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MMR Vaccination and Febrile Seizures
Evaluation of Susceptible Subgroups and Long-term Prognosis
seiMogens 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
HE 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
and Participants A populationbased cohort study of all children born in Denmark between January 1. 973 of these febrile seizures occurred within 2 weeks of MMR vaccination.ama-assn.org by guest on November 18. 1991.97 per 1000 (95% CI.44-1. T ©2004 American Medical Association. Results A total of 439251 children (82%) received MMR vaccination and 17 986 children developed febrile seizures at least once. 1.33-1. At 15 to 17 months. Centers for Disease Control and Prevention. Aarhus larly high risk. perinatal factors. zures are in general associated with Author Affiliations: The Danish Epidemiology Scian ence Centre. 95% confidence interval [CI].70. 16.56 per 1000 children overall (95% CI. Aarhus University. 95% CI.47 per 1000 (95% CI. Statens Serum Institut. The RR of febrile seizures increased during the 2 weeks following MMR vaccination (2. recurrent febrile seizures. Setting. 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. All rights reserved. 2. who were alive at 3 months. Conclusions MMR vaccination was associated with a transient increased rate of febrile seizures but the risk difference was small even in high-risk children. Aarhus (Drs Vestergaard. the risk difference of febrile seizures within 2 weeks following MMR vaccination was 1. To address these questions. The Danish Epiredemiology Science Centre.ment of Epidemiology and Social Medicine. Corresponding Author: Mogens Vestergaard. little is known about the long-term outcome of febrile seizures following vaccination. 2. and subsequent epilepsy. Departing MMR vaccination carry a particu. 95% CI. Madsen. Denmark. The RR did not vary significantly in the subgroups of children that had been defined by their family history of seizures.50) compared with children who were nonvaccinated at the time of their first febrile seizure. 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.05-23. and 19. 1999. and rubella (MMR) vaccination but it is unknown whether the rate varies according to personal or family history of seizures. Context The rate of febrile seizures increases following measles. 3. Vennelyst Blvd 6.41) but no increased rate of epilepsy (RR.97). 2004—Vol 292. Copenhagen mains unclear if febrile seizures (Dr Melbye and Mr Hviid and Ms Wohlfahrt). or socioeconomic status. (Reprinted) JAMA. Furthermore. Department of Epidemiology and Social Medicine.19. and thereafter was close to the observed RR for nonvaccinated children. Department of Epidemiology and increased risk of epilepsy11-13 but it Social Medicine.292:351-357 www. and December 31. DK-8000 Aarhus C.75. Department of Epidemiology Research. The Danish Epidemiology Science Centre. MD. 2004. 3 351 Downloaded from jama. 1998.01-1. 0. and followNorth Atlantic Neuro-Epidemiology Alliances.jama.and 4 other national registries. 1. Children with febrile seizures following MMR vaccinations had a slightly increased rate of recurrent febrile seizures (RR. mumps. perinatal factors.au.55-2.com (Drs Thorsen and Schendel). JAMA. 537171 children were followed up until December 31.905.55) for children with a personal history of febrile seizures. Ga (Dr Schendel). July 21. No. or socioeconomic status. and Olsen).dk). Denmark (mv@soci. 0. Design. 1.40) for siblings of children with a history of febrile seizures. 2011 . Atlanta. by using data from the Danish Civil Registration System Main Outcome Measures Incidence of first febrile seizure. we performed a large population-based cohort study. Aarhus University. and National Center on Birth Defects and Developmental Disabilities. PhD.68).
