. 1461-13 and
14. This study was declared prior to initiation on the EPI-PHARE registry of
studies requiring the use of the SNDS (n° EP-0311). No informed consent was
required because data are anonymized.
Exposure and covariates. Exposure was defined as vaccination with an mRNA
vaccine 1 to 7 days or 8 to 21 days prior to the index date, considering the first and
second dose separately. Non-vaccinated subjects, and those vaccinated more than
21 days before the index date were considered to be non-exposed. In addition to the
matching variables, three covariates potentially associated with a risk of myocarditis
or pericarditis, and with vaccine exposure were considered. A prior history of
myocarditis or pericarditis was defined as a hospital admission with an ICD-10 code
for myocarditis or pericarditis (cf. above) in the five years preceding the index date. A
history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
was defined by hospital admission for Covid-19 or a positive polymerase-chain-
reaction (PCR) or antigenic testing 30 days prior to the index date. The socio-
economic level was defined by a deprivation index, summarized in two categories34.
Statistical analysis. We used conditional logistic regression models to estimate
the odds ratios (OR) of myocarditis and pericarditis associated with exposure to
recent vaccination, adjusted for covariates and matching variables35.Analyses
were conducted with reference to the ranking of vaccine dose (first or second
dose) and the time elapsed since vaccination (1 to 7 days or 8 to 21 days), across
the study group as a whole and separately for males and females and according
to five age brackets (12–17, 18–24, 25–29, 30–39 and 40 to 50 years). Associa-
tions were measured relative to the most recent exposure. We estimated the
number of cases attributable to vaccine exposure using the odds ratio as an
estimate of relative risk and assuming a causal relationship36. We then derived
two measures of population burden using information on exposure to vaccines
across the 32.2 million people aged 12 to 50 years, including the vaccine type
and date of receipt of each dose (Table S1). First, the number of doses required
for the occurrence of a vaccine-associated case was estimated as the ratio of
doses administered to the number of attributable cases. Second, the number of
excess cases per 100,000 doses was derived by inverting this ratio. We applied a
correction factor to the numbers of exposed cases to account for under-reporting
of hospitalizations in October 2021. Confidence intervals for the number of cases
attributable to exposure were obtained by application of the delta-method37,38.
We assessed the sensitivity of the results to a potential ascertainment bias by
performing an analysis restricted to the time period before July 19, 2021, i.e.
before myocarditis and pericarditis were officially announced as adverse events
of mRNA vaccines. Additional analyses were conducted by excluding (i) patients
with a previous history of myocarditis or pericarditis, (ii) those with a history of
SARS-CoV-2 infection, (iii) patients having both diagnoses of myocarditis and
pericarditis, and (iv) persons with a hospitalization within 28 days of index date.
Data collection used SAS Enterprise Guide version 4.3 software (SAS Institute,
Cary, North Carolina). All analyses were performed using R software version
4.1.3, and survival package version 3.2–1339,40.
Reporting summary. Further information on research design is available in the Nature
Research Reporting Summary linked to this article.
Data availability
According to data protection and the French regulation, the authors cannot publicly
release the data from the French national health data system (SNDS). However, any
person or structure, public or private, for-profit or non-profit, is able to access SNDS data
upon authorization from the French Data Protection Office (CNIL Commission
Nationale de l’Informatique et des Libertés) to carry out a study, a research, or an
evaluation of public interest (https://www.snds.gouv.fr/SNDS/Processus-d-acces-aux-
donnees and https://www.indsante.fr/).
Code availability
The code to reproduce the analyses presented in the paper is publicly available41.
NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-022-31401-5 ARTICLE
NATURE COMMUNICATIONS | (2022) 13:3633 | https://doi.org/10.1038/s41467-022-31401-5 | www.nature.com/naturecommunications 7
Content courtesy of Springer Nature, terms of use apply. Rights reserved
Received: 25 February 2022; Accepted: 15 June 2022;
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Author contributions
S.L.V., M.B., A.W., R.D.S. and M.Z. conceived the study. A.W., R.D.S. and M.Z.
supervised the project. M.B. and J.D. carried out the clinical data collection and data
curation. S.L.V. and M.B. designed and performed the statistical analyses with M.J.J., B.B.
and J.B. providing input. S.L.V. wrote the first draft of the manuscript. All authors
interpreted the results, provided critical revision of the manuscript and approved its final
version for submission.
Competing interests
The authors declare no competing interests.
Additional information
Supplementary information The online version contains supplementary material
available at https://doi.org/10.1038/s41467-022-31401-5.
Correspondence and requests for materials should be addressed to Stéphane Le Vu.
Peer review information Nature Communications thanks Ian Wong and the other,
anonymous, reviewer(s) for their contribution to the peer review of this work. Peer
reviewer reports are available.
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