ORIGINAL CONTRIBUTION
MMR Vaccination and Febrile Seizures
Evaluation of Susceptible Subgroups and Long-term Prognosis
Mogens Vestergaard, MD, PhD
Anders Hviid, MSci
Kreesten Meldgaard Madsen, MD, PhD
Jan Wohlfahrt, MSci
Poul Thorsen, MD, PhD
Diana Schendel, PhD
Mads Melbye, MD, DMSci
Jørn Olsen, MD, PhD
T
HE SAFETY OF THE MEASLES ,
mumps, and rubella (MMR)
vaccine is of major public
health interest because mil-
lions of children are vaccinated every
year. Fortunately, the vaccine is gen-
erally well-tolerated, rarely associated
with serious adverse effects, and may
even have nonspecific health ben-
efits.1-5 However, MMR vaccination is
followed by a transient increased risk
of febrile seizures compared with non-
vaccinated children, probably due to
vaccine-induced fever.6-10 It may have
clinical implications if susceptible chil-
dren could be identified before the vac-
cination but no study has been large
enough to identify such subgroups. For
example, it is unknown whether chil-
dren with a personal or a family his-
tory of seizures are more prone to
MMR-induced febrile seizures than chil-
dren without such history. Febrile sei-
zures are in general associated with an
increased risk of epilepsy11-13 but it re-
mains unclear if febrile seizures follow-
ing MMR vaccination carry a particu-
larly high risk. To address these
questions, we performed a large popu-
lation-based cohort study.
©2004 American Medical Association. All rights reserved.
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Context The rate of febrile seizures increases following measles, mumps, and ru-
bella (MMR) vaccination but it is unknown whether the rate varies according to per-
sonal or family history of seizures, perinatal factors, or socioeconomic status. Further-
more, little is known about the long-term outcome of febrile seizures following
vaccination.
Objectives To estimate incidence rate ratios (RRs) and risk differences of febrile sei-
zures following MMR vaccination within subgroups of children and to evaluate the
clinical outcome of febrile seizures following vaccination.
Design, Setting, and Participants A population-based cohort study of all chil-
dren born in Denmark between January 1, 1991, and December 31, 1998, who were
alive at 3 months; 537171 children were followed up until December 31, 1999, by
using data from the Danish Civil Registration System and 4 other national registries.
Main Outcome Measures Incidence of first febrile seizure, recurrent febrile sei-
zures, and subsequent epilepsy.
Results A total of 439251 children (82%) received MMR vaccination and 17 986
children developed febrile seizures at least once; 973 of these febrile seizures occurred
within 2 weeks of MMR vaccination. The RR of febrile seizures increased during the 2
weeks following MMR vaccination (2.75; 95% confidence interval [CI], 2.55-2.97),
and thereafter was close to the observed RR for nonvaccinated children. The RR did
not vary significantly in the subgroups of children that had been defined by their fam-
ily history of seizures, perinatal factors, or socioeconomic status. At 15 to 17 months,
the risk difference of febrile seizures within 2 weeks following MMR vaccination was
1.56 per 1000 children overall (95% CI, 1.44-1.68), 3.97 per 1000 (95% CI, 2.90-
5.40) for siblings of children with a history of febrile seizures, and 19.47 per 1000 (95%
CI, 16.05-23.55) for children with a personal history of febrile seizures. Children with
febrile seizures following MMR vaccinations had a slightly increased rate of recurrent
febrile seizures (RR, 1.19; 95% CI, 1.01-1.41) but no increased rate of epilepsy (RR,
0.70; 95% CI, 0.33-1.50) compared with children who were nonvaccinated at the time
of their first febrile seizure.
Conclusions MMR vaccination was associated with a transient increased rate of
febrile seizures but the risk difference was small even in high-risk children. The
long-term rate of epilepsy was not increased in children who had febrile seizures
following vaccination compared with children who had febrile seizures of a different
etiology.