vaccination inforstudy period was mation and the age of the child were identical to that used recorded with the civil registry numin the United States and ber of the accompanying adult. through December 31. 1991. and had no recorded history of nonfebrile seizures. and December 31. We obtained permission from the Danish Data Protection Board before the study was initiated. emigration. Jeryl Lynn therefore. who were alive at the age of 3 months (N = 537171).5% of the children were (mumps). (measles). address. and family structure (link to mother and father). which is stored in the Danish Civil Registration System together with information on vital status. 1998. The febrile seizures could not be classified as simple or complex be- . vaccination informarecommended. The general practitioners are reimbursed by the state based on these reports. The MMR vaccine data are transferred to the National Board was introduced in of Health once a week without specifyDenmark in 1987 and ing the day of vaccination. were aged between 3 and 60 months at the time of discharge. cerebral palsy. The tion has been recorded with the child’s MMR own civil registry number and the invaccine used in formation directly linked with other regDenmark during the istries. MMR Vaccination Status We determined MMR vaccination status from vaccination data reported to the National Board of Health by general practitioners. 1991. Since 1996. We retrieved information on vaccinations from January 1. The cohort was established by means of data from the Danish Civil Registration System and 4 other national registries.21 or ICD-10 code R56. All treatments in Danish hospitals are free of charge for all Danish citizens. All live-born children and new residents in Denmark are assigned a unique personal identification number (civil registry number). 98.5% of vaccinated chiling the entire study dren were identified based on the civil period that chilregistry number of other relatives and dren should be the child’s address at the time of vaccivaccinated twice. and identified with the use of the child’s civil Wistar RA 27/3 (rubella).14 The registry is updated every week and all changes regarding the status of the above-mentioned variables are required by law.0.17 We classified children as having a febrile seizure when they were registered with ICD-8 code 780.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. outpatients (visits to emergency department and hospital clinics) have been included in the register since 1995. We used contained the information from the Danish Civil Regfollowing vaccine istration System to identify the link from strains: Moraten the accompanying adult to the child. Before 1996. The civil registry number can be used to link individual information in all national registries. meningitis. at 15 nation. recommended durThe remaining 1. who provide MMR vaccinations in Denmark. intracranial tumors. severe head traumas. months and at 12 years. 1999. 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. we had to sea single-antigen lect 1 day as the day of vaccination in measles vaccine has our analyses and we chose Wednesnever been day.15 which conthe vaccination tains information on all patients discharged from Danish hospitals since 1977. Because Hospital Register (NHR). registry number or the civil registry The national number of the mother or father and vaccination program the age of the child at vaccination. Only the first Febrile Seizures and Epilepsy vaccination is relevant Information on febrile seizures and epito the end point lepsy was obtained from the National under study. or encephalitis.
a diagnosis of epilepsy. severe brain injury. producing incidence rate ratios (RRs). to December 31. and type of febrile seizures (generalized or focal onset). 2011 . July 21.15 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. All RRs were adjusted for age (3-month categories) and calendar JAMA. cerebral palsy. No.ama-assn. Potential Effect Modifiers and Confounders We obtained information on febrile seizures and epilepsy in siblings from the NHR during the period January 1. duration of the febrile seizures. 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. From that day. 1999.cause the NHR contains no information on number of febrile seizures occurring within the febrile episode. 2004—Vol 292. Statistical Analysis To study the association of MMR vaccination with a first episode of febrile seizure. Children were categorized with epilepsy if they had ICD-8 code 345 or ICD-10 code G40. 1999. We evaluated whether the RR of febrile seizures following MMR vaccination varied between subgroups of children by testing for statistical interaction. Downloaded from jama.19 We considered MMR vaccination a time-varying covariate. emigration. meningitis. or until December 31.org by guest on November 18. We obtained information on 352 birth weight and gestational age from the Danish Medical Birth Register18 and the NHR. we followed the children from the age of 3 months until the first diagnosis of febrile seizure registered in the NHR. death. whichever came first. aged 5 years. 3 (Reprinted) ©2004 American Medical Association. encephalitis. the children were assigned to the nonvaccinated group until they received the MMR vaccine. brain tumor. 1977. All rights reserved. The resulting person-years at risk were aggregated and analyzed using Poisson regression. they were included in the vaccinated cohort.
