Context The rate of febrile seizures increases following measles, mumps, and
rubella (MMR) vaccination but it is unknown whether the rate varies according
to personal or family history of seizures, perinatal factors, or socioeconomic
status. Furthermore, 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
seizures 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 children born in Denmark between
January 1, 1991, and December 31, 1998, who were alive at 3 months; 537 171
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 seizures, and
subsequent epilepsy.
Results A total of 439 251 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 family 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.
The safety of the measles, mumps, and rubella (MMR) vaccine is of major
public health interest because millions of children are vaccinated every year.
Fortunately, the vaccine is generally well-tolerated, rarely associated with
serious adverse effects, and may even have nonspecific health benefits.1-5 However,
MMR vaccination is followed by a transient increased risk of febrile seizures
compared with nonvaccinated children, probably due to vaccine-induced fever.6-10 It
may have clinical implications if susceptible children could be identified
before the vaccination but no study has been large enough to identify such
subgroups. For example, it is unknown whether children with a personal or
a family history of seizures are more prone to MMR-induced febrile seizures
than children without such history. Febrile seizures are in general associated
with an increased risk of epilepsy11-13 but
it remains unclear if febrile seizures following MMR vaccination carry a particularly
high risk. To address these questions, we performed a large population-based
cohort study.
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 = 537 171). The cohort was established by means
of data from the Danish Civil Registration System and 4 other national registries.
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 System 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 required by law.
The civil registry number can be used to link individual information in all
national registries. We obtained permission from the Danish Data Protection
Board before the study was initiated.
We determined MMR vaccination status from vaccination data reported
to the National Board of Health by general practitioners, who provide MMR
vaccinations in Denmark. The general practitioners are reimbursed by the state
based on these reports.
We retrieved information on vaccinations 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 during the entire study period that children 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 data are
transferred to the National Board of Health once a week without specifying
the day of vaccination, we had to select 1 day as the day of vaccination in
our analyses and we chose Wednesday. Since 1996, vaccination information has
been recorded with the child's own civil registry number and the information
directly linked with other registries. Before 1996, vaccination information
and the age of the child were recorded with the civil registry number of the
accompanying adult. We used information from the Danish Civil Registration
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 children were identified
based on the civil registry number of other relatives and the child's address
at the time of vaccination.
Febrile Seizures and Epilepsy
Information on febrile seizures and epilepsy was obtained from the National
Hospital Register (NHR),15 which contains information
on all patients discharged from Danish hospitals since 1977; outpatients (visits
to emergency department and hospital clinics) have been included in the register
since 1995. All treatments in Danish hospitals are free of charge for all
Danish citizens. Diagnostic information was classified according to the Danish
version 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 having a febrile seizure when they were registered
with ICD-8 code 780.21 or ICD-10 code R56.0, were aged between 3 and 60 months at the time of discharge,
and had no recorded history of nonfebrile seizures, cerebral palsy, severe
head traumas, intracranial tumors, meningitis, or encephalitis. The febrile
seizures could not be classified as simple or complex because the NHR contains
no information on number of febrile seizures occurring within the febrile
episode, duration of the febrile seizures, and type of febrile seizures (generalized
or focal 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 seizures 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 seizures from the day a sibling was
admitted 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 socioeconomic status
(as indicated by the employment status of the head of the household) and maternal
education was obtained from Statistics Denmark at the time the child was aged
15 months.
To study the association of MMR vaccination with a first episode of
febrile seizure, we followed the children from the age of 3 months until the
first diagnosis of febrile seizure registered in the NHR, death, emigration,
a diagnosis of epilepsy, cerebral palsy, severe brain injury, brain tumor,
meningitis, encephalitis, aged 5 years, or until December 31, 1999, whichever
came first. The resulting person-years at risk were aggregated and analyzed
using Poisson regression, producing incidence rate ratios (RRs).19 We
considered MMR vaccination a time-varying covariate; the children were assigned
to the nonvaccinated group until they received the MMR vaccine. From that
day, they were included in the vaccinated cohort. We evaluated whether the
RR of febrile seizures following MMR vaccination varied 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 multivariable analyses, we considered confounding
by sex, number of siblings with febrile seizures (no siblings, no siblings
with febrile seizures, 1 sibling with febrile seizures, ≥2 siblings with
febrile seizures), number of siblings with epilepsy (no siblings, no siblings
with epilepsy, ≥1 siblings with epilepsy), birth order (1, 2, 3, ≥4),
gestational age in weeks (≤36, 37-41, ≥42), birth weight in grams (≤2499,
2500-2999, 3000-3499, 3500-3999, ≥4000), maternal education (postgraduate
education, college, vocational training, secondary school, primary school),
and socioeconomic status as indicated by the employment status of the head
of the household (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 available for children born after December
31, 1996. When evaluating confounding, we used 2 different strategies for
the handling of missing values. First, we used the method of single imputation,
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 socioeconomic status, and vocational training
for maternal education. Second, we analyzed only those children with complete
information on all variables (358 702). 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 qualified. Only age and calendar period were included in
the final model. When evaluating effect modification, we analyzed only those
children with complete information on the variable of interest.