JAMA. 2004;292:351-357 www.jama.com
Author Affiliations: The Danish Epidemiology Sci- (Drs Thorsen and Schendel), Denmark; and National
ence Centre, Department of Epidemiology and Center on Birth Defects and Developmental Disabili-
Social Medicine, Aarhus University, Aarhus (Drs ties, Centers for Disease Control and Prevention, At-
Vestergaard, Madsen, and Olsen), The Danish Epi- lanta, Ga (Dr Schendel).
demiology Science Centre, Department of Epidemi- Corresponding Author: Mogens Vestergaard, MD,
ology Research, Statens Serum Institut, Copenhagen PhD, Department of Epidemiology and Social Medi-
(Dr Melbye and Mr Hviid and Ms Wohlfahrt), and cine, The Danish Epidemiology Science Centre, Aarhus
North Atlantic Neuro-Epidemiology Alliances, Depart- University, Vennelyst Blvd 6, DK-8000 Aarhus C, Den-
ment of Epidemiology and Social Medicine, Aarhus mark (mv@soci.au.dk).
(Reprinted) JAMA, July 21, 2004—Vol 292, No. 3 351
 MMR VACCINATION AND RATE OF FEBRILE SEIZURES
METHODS
Study Population
This population-based cohort study was
based on a previously described study
population2 and includes all children
born in Denmark between January 1,
1991, and December 31, 1998, who were
alive at the age of 3 months (N =
537171). The cohort was established by
means of data from the Danish Civil Reg-
istration System and 4 other national reg-
istries. All live-born children and new
residents in Denmark are assigned a
unique personal identification number
(civil registry number), which is stored
in the Danish Civil Registration Sys-
tem together with information on vital
status, emigration, address, and family
structure (link to mother and father).14
The registry is updated every week and
all changes regarding the status of the
above-mentioned variables are re-
quired by law. The civil registry num-
ber can be used to link individual infor-
mation in all national registries. We
obtained permission from the Danish
Data Protection Board before the study
was initiated.
MMR Vaccination Status
We determined MMR vaccination sta-
tus from vaccination data reported to
the National Board of Health by gen-
eral practitioners, who provide MMR
vaccinations in Denmark. The general
practitioners are reimbursed by the state
based on these reports.
We retrieved information on vacci-
nations from January 1, 1991, through
December 31, 1999. The MMR vaccine
was introduced in Denmark in 1987 and
a single-antigen measles vaccine has
never been recommended. The MMR
vaccine used in Denmark during the
study period was identical to that used
in the United States and contained the
following vaccine strains: Moraten
(measles), Jeryl Lynn (mumps), and
Wistar RA 27/3 (rubella). The national
vaccination program recommended dur-
ing the entire study period that chil-
dren should be vaccinated twice, at 15
months and at 12 years. Only the first
vaccination is relevant to the end point
under study. Because the vaccination
352 JAMA, July 21, 2004—Vol 292, No. 3 (Reprinted)
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data are transferred to the National Board
of Health once a week without specify-
ing the day of vaccination, we had to se-
lect 1 day as the day of vaccination in
our analyses and we chose Wednes-
day. Since 1996, vaccination informa-
tion has been recorded with the child’s
own civil registry number and the in-
formation directly linked with other reg-
istries. Before 1996, vaccination infor-
mation and the age of the child were
recorded with the civil registry num-
ber of the accompanying adult. We used
information from the Danish Civil Reg-
istration System to identify the link from
the accompanying adult to the child;
therefore, 98.5% of the children were
identified with the use of the child’s civil
registry number or the civil registry
number of the mother or father and
the age of the child at vaccination.
The remaining 1.5% of vaccinated chil-
dren were identified based on the civil
registry number of other relatives and
the child’s address at the time of vacci-
nation.
Febrile Seizures and Epilepsy
Information on febrile seizures and epi-
lepsy was obtained from the National
Hospital Register (NHR),15 which con-
tains information on all patients dis-
charged from Danish hospitals since
1977; outpatients (visits to emer-
gency department and hospital clin-
ics) have been included in the register
since 1995. All treatments in Danish
hospitals are free of charge for all Dan-
ish citizens. Diagnostic information was
classified according to the Danish ver-
sion of the International Classification
of Diseases (ICD) as follows: ICD-8 was
used from 1977 to 199316 and ICD-10
was used from 1994 to the end of
1999.17 We classified children as hav-
ing a febrile seizure when they were reg-
istered with ICD-8 code 780.21 or
ICD-10 code R56.0, were aged be-
tween 3 and 60 months at the time of
discharge, and had no recorded his-
tory of nonfebrile seizures, cerebral
palsy, severe head traumas, intracra-
nial tumors, meningitis, or encephali-
tis. The febrile seizures could not be
classified as simple or complex be-
©2004 American Medical Association. All rights reserved.