no These meningitis.came first. 37 to 41 weeks for gestational age at birth. birth order (1.until December 31.(82%) received MMR vaccination. cerebral palsy. 37-41. gestational age in sis of epilepsy. 1999. 1999. incidence). number of siblings time of the first febrile seizure.2 (SAS in grams ( 2499. secondary were school. 3. respectively. and calendar period. primary school). we first calcu. and vocational train- . aged 5 years. death. meningitis. a epidiagnolepsy (no siblings. death. earner tion compared with nonvaccinated RRs of Febrile Seizures [high]. severe All analyses were conducted using weeks ( 36.MMR VACCINATION AND RATE OF FEBRILE SEIZURES period (1-year categories). Cary. 4000). 3500-3999. The RRs We followed up 537171 children for a lege. wage earner (standard level) for socioeconomic status. replacing a missing value with the exp (−incidence rate time). personbirth.years at risk. age at first febrile total of 1. with tered febrile seizure until the second calendar period. and current vaccination status.3% of the children. whichever lings with febrile seizures. age at first febrile seifebrile seizures.7%.05 was De3499. with febrile seizures (no siblings. 42). We considered MMR vaccination a RESULTS coltime-varying covariate. 1 siblings with epilepsy). First.encephalitis. or sibchildren were followed up prospec. gestational age at nonvaccinated children that vaccinated children (7445. whichever came first. 2.21 The for. 2. P . 2 siblings with episode of febrile seizure registered zure. Durhousein ing the study period. foland lowed up for 2 weeks (cumulative 0. SAS statistical software version 8. no siblings with epilepsy.2%. education (postgraduate education. wage chilearner [low].of these febrile seizures occurred within ment status of the head of the tional febrile seizures that occurred 2 weeks of the MMR vaccination. brain tumor. and maternal febrile seizures at a given age when education for 6. 2500-2999. The RRs were adjusted for age.7%. vocational training. we used 2 different strategies for the handling of missing values. oped febrile seizures at least once. NC). considered statistically significant.After MMR Vaccination Overall. birth weight brain injury. dren (risk difference). We had no lated the proportion of vaccinated febrile seizures was 10% higher among information and on birth weight. we come of interest (a second episode of variable analyses. wage earner [minimal]. In multi. encephalitis.febrile seizures or a first diagnosis of condren who were nonvaccinated at the epilepsy). we used the method of single imputation. we considered constructed a cohort of 10 541 chil. 1151661) compared with most common value of that variable: 3000 to 3499 g for birth weight. palsy. maternal cember 31. emigration. wage earner [medium]. we found that the rate of first unemployed). When evaluating confounding. aged 5 years. 973 employTo estimate the number of addi. number of siblings with the NHR. 3000. severe brain injury. cerebral founding by sex. developed socioeconomic status. febrile in seizures). 1996. or until Institute Inc.9 million person-years and socioecoseiidentified 17986 children who develnomic status as indicated by the zure.sonal history of febrile seizures. wage the 2 weeks following MMR vaccina. and adjusted for age. brain tumor. 31. 439251 children hold (managers [very high]. emigration. 4). The cumulative Data incidences on gestational age at birth was not were calculated by using the availexponenable for children born after tial formula: cumulative incidence=1 December − 31. 1 sibling tively from the day of the first regis.
The highest RR was found seizures of a different etiology. comof febrile seizures following MMR pared with nonvaccinated children vacwithin the subgroup under study cination compared with febrile (FIGURE 2). perthe son-years at risk. we analyzed only those children with complete information on the variable of interest.with nonvaccinated children. we decided to add all variables to the final model that changed the estimate of interest by at least 10% using either strategy. birth prognosis weight.ama-assn.org by guest on November 18. we analyzed only those children with complete information on all variables (358702). All rights reserved. The age-specific calendar period.17.22-2. 95% CI. No. Confidence intervals (CIs) no statistically significant difference in for the RR of febrile seizures in the 2 weeks the risk difference were calculated following vaccination between subusgroups of children characterized by ing the Delta method. However. These children were followed up from the day of the first registered febrile seizure until the out(Reprinted) JAMA.05-1. or socioeconomic factors. 95% CI.ing for maternal education.10.20 None of the variables with missing data qualified.22 family history of seizures. 2. the Overall.46. gestational age at birth. and 6472 children were vaccinated more than 2 weeks ago. 3 353 ©2004 American Medical Association. A priori.49) following vaccination only nonvaccinated (FIGURE 1). birth orTo evaluate the long-term der. pe1. 3.55-2. Second. thereafter the rate was close children within each subgroup and to that for nonvaccinated children. 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. Only age and calendar period were included in the final model. To study the association of MMR vaccination and a second episode of febrile seizures in children with a per- mula is based on the assumption that nonvaccinated children (10 541. When evaluating effect modification.15). 2. 1. Downloaded from jama. 2004—Vol 292. 2. 2011 . July 21.97) compared ence between the cumulative inci. 95% CI.73) and secsepaond week (RR. 973 children had been vaccinated within the previous 2 weeks.75 (95% CI. the rate of cumufebrile seizures increased during the first lative incidence was calculated (RR. after adjusting for age and riod of interest. 2. the RR of febrile seizures risk difference calculated as the within 2 weeks of MMR vaccination was differ2.89rately for vaccinated and 3. 793568) during the incidence rate is constant during the study period (RR. We found dences. sex.