To study the association of MMR vaccination and a second episode of
febrile seizures in children with a personal history of febrile seizures,
we constructed a cohort of 10 541 children who were nonvaccinated at
the time of the first febrile seizure. These children were followed up prospectively
from the day of the first registered febrile seizure until the second episode
of febrile seizure registered in the NHR, death, emigration, a diagnosis of
epilepsy, cerebral palsy, severe brain injury, brain tumor, meningitis, encephalitis,
aged 5 years, or until December 31, 1999, whichever came first. We considered
MMR vaccination a time-varying covariate. The RRs were adjusted for age, age
at first febrile seizure, and calendar period.
To estimate the number of additional febrile seizures that occurred
in the 2 weeks following MMR vaccination compared with nonvaccinated children
(risk difference), we first calculated the proportion of vaccinated and nonvaccinated
children that developed febrile seizures at a given age when followed up for
2 weeks (cumulative incidence). The cumulative incidences were calculated
by using the exponential formula: cumulative incidence = 1 − exp (−incidence
rate × time).21 The formula is based
on the assumption that the incidence rate is constant during the period of
interest. The age-specific cumulative incidence was calculated separately
for vaccinated and nonvaccinated children within each subgroup and the risk
difference calculated as the difference between the cumulative incidences.
Confidence intervals (CIs) for the risk difference were calculated using the
Delta method.22
To evaluate the long-term prognosis of febrile seizures following MMR
vaccination compared with febrile seizures of a different etiology, we categorized
children with febrile seizures into 3 groups according to the vaccination
status at the time of the first febrile seizure: 10 541 children were
nonvaccinated, 973 children had been vaccinated within the previous 2 weeks,
and 6472 children were vaccinated more than 2 weeks ago. These children were
followed up from the day of the first registered febrile seizure until the
outcome 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 seizure, 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.
We followed up 537 171 children for a total of 1.9 million person-years
and identified 17 986 children who developed febrile seizures at least
once; 973 of these febrile seizures occurred within 2 weeks of the MMR vaccination.
During the study period, 439 251 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, 1 151 661)
compared with nonvaccinated children (10 541; person-years at risk, 793 568)
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 second 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 subgroups of children characterized
by family history of seizures, sex, birth order, gestational age at birth,
birth weight, or socioeconomic factors, compared with nonvaccinated children
within the subgroup under study (Figure 2). The highest RR was found among siblings of children with a history
of epilepsy who had a 4-fold increased rate of febrile seizures in the 2 weeks
following vaccination compared 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 seizure within 2 weeks of the MMR vaccination.
The RR of febrile seizures in the 2 weeks following vaccination was 2.75 (95%
CI, 2.32-3.26) after adjusting for age, age at the first febrile seizure,
and calendar period, compared with nonvaccinated children with a personal
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
vaccination 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 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
history of febrile seizures (19.47 per 1000; 95% CI, 16.05-23.55) and for
children with a family history of febrile seizures (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 experienced febrile seizures within 2 weeks
of MMR vaccination had a 19% 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) 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).
The incidence rate of febrile seizures was increased in the 2 weeks
following MMR vaccination and thereafter the rate was close to that observed
for nonvaccinated children. This finding is consistent with previous reports6-10 and
is expected since MMR vaccination often 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 significantly
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 seizures following
MMR vaccination was observed compared with nonvaccinated siblings of children
with epilepsy. 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 vaccination
than other children, or the finding 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 approximately 2.75 times higher within 2 weeks
of MMR vaccination than it would have been had the children not been vaccinated.
The absolute increase in incidence of febrile seizures following vaccination
depends therefore on the underlying risk of febrile seizures in each subgroup.
In Denmark, most children 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 experiencing febrile seizures within 2 weeks
was 1.56 more per 1000 vaccinated children compared with nonvaccinated children.