cause the NHR contains no informa-
tion on number of febrile seizures oc-
curring within the febrile episode,
duration of the febrile seizures, and type
of febrile seizures (generalized or fo-
cal onset). Children were categorized
with epilepsy if they had ICD-8 code
345 or ICD-10 code G40.
Potential Effect Modifiers and
Confounders
We obtained information on febrile sei-
zures and epilepsy in siblings from the
NHR during the period January 1, 1977,
to December 31, 1999. Children were
labeled with a family history of sei-
zures from the day a sibling was admit-
ted to a Danish hospital or had been in
outpatient care with febrile seizures or
epilepsy. We obtained information on
birth weight and gestational age from
the Danish Medical Birth Register18 and
the NHR.15 Information on socioeco-
nomic status (as indicated by the em-
ployment status of the head of the
household) and maternal education was
obtained from Statistics Denmark at the
time the child was aged 15 months.
Statistical Analysis
To study the association of MMR vac-
cination with a first episode of febrile
seizure, we followed the children from
the age of 3 months until the first di-
agnosis of febrile seizure registered in
the NHR, death, emigration, a diagno-
sis of epilepsy, cerebral palsy, severe
brain injury, brain tumor, meningitis,
encephalitis, aged 5 years, or until De-
cember 31, 1999, whichever came first.
The resulting person-years at risk were
aggregated and analyzed using Pois-
son regression, producing incidence
rate ratios (RRs).19 We considered MMR
vaccination a time-varying covariate;
the children were assigned to the non-
vaccinated group until they received the
MMR vaccine. From that day, they were
included in the vaccinated cohort. We
evaluated whether the RR of febrile sei-
zures following MMR vaccination var-
ied between subgroups of children by
testing for statistical interaction.
All RRs were adjusted for age
(3-month categories) and calendar

period (1-year categories). In multi-
variable analyses, we considered con-
founding by sex, number of siblings
with febrile seizures (no siblings, no sib-
lings with febrile seizures, 1 sibling with
febrile seizures, ⱖ2 siblings with febrile
seizures), number of siblings with epi-
lepsy (no siblings, no siblings with epi-
lepsy, ⱖ1 siblings with epilepsy), birth
order (1, 2, 3, ⱖ4), gestational age in
weeks (ⱕ36, 37-41, ⱖ42), birth weight
in grams (ⱕ2499, 2500-2999, 3000-
3499, 3500-3999, ⱖ4000), maternal
education (postgraduate education, col-
lege, vocational training, secondary
school, primary school), and socioeco-
nomic status as indicated by the employ-
ment status of the head of the house-
hold (managers [very high], wage earner
[high], wage earner [medium], wage
earner [low], wage earner [minimal],
unemployed). We had no information
on birth weight, gestational age at birth,
socioeconomic status, and maternal
education for 6.2%, 31.7%, 2.7%, and
0.3% of the children, respectively. Data
on gestational age at birth was not avail-
able for children born after December
31, 1996. When evaluating confound-
ing, we used 2 different strategies for
the handling of missing values. First,
we used the method of single imputa-
tion, replacing a missing value with the
most common value of that variable:
3000 to 3499 g for birth weight, 37 to
41 weeks for gestational age at birth,
wage earner (standard level) for socio-
economic status, and vocational train-
ing for maternal education. Second, we
analyzed only those children with com-
plete information on all variables
(358702). A priori, we decided to add
all variables to the final model that
changed the estimate of interest by at
least 10% using either strategy.20 None
of the variables with missing data quali-
fied. Only age and calendar period were
included in the final model. When
evaluating effect modification, we ana-
lyzed only those children with com-
plete information on the variable of
interest.
To study the association of MMR vac-
cination and a second episode of fe-
brile seizures in children with a per-
©2004 American Medical Association. All rights reserved.