preterm birth.0 1. seiCOMMENT zure. which was used in our study.MMR VACCINATION AND RATE OF FEBRILE SEIZURES Figure 1.64 per 1000 (95% seizures hisin the 2 weeks following CI. However. nated siblings of children with epilepsy. low birth weight.0 3.44-1. 1.41) but in no increased rate of epilepsy (RR. This finding is consistent with previous reports6-10 and is expected since MMR vaccination often induces fever. 95% CI.68) for children dren with a family history of febrile seifebrile seizures following zures (3. The incidence rate of febrile seizures compared with nonvaccinated children with a was increased in the 2 weeks followpering MMR vaccination and thereafter the sonal history of febrile seizures.5 1 2 3 4 5 6 7 8 9-26 27-52 53-104 105-156 157-260 rate was close to that observed for nonvaccinated children. The reference 2. the 2 weeks following vaccination 95% CI.46 per 5. 16. The RR of febrile seizures zures (RR. a 4-fold increased rate of febrile seizures following MMR vaccination was MMR indicates measles. of 1. mumps. 0.09).10-1. Adjusted Rate Ratios of Febrile Seizures According to Time Since MMR Vaccination vs Nonvaccinated Children in a Cohort of Children Born in Denmark.26) after group consisted of children who had adjustnot been vaccinated when having their ing for age. 95% CI. children was 1. and 0. 0. our statistical power in among siblings of children with a to 20 months.7-fold increased rate 95% CI. 1.1 a necessary cause of febrile seizures.40) for children vaccinated tory of epilepsy who had a 4-fold inat 21 to 23 months.0 2.56 per pared with a 2.32-3. and calendar period.40. TABLE 1).55) and for chil1000 (95% CI.01-1. and rubella. Point esobserved compared with nonvaccitimates are given with error bars representing 95% confidence intervals.33-1.90vaccinated at 15 vaccination in to 17 months. wk Risk Difference of Febrile Seizures Among Subgroups of Vaccinated Children The risk difference of febrile . Time Since Vaccination. MMR vaccicreased rate of febrile seizures in The highest risk difference was found nation compared with the 2 among children with a personal hisnonvaccinated weeks following vaccination comtory of febrile seizures (19.22-1. 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. 2. siblings of children with no history of 1000 (95% CI. age at the first febrile first febrile seizure (TABLE 2).50) during up to 105 was months of follow-up.19. 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.91) for children Long-term Prognosis of Febrile Seizures interaction=. 0.75 (95% CI.0 0. 1. The highest RR was found among siblings of children with epilepsy. 2.97 per 1000. Family history of seizures. Rate ratios are adjusted for age and calendar period.70. vaccinated at 18 Following MMR Vaccination Among the 10 541 children with a We found that children who experipersonal history of febrile seizures. 1991-1998 4.47 per 1000. epilepsy (P value for 1.05-23. 175 enced febrile seizures within 2 weeks children had a recurrent febrile seiof MMR vaccination had a 19% inzure within 2 weeks of the MMR vaccreased rate of recurrent febrile seicination.