No previous studies have calculated the risk difference according to age at
vaccination, but 2 studies found that approximately 0.33 febrile seizures
were attributable to 1000 doses of MMR vaccine overall.6,7
As expected, we found the highest risk difference in children with a
personal history of febrile seizures. The underlying risk of febrile seizures
in these children is high; approximately one third will have at least 1 episode
of recurrent febrile seizures before they reach 5 years of age.25 In
this very high-risk group, we found 19 additional febrile seizures within
2 weeks of the vaccination per 1000 children compared with nonvaccinated children
aged 15 to 17 months. The Advisory Committee on Immunization Practices has
suggested that the benefits of administering MMR vaccine to children with
a personal or family history of convulsions substantially outweigh the risks,
and these children should be vaccinated following the recommendations for
children who have no contraindications.26,27
We found no increased rate of epilepsy among children who had febrile
seizures after MMR vaccination compared with children who had febrile seizures
of a different etiology. The rate of recurrent febrile seizures was slightly
increased, possibly because the MMR vaccination introduced an extra febrile
episode during the window of highest susceptibility and the total number of
febrile episodes is a well known risk factor for recurrence.28 We
know of only 1 study6 evaluating the clinical
outcome of children with febrile seizures following MMR vaccination. No increased
rate of subsequent seizures was found in 41 children with febrile seizures
following MMR vaccination compared with 521 children who had febrile seizures
in the absence of vaccination.6 However, the
statistical power of this study was limited, in particular when evaluating
the rate of subsequent epilepsy.
The strengths of our study include its size and population-based nature.
The follow-up was virtually complete, which eliminates bias due to nonresponse.
Information on MMR vaccinations and febrile seizures was collected prospectively
and independent of parental recall. We expect the data quality of the MMR
vaccination to be high because the general practitioners are reimbursed only
after reporting immunization data to the National Board of Health.
The information on vaccination was reported to the National Board of
Health on a weekly basis but without information on the exact day of vaccination.
We chose Wednesday as the day of vaccination. Because children in Denmark
are vaccinated Monday thru Friday, we have misclassified some vaccinations
by up to 2 days. Previous studies have shown that the attenuated viruses 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 febrile seizures is probably not elevated during the first 4 days
following vaccination.
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 followed
up until age 10 years.30 We collected information
about febrile seizures in the cohort using a parental questionnaire. All potential
febrile seizures were confirmed by diagnostic telephone interview or review
of medical records. We found that 323 children (4.9%) in the cohort fulfilled
the criteria for febrile seizures and 231 of those were registered in the
NHR (completeness, 71.5%; 95% CI, 66.3%-76.4%). Among the 249 children registered
with febrile seizures in the NHR, we confirmed the diagnosis in 231 children
(predictive value of a positive registration, 92.8%; 95% CI, 88.8%-95.7%).
We believe it is unlikely that MMR vaccination status influences the threshold
for hospitalization or the coding of febrile seizures. Any misclassification
of febrile seizures is likely to be nondifferential 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
during the period 1991 to 1994 (2.68; 95% CI, 2.38-3.02) compared with the
period 1995 to 1998 (2.79; 95% CI, 2.55-3.05), although outpatients were included
in the latter period only.
The Danish national vaccination program recommends that children be
vaccinated 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 variables
related both to avoidance of vaccination and to the outcome of interest. We
adjusted our results for several potential confounders but found little change
in the estimate of interest. However, the strongest argument against serious
confounding is that the risk of febrile seizures was almost the same for nonvaccinated
and vaccinated children 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
increased in children who had febrile seizures following MMR vaccination compared
with children who had febrile seizures of a different etiology.
1.Peltola H, Heinonen OP. Frequency of true adverse reactions to measles-mumps-rubella vaccine:
a double-blind placebo-controlled trial in twins.
Lancet.1986;1:939-942.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2871241&dopt=Abstract
Google Scholar 2.Madsen KM, Hviid A, Vestergaard M.
et al. A population-based study of measles, mumps, and rubella vaccination
and autism.
N Engl J Med.2002;347:1477-1482.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12421889&dopt=Abstract
Google Scholar 3.Patja A, Davidkin I, Kurki T.
et al. Serious adverse events after measles-mumps-rubella vaccination during
a fourteen-year prospective follow-up.
Pediatr Infect Dis J.2000;19:1127-1134.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11144371&dopt=Abstract
Google Scholar 4.Makela A, Nuorti JP, Peltola H. Neurologic disorders after measles-mumps-rubella vaccination.
Pediatrics.2002;110:957-963.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12415036&dopt=Abstract
Google Scholar 5.Aaby P, Samb B, Simondon F.
et al. Non-specific beneficial effect of measles immunisation: analysis of
mortality studies from developing countries.
BMJ.1995;311:481-485.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7647643&dopt=Abstract
Google Scholar 6.Barlow WE, Davis RL, Glasser JW.
et al. The risk of seizures after receipt of whole-cell pertussis or measles,
mumps, and rubella vaccine.
N Engl J Med.2001;345:656-661.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11547719&dopt=Abstract
Google Scholar 7.Farrington P, Pugh S, Colville A.
et al. A new method for active surveillance of adverse events from diphtheria/tetanus/pertussis
and measles/mumps/rubella vaccines.
Lancet.1995;345:567-569.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7619183&dopt=Abstract
Google Scholar 8.Griffin MR, Ray WA, Mortimer EA, Fenichel GM, Schaffner W. Risk of seizures after measles-mumps-rubella immunization.