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MMR VACCINATION AND RATE OF FEBRILE SEIZURES
sonal history of febrile seizures, we
constructed a cohort of 10 541 chil-
dren who were nonvaccinated at the
time of the first febrile seizure. These
children were followed up prospec-
tively from the day of the first regis-
tered febrile seizure until the second
episode of febrile seizure registered in
the NHR, death, emigration, a diagno-
sis of epilepsy, cerebral palsy, severe
brain injury, brain tumor, meningitis,
encephalitis, aged 5 years, or until De-
cember 31, 1999, whichever came first.
We considered MMR vaccination a
time-varying covariate. The RRs were
adjusted for age, age at first febrile sei-
zure, and calendar period.
To estimate the number of addi-
tional febrile seizures that occurred in
the 2 weeks following MMR vaccina-
tion compared with nonvaccinated chil-
dren (risk difference), we first calcu-
lated the proportion of vaccinated and
nonvaccinated children that developed
febrile seizures at a given age when fol-
lowed up for 2 weeks (cumulative
incidence). The cumulative incidences
were calculated by using the exponen-
tial formula: cumulative incidence=1 −
exp (−incidence rate ⫻ time).21 The for-
mula is based on the assumption that the
incidence rate is constant during the pe-
riod of interest. The age-specific cumu-
lative incidence was calculated sepa-
rately for vaccinated and nonvaccinated
children within each subgroup and the
risk difference calculated as the differ-
ence between the cumulative inci-
dences. Confidence intervals (CIs) for
the risk difference were calculated us-
ing the Delta method.22
To evaluate the long-term prognosis
of febrile seizures following MMR vac-
cination compared with febrile seizures
of a different etiology, we categorized
children with febrile seizures into 3
groups according to the vaccination sta-
tus at the time of the first febrile sei-
zure: 10 541 children were nonvacci-
nated, 973 children had been vaccinated
within the previous 2 weeks, and 6472
children were vaccinated more than 2
weeks ago. These children were fol-
lowed up from the day of the first reg-
istered febrile seizure until the out-
(Reprinted) JAMA, July 21, 2004—Vol 292, No. 3 353
come of interest (a second episode of
febrile seizures or a first diagnosis of
epilepsy), death, emigration, cerebral
palsy, severe brain injury, brain tumor,
meningitis, encephalitis, aged 5 years, or
until December 31, 1999, whichever
came first. The RRs were adjusted for age,
calendar period, age at first febrile sei-
zure, and current vaccination status.
All analyses were conducted using
SAS statistical software version 8.2 (SAS
Institute Inc, Cary, NC). P⬍.05 was
considered statistically significant.
RESULTS
We followed up 537171 children for a
total of 1.9 million person-years and
identified 17986 children who devel-
oped febrile seizures at least once; 973
of these febrile seizures occurred within
2 weeks of the MMR vaccination. Dur-
ing the study period, 439251 children
(82%) received MMR vaccination.
RRs of Febrile Seizures
After MMR Vaccination
Overall, we found that the rate of first
febrile seizures was 10% higher among
vaccinated children (7445; person-
years at risk, 1151661) compared with
nonvaccinated children (10 541; per-
son-years at risk, 793568) during the
study period (RR, 1.10; 95% CI,
1.05-1.15), after adjusting for age and
calendar period. However, the rate of
febrile seizures increased during the first
(RR, 2.46; 95% CI, 2.22-2.73) and sec-
ond week (RR, 3.17; 95% CI, 2.89-
3.49) following vaccination only
(FIGURE 1); thereafter the rate was close
to that for nonvaccinated children.
Overall, the RR of febrile seizures
within 2 weeks of MMR vaccination was
2.75 (95% CI, 2.55-2.97) compared
with nonvaccinated children. We found
no statistically significant difference in
the RR of febrile seizures in the 2 weeks
following vaccination between sub-
groups of children characterized by
family history of seizures, sex, birth or-
der, gestational age at birth, birth
weight, or socioeconomic factors, com-
pared with nonvaccinated children
within the subgroup under study
(FIGURE 2). The highest RR was found
 MMR VACCINATION AND RATE OF FEBRILE SEIZURES
Figure 1. Adjusted Rate Ratios of Febrile Seizures According to Time Since MMR Vaccination
vs Nonvaccinated Children in a Cohort of Children Born in Denmark, 1991-1998
4.0
3.0
2.0
Rate Ratio
1.0
0.5
1 2 3 4 5 6
Time Since Vaccination, wk
MMR indicates measles, mumps, and rubella. Rate ratios are adjusted for age and calendar period. Point es-
timates are given with error bars representing 95% confidence intervals.
among siblings of children with a his-
tory of epilepsy who had a 4-fold in-
creased rate of febrile seizures in the 2
weeks following vaccination com-
pared with a 2.7-fold increased rate of
febrile seizures following vaccination in
siblings of children with no history of
epilepsy (P value for interaction=.09).
Among the 10 541 children with a
personal history of febrile seizures, 175
children had a recurrent febrile sei-
zure within 2 weeks of the MMR vac-
cination. The RR of febrile seizures in
the 2 weeks following vaccination was
2.75 (95% CI, 2.32-3.26) after adjust-
ing for age, age at the first febrile sei-
zure, and calendar period, compared
with nonvaccinated children with a per-
sonal history of febrile seizures.
Risk Difference of Febrile Seizures
Among Subgroups of
Vaccinated Children
The risk difference of febrile seizures
in the 2 weeks following MMR vacci-
nation compared with nonvaccinated
children was 1.56 per 1000 (95% CI,
1.44-1.68) for children vaccinated at 15
to 17 months, 1.46 per 1000 (95% CI,
1.10-1.91) for children vaccinated at 18
354 JAMA, July 21, 2004—Vol 292, No. 3 (Reprinted)
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7 8 9-26 27-52 53-104 105-156 157-260
to 20 months, and 0.64 per 1000 (95%
CI, 0.22-1.40) for children vaccinated
at 21 to 23 months.
The highest risk difference was found
among children with a personal his-
tory of febrile seizures (19.47 per 1000;
95% CI, 16.05-23.55) and for chil-
dren with a family history of febrile sei-
zures (3.97 per 1000; 95% CI, 2.90-
5.40; TABLE 1).
Long-term Prognosis
of Febrile Seizures
Following MMR Vaccination
We found that children who experi-
enced febrile seizures within 2 weeks
of MMR vaccination had a 19% in-
creased rate of recurrent febrile sei-
zures (RR, 1.19; 95% CI, 1.01-1.41) but
no increased rate of epilepsy (RR, 0.70;
95% CI, 0.33-1.50) during up to 105
months of follow-up. The reference
group consisted of children who had
not been vaccinated when having their
first febrile seizure (TABLE 2).
COMMENT
The incidence rate of febrile seizures
was increased in the 2 weeks follow-
ing MMR vaccination and thereafter the
©2004 American Medical Association. All rights reserved.
rate was close to that observed for non-
vaccinated children. This finding is con-
sistent with previous reports6-10 and is
expected since MMR vaccination of-
ten induces fever,1 a necessary cause of
febrile seizures. Farrington et al7 found
an increased rate of febrile seizures up
to 35 days after vaccination with the
Urabe mumps strain but the rate was
increased no longer than 2 weeks for
the Jeryl Lynn vaccine, which was used
in our study.
Family history of seizures, preterm
birth, low birth weight, and male sex
are risk factors for febrile seizures23 but
the RR of febrile seizures following
MMR vaccination did not vary signifi-
cantly according to these factors in this
study. The highest RR was found among
siblings of children with epilepsy; a
4-fold increased rate of febrile sei-
zures following MMR vaccination was
observed compared with nonvacci-
nated siblings of children with epi-
lepsy. However, our statistical power in
this subgroup was limited and further
studies are needed to determine
whether the siblings of children with
epilepsy are more likely to experience
a febrile seizure after MMR vaccina-
tion than other children, or the find-
ing is merely due to chance. The RR of
febrile seizure was not modified by a
family history of febrile seizures.