24 At this age. most children are vaccinated against MMR at age 15 to 17 months when the incidence rate of febrile seizures is peaking.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. July 21. No previous studies have cal- JAMA. 3 (Reprinted) ©2004 American Medical Association. The absolute increase in incidence of febrile seizures following vaccination depends therefore on the underlying risk of febrile seizures in each subgroup. Rate Ratio Downloaded from jama.ama-assn.75 times higher within 2 weeks of MMR vaccination than it would have been had the children not been vaccinated. Overall. The RR of febrile seizure was not modified by a family history of febrile seizures. In Denmark.56 more per 1000 vaccinated children compared with nonvaccinated children. 2004—Vol 292.org by guest on November 18. 2011 . the rate of febrile seizures in all subgroups of children is approximately 2. the number of children experiencing febrile seizures within 2 weeks was 1. All rights reserved. or the finding is merely due to chance. No. our data suggest that MMR vaccination and the other indicators for febrile seizures follow a multiplicative 354 model.
but 2 studies recall.97) 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.26.75 (2. we found the highest afrisk ter reporting immunization data to difference in children with a the personal National Board of Health. The underlying risk of febrile seizures in these children is high. Because children in Dendoses genmark are vaccinated Monday thru Friof MMR vaccine overall. and these children should be vaccinated following the recommendations for children who have no contraindications.7 eral practitioners are reimbursed only As expected. possibly because the MMR Rate Ratio P Value for (95% Confidence Interval)∗Interaction 2.27 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. on a weekly basis but without inforfound We expect the data quality of the mation on the exact day of vaccinathat approximately 0.28 We know of only 1 study6 evaluating the clinical outcome of children with febrile seizures following MMR vaccination.MMR VACCINATION AND RATE OF FEBRILE SEIZURES culated the risk difference according brile seizures was collected prospec. history of febrile seizures. 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.33 febrile sei. wk <37 37-41 ≥42 Birth Weight. We chose Wednesday as the day zures were attributable to 1000 vaccination to be high because the of vaccination. The rate of recurrent febrile seizures was slightly increased.6. All Children Siblings With Febrile Seizures we found 19 additional febrile seizures within 2 weeks of the vaccination per 1000 children compared with nonvaccinated children aged 15 to 17 months.MMR tion.55-2. Student No Siblings With Febrile Mother’s Educational Level Seizures Primary Education 1 Sibling With Febrile Secondary Education Seizures Vocational Training ≥2 Siblings With Febrile College Seizures Postgraduate Education Siblings With Epilepsy No Siblings No Siblings With Epilepsy ≥1 Siblings With Epilepsy Sex Boy Girl Birth Order 1 2 3 ≥4 Gestational Age.The information on vaccination was to tively and independent of parental reported to the National Board of Health age at vaccination.25 In this very high-risk group. . No increased rate of subsequent seizures was found in 41 children with febrile seizures following MMR vaccination compared with 521 children who had No Siblings Pensioner. approximately one third will have at least 1 episode of recurrent Figure 2. Adjusted Rate Ratios of Febrile Seizures Within 2 Weeks Following MMR Vaccination for Children With Specific Characteristics vs Nonvaccinated Children With the Same Characteristics febrile seizures before they reach 5 Strata years of age. g <2500 2500-2999 3000-3499 3500-3999 ≥4000 Socioeconomic Status Manager (Very High) Wage Earner (High Level) Wage Earner (Medium Level) Wage Earner (Standard Level) Wage Earner (Other) Unemployed.
All rights reserved.73 (2. †Test for interaction was performed by a test for trend.94) 2.14) 2.73 (2.86) 2.33-4.08 (1. which eliminates bias due to nonresponse.93 (2. the statistical power of this study was limited.35 (1.22) 2. July 21. The analyses including siblings were additionally adjusted for the total number of siblings.82 .21) 2.23-3.35-3. 2011 .90† .93-3.48-3.51) 2.48) .11 (2.61 (2.97 (2.59 (1.25) 2.30) 2.40-3. mumps.88 (2.78 (2.48-3.98) 2.34) 2. Information on MMR vaccinations and fe©2004 American Medical Association.68 (2. size and population-based nature.75 (2.69 (2.85) 2.67-3.17-3. No.02) 2.93-2.41-3.20-3.65 (2.93 (2.68 (2. and rubella.46-3. follow-up was virtually complete.26-3.60) 3.56-3.99) 2. Point quent epilepsy.48) 3.16) 2.36-2.90 (2.84 (2. Children with missing values were excluded when the effect of the variable its concerned was evaluated.34) 2.74 (2.13) 2.ama-assn.54† .10) 2.07) 2.41-3.00) 2. When evaluating the possible effect modification by siblings with febrile seizures or by siblings with epilepsy.09) .73 (2.84† febrile seizures in the absence of vaccination.99) 3. (Reprinted) JAMA. estimates are given with error bars representing 95% confidence intervals. The strengths of our study include *The RRs are adjusted for age and calendar period.38) .54-3.48) 2.60-3.26-3.34 2. children without siblings were not included in the test The for interaction.02 (2.89) 2.68† .69 (2.84 (2.78 (2.42-2.09 2.21 (2.95 .90) 2.23-3.06) 2.64 (2. 2004—Vol 292.21-3.40-2.6 However.63-5.82 (2.51-3.2.66 (2.20-3.10) 2.MMR indicates measles.75-3. in particular 1 2 3 4 56 7 Rate Ratio (95% Confidence Interval) when evaluating the rate of subse.50-3.01) 3.org by guest on November 18. 3 355 Downloaded from jama.47 (1.45-3. Vertical dashed line represents the overall rate ratio (RR) for febrile seizures within the 2 weeks following MMR vaccination compared with nonvaccinated children.49-6.93 (2.67-3.57) 3.95 (2.