Pediatrics.1991;88:881-885.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1945626&dopt=Abstract
Google Scholar 9.Miller C, Miller E, Rowe K.
et al. Surveillance of symptoms following MMR vaccine in children.
Practitioner.1989;233:69-73.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2798288&dopt=Abstract
Google Scholar 10.Hirtz DG, Nelson KB, Ellenberg JH. Seizures following childhood immunizations.
J Pediatr.1983;102:14-18.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6848712&dopt=Abstract
Google Scholar 11.Annegers JF, Hauser WA, Shirts SB, Kurland LT. Factors prognostic of unprovoked seizures after febrile convulsions.
N Engl J Med.1987;316:493-498.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3807992&dopt=Abstract
Google Scholar 12.Nelson KB, Ellenberg JH. Predictors of epilepsy in children who have experienced febrile seizures.
N Engl J Med.1976;295:1029-1033.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=972656&dopt=Abstract
Google Scholar 13.Ellenberg JH, Nelson KB. Sample selection and the natural history of disease: studies of febrile
seizures.
JAMA.1980;243:1337-1340.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7359696&dopt=Abstract
Google Scholar 14.Malig C. The civil registration system in Denmark.
Technical Papers IIVRS.1996;66:1-6.Google Scholar 15.Andersen TF, Madsen M, Jorgensen J.
et al. The Danish National Hospital Register: a valuable source of data for
modern health sciences.
Dan Med Bull.1999;46:263-268.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10421985&dopt=Abstract
Google Scholar 16.World Health Organization. Manual of the International Statistical Classification
of Diseases, Injuries, and Causes of Death. Geneva, Switzerland: World Health Organization; 1967.
17.World Health Organization. The International Statistical Classification of Diseases
and Related Health Problems, 10th Revision. Geneva, Switzerland: World Health Organization; 1993.
18.Knudsen LB, Olsen J. The Danish Medical Birth Registry.
Dan Med Bull.1998;45:320-323.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9675544&dopt=Abstract
Google Scholar 19.Clayton D, Hills M. Statistical Models in Epidemiology. New York, NY: Oxford University Press; 1993.
20.Greenland S. Modeling and variable selection in epidemiologic analysis.
Am J Public Health.1989;79:340-349.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2916724&dopt=Abstract
Google Scholar 21.Rothman KJ, Greenland S. Modern Epidemiology. 2nd ed. Baltimore, Md: Williams & Wilkins; 1998.
22.Agresti A. Categorical Data Analysis. New York, NY: John Wiley & Sons; 1990.
23.Vestergaard M, Basso O, Henriksen TB.
et al. Risk factors for febrile convulsions.
Epidemiology.2002;13:282-287.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11964929&dopt=Abstract
Google Scholar 24.Stafstrom CE. The incidence and prevalence of febrile seizures. In: Baram TZ, Shinnar S, eds. Febrile Seizures. London, England: Academic Press; 2002.
25.Offringa M, Bossuyt PM, Lubsen J.
et al. Risk factors for seizure recurrence in children with febrile seizures:
a pooled analysis of individual patient data from five studies.
J Pediatr.1994;124:574-584.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8151472&dopt=Abstract
Google Scholar 26. Leads from the MMWR. Pertussis immunization; family history of convulsions
and use of antipyretics: supplementary ACIP statement.
JAMA.1987;257:2894.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3494860&dopt=Abstract
Google Scholar 27.Watson JC, Hadler SC, Dykewicz CA.
et al. Measles, mumps, and rubella—vaccine use and strategies for elimination
of measles, rubella, and congenital rubella syndrome and control of mumps:
recommendations of the Advisory Committee on Immunization Practices (ACIP).
MMWR Recomm Rep.1998;47(RR-8):1-57.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9639369&dopt=Abstract
Google Scholar 28.Knudsen FU. Frequent febrile episodes and recurrent febrile convulsions.
Acta Neurol Scand.1988;78:414-417.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3218448&dopt=Abstract
Google Scholar 29. Update: vaccine side effects, adverse reaction, contraindications, and
precautions: recommendations of the Advisory Committee on Immunization Practices
(ACIP).
MMWR Recomm Rep.1996;45(RR-12):1-35.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8801442&dopt=Abstract
Google Scholar 30.Vestergaard M. Genetic and Prenatal Epidemiology of Febrile Convulsions [PhD thesis]. Aarhus, Denmark: University of Aarhus; May 31, 2002.
31.Peltola H, Davidkin I, Paunio M.
et al. Mumps and rubella eliminated from Finland.
JAMA.2000;284:2643-2647.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11086376&dopt=Abstract
Google Scholar 32.de Quadros CA, Olive JM, Hersh BS.
et al. Measles elimination in the Americas: evolving strategies.
JAMA.1996;275:224-229.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8604176&dopt=Abstract
Google Scholar