Overall, our data suggest that MMR
vaccination and the other indicators for
febrile seizures follow a multiplicative
model; the rate of febrile seizures in
all subgroups of children is approxi-
mately 2.75 times higher within 2 weeks
of MMR vaccination than it would have
been had the children not been vacci-
nated. The absolute increase in inci-
dence of febrile seizures following vac-
cination depends therefore on the
underlying risk of febrile seizures in
each subgroup. In Denmark, most chil-
dren are vaccinated against MMR at age
15 to 17 months when the incidence
rate of febrile seizures is peaking.24 At
this age, the number of children expe-
riencing febrile seizures within 2 weeks
was 1.56 more per 1000 vaccinated chil-
dren compared with nonvaccinated
children. No previous studies have cal-
 MMR VACCINATION AND RATE OF FEBRILE SEIZURES

culated the risk difference according to brile seizures was collected prospec- The information on vaccination was
age at vaccination, but 2 studies found tively and independent of parental recall. reported to the National Board of Health
that approximately 0.33 febrile sei- We expect the data quality of the MMR on a weekly basis but without infor-
zures were attributable to 1000 doses vaccination to be high because the gen- mation on the exact day of vaccina-
of MMR vaccine overall.6,7 eral practitioners are reimbursed only af- tion. We chose Wednesday as the day
As expected, we found the highest risk ter reporting immunization data to the of vaccination. Because children in Den-
difference in children with a personal National Board of Health. mark are vaccinated Monday thru Fri-
history of febrile seizures. The under-
lying risk of febrile seizures in these chil- Figure 2. Adjusted Rate Ratios of Febrile Seizures Within 2 Weeks Following MMR
dren is high; approximately one third Vaccination for Children With Specific Characteristics vs Nonvaccinated Children With the
will have at least 1 episode of recurrent Same Characteristics
febrile seizures before they reach 5 years Rate Ratio P Value for
of age.25 In this very high-risk group, we Strata (95% Confidence Interval)∗ Interaction
found 19 additional febrile seizures All Children 2.75 (2.55-2.97)
within 2 weeks of the vaccination per Siblings With Febrile Seizures
1000 children compared with nonvac- No Siblings 2.68 (2.41-3.00)
No Siblings With Febrile Seizures 2.78 (2.51-3.07)
cinated children aged 15 to 17 months. 1 Sibling With Febrile Seizures 2.84 (2.23-3.60) .68†
The Advisory Committee on Immuni- ≥2 Siblings With Febrile Seizures 3.08 (1.49-6.34)
zation Practices has suggested that the Siblings With Epilepsy
benefits of administering MMR vac- No Siblings 2.68 (2.40-2.99)
No Siblings With Epilepsy 2.73 (2.48-3.01) .09
cine to children with a personal or fam- ≥1 Siblings With Epilepsy 3.95 (2.63-5.94)
ily history of convulsions substantially Sex
outweigh the risks, and these children Boy 2.74 (2.48-3.02)
.82
Girl 2.78 (2.50-3.09)
should be vaccinated following the rec-
ommendations for children who have no Birth Order
1 2.69 (2.42-2.98)
contraindications.26,27 2 2.65 (2.36-2.99)
.54†
We found no increased rate of epi- 3 3.21 (2.67-3.85)
≥4 2.47 (1.75-3.48)
lepsy among children who had febrile
Gestational Age, wk
seizures after MMR vaccination com- <37 3.11 (2.33-4.16)
pared with children who had febrile sei- 37-41 2.93 (2.67-3.22) .84†
zures of a different etiology. The rate ≥42 2.97 (2.26-3.90)

of recurrent febrile seizures was slightly Birth Weight, g

<2500 2.93 (2.21-3.89)
increased, possibly because the MMR 2500-2999 2.66 (2.20-3.21)
vaccination introduced an extra fe- 3000-3499 2.88 (2.56-3.25) .90†
3500-3999 2.73 (2.40-3.10)
brile episode during the window of ≥4000 2.82 (2.35-3.38)
highest susceptibility and the total num-
Socioeconomic Status
ber of febrile episodes is a well known Manager (Very High) 2.84 (2.26-3.57)
risk factor for recurrence.28 We know Wage Earner (High Level) 3.02 (2.60-3.51)
Wage Earner (Medium Level) 2.64 (2.23-3.13)
of only 1 study6 evaluating the clinical Wage Earner (Standard Level) 2.90 (2.54-3.30)
.34
outcome of children with febrile sei- Wage Earner (Other) 2.35 (1.93-2.86)
Unemployed, Pensioner, Student 2.61 (2.20-3.10)
zures following MMR vaccination. No
increased rate of subsequent seizures Mother’s Educational Level
Primary Education 2.75 (2.41-3.14)
was found in 41 children with febrile Secondary Education 2.69 (2.17-3.34)
seizures following MMR vaccination Vocational Training 2.73 (2.45-3.06) .95
College 2.93 (2.46-3.48)
compared with 521 children who had Postgraduate Education 2.59 (1.93-3.48)
febrile seizures in the absence of vac-
1 2 3 4 5 6 7
cination.6 However, the statistical power Rate Ratio (95% Confidence Interval)
of this study was limited, in particular
when evaluating the rate of subse- MMR indicates measles, mumps, and rubella. Vertical dashed line represents the overall rate ratio (RR) for
febrile seizures within the 2 weeks following MMR vaccination compared with nonvaccinated children. Point
quent epilepsy. estimates are given with error bars representing 95% confidence intervals.
The strengths of our study include its *The RRs are adjusted for age and calendar period. The analyses including siblings were additionally adjusted
size and population-based nature. The for the total number of siblings. Children with missing values were excluded when the effect of the variable
concerned was evaluated.
follow-up was virtually complete, which †Test for interaction was performed by a test for trend. When evaluating the possible effect modification by
eliminates bias due to nonresponse. In- siblings with febrile seizures or by siblings with epilepsy, children without siblings were not included in the test
for interaction.
formation on MMR vaccinations and fe-
©2004 American Medical Association. All rights reserved. (Reprinted) JAMA, July 21, 2004—Vol 292, No. 3 355

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 MMR VACCINATION AND RATE OF FEBRILE SEIZURES

Table 1. Cumulative Incidence and Risk Difference of Febrile Seizures Within 14 Days for Vaccinated and Nonvaccinated Children at 15 to 17
Months
No. of Febrile Seizures Within 14 Days per 1000 Children

Cumulative Incidence

Characteristic Nonvaccinated Vaccinated Risk Difference (95% CI)

All children 0.90 2.46 1.56 (1.44-1.68)
Children with personal history of febrile seizures 11.50 30.97 19.47 (16.05-23.55)
Siblings of children with history of febrile seizures 2.62 6.60 3.97 (2.90-5.40)
Siblings of children with history of epilepsy 1.59 4.97 3.38 (1.90-5.92)
Children with birth weight ⬍2500 g 1.24 2.93 1.69 (1.18-2.41)
Children with gestational age at birth ⬍37 weeks 1.36 3.19 1.83 (1.27-2.62)
Abbreviation: CI, confidence interval.

Table 2. Adjusted Rate Ratios of Recurrent Febrile Seizures and Subsequent Epilepsy*
Recurrent Febrile Seizures Subsequent Epilepsy
MMR
Vaccination Status No. of Rate Ratio Rate Ratio
at Time of First No. of Recurrent Person-Years (95% Confidence No. of Person-Years (95% Confidence
Febrile Seizure Children Febrile Seizures at Risk Interval)† Epilepsy at Risk Interval)†
None 10 541 2753 23 560 1.00 251 41 310 1.00
Within 14 days 973 236 2212 1.19 (1.01-1.41) 9 3825 0.70 (0.33-1.50)
⬎14 days prior 6472 918 12 675 1.10 (0.96-1.26) 95 21 938 0.92 (0.59-1.43)
Abbreviation: MMR, measles, mumps, and rubella.
*Among 17 986 Danish children who had febrile seizures between 1991 and 1999. Children were categorized according to vaccination status at time of first febrile seizure.
†Rate ratios are adjusted for age, calendar period, age at first febrile seizure, and current vaccination status.

day, we have misclassified some vacci-
nations by up to 2 days. Previous studies
have shown that the attenuated vi-
ruses in the MMR vaccine cause fever
in approximately 10% of nonimmune
vaccinees between 5 and 12 days after
immunization.1,29 Thus, the rate of fe-
brile seizures is probably not elevated
during the first 4 days following vac-
cination.
We have previously validated the
quality of febrile seizure registration in
the NHR in a cohort of 6624 children
born between 1991 and 1992 and fol-
lowed up until age 10 years.30 We col-
lected information about febrile sei-
zures in the cohort using a parental
questionnaire. All potential febrile sei-
zures were confirmed by diagnostic tele-
phone interview or review of medical
records. We found that 323 children
(4.9%) in the cohort fulfilled the cri-
teria for febrile seizures and 231 of those
were registered in the NHR (complete-
ness, 71.5%; 95% CI, 66.3%-76.4%).
Among the 249 children registered with
febrile seizures in the NHR, we con-
firmed the diagnosis in 231 children
(predictive value of a positive registra-
tion, 92.8%; 95% CI, 88.8%-95.7%). We
believe it is unlikely that MMR vacci-
nation status influences the threshold
for hospitalization or the coding of fe-
brile seizures. Any misclassification of
febrile seizures is likely to be nondif-
ferential and will therefore bias the RR
toward 1.0.21 In fact, we found that the
RR of febrile seizures following MMR
vaccination was virtually the same dur-
ing the period 1991 to 1994 (2.68; 95%
CI, 2.38-3.02) compared with the pe-
riod 1995 to 1998 (2.79; 95% CI,
2.55-3.05), although outpatients were
included in the latter period only.
The Danish national vaccination pro-
gram recommends that children be vac-
cinated with MMR at age 15 months
and provides vaccinations free of
charge. Overall, vaccination coverage
was found to be 82%, which increased
during the study period. The effect of
vaccination may be confounded by vari-
ables related both to avoidance of vac-
cination and to the outcome of inter-
est. We adjusted our results for several
potential confounders but found little
change in the estimate of interest. How-
ever, the strongest argument against se-
rious confounding is that the risk of fe-
brile seizures was almost the same for
nonvaccinated and vaccinated chil-
dren outside the time frame of 2 weeks
following vaccination.
MMR vaccination is an effective
health intervention. The 3 diseases and
their neurological sequelae are rarely
observed today in countries with high
vaccination coverage.31,32 Our study
showed that the transient increased rate
of febrile seizures was restricted to 2
weeks following vaccination, the risk
difference was small even in children
at high risk of febrile seizures, and the
long-term rate of epilepsy was not in-
creased in children who had febrile sei-
zures following MMR vaccination com-
pared with children who had febrile
seizures of a different etiology.
Author Contributions: Dr Melbye had access to all of
the data in the study and takes full responsibility for
the integrity of the data and the accuracy of the data
analysis.
Study concept and design: Vestergaard, Hviid, Madsen,
Wohlfahrt, Melbye, Olsen.

356 JAMA, July 21, 2004—Vol 292, No. 3 (Reprinted) ©2004 American Medical Association. All rights reserved.

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Acquisition of data: Vestergaard, Madsen, Thorsen,
Melbye.
Analysis and interpretation of data: Vestergaard, Hviid,
Madsen, Wohlfahrt, Schendel, Melbye, Olsen.
Drafting of the manuscript: Vestergaard.
Critical revision of the manuscript for important in-
tellectual content: Vestergaard, Hviid, Madsen,
Wohlfahrt, Thorsen, Schendel, Melbye, Olsen.
Statistical Analysis: Hviid, Wohlfahrt.
Obtained funding: Vestergaard, Madsen, Thorsen,
Schendel, Melbye.
Administrative, technical, or material support:
Vestergaard, Thorsen, Schendel.
Supervision: Vestergaard, Melbye, Olsen.
Funding/Support: This study was supported by grant
22-02-0207 from the Danish Medical Research Coun-
cil. The Danish National Research Foundation funds
the activities of the Danish Epidemiology Science
Centre.
Role of the Sponsors: The Danish Medical Research
Council and the Danish National Research Founda-
tion did not participate in the design and conduct of
the study, in the collection, analysis, and interpreta-
tion of the data, or in the preparation, review, or ap-
proval of the manuscript.
Acknowledgment: We thank Lars Pedersen, MSci, and
Anders Riis, MSci, Department of Clinical Epidemiol-
ogy, Aarhus University Hospital, Denmark, for help-
ing us to create Figure 2.
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