age at first febrile seizure.92) Children with birth weight 2500 g 37 weeks 1.29 Thus.19 1. *Among 17 986 Danish children who had febrile seizures between 1991 and 1999.59-1.0. 92.44-1. Among the 249 children registered with febrile seizures in the NHR.27-2. we have misclassified some vaccinations by up to 2 days. Any misclassification of febrile seizures is likely to be nondifferential and will therefore bias the RR toward 1.93 3. All potential febrile seizures were confirmed by diagnostic telephone interview or review of medical records. †Rate ratios are adjusted for age.68) 19. of Epilepsy 251 9 95 Person-Years at Risk 41 310 3825 21 938 Rate Ratio (95% Confidence Interval)† 1. and rubella. Cumulative Incidence and Risk Difference of Febrile Seizures Within 14 Days for Vaccinated and Nonvaccinated Children at 15 to 17 Months No. we found that the RR of febrile seizures following MMR vaccination was virtually the same during the period 1991 to 1994 (2. 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.46 30.36 2. measles. we confirmed the diagnosis in 231 children (predictive value of a positive registration.8%. The effect of vaccination may be confounded by variables related both to avoidance of vaccination and to the outcome of interest.1. 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.41) 1.8%-95.90-5.00 1.97 Risk Difference (95% CI) 1. day. which increased during the study period. 95% CI.33-1.05-23.97 (2.7%).10 (0. 2. The Danish national vaccination program recommends that children be vaccinated with MMR at age 15 months and provides vaccinations free of charge.68. 71. Children were categorized according to vaccination status at time of first febrile seizure.41) 1. We adjusted our results for several potential confounders but found little . calendar period.5%.43) Subsequent Epilepsy Abbreviation: MMR.38 (1.47 (16. Table 2.69 (1.55-3.24 1. of Febrile Seizures Within 14 Days per 1000 Children Cumulative Incidence Characteristic All children Children with personal history of febrile seizures Siblings of children with history of febrile seizures Siblings of children with history of epilepsy Nonvaccinated 0.26) No.4%).62) Children with gestational age at birth Abbreviation: CI. 95% CI.50 2.83 (1.19 (1.96-1. 66.9%) in the cohort fulfilled the criteria for febrile seizures and 231 of those were registered in the NHR (completeness.05).3%-76.92 (0. We found that 323 children (4.62 1. Adjusted Rate Ratios of Recurrent Febrile Seizures and Subsequent Epilepsy* Recurrent Febrile Seizures MMR Vaccination Status at Time of First Febrile Seizure None Within 14 days 14 days prior No.00 0. 88.90 11. 95% CI. mumps. the rate of febrile seizures is probably not elevated during the first 4 days following vaccination.MMR VACCINATION AND RATE OF FEBRILE SEIZURES Table 1.18-2. of Recurrent Febrile Seizures 2753 236 918 Person-Years at Risk 23 560 2212 12 675 Rate Ratio (95% Confidence Interval)† 1.56 (1.90-5.40) 3.01-1.97 6. vaccination coverage was found to be 82%.50) 0. although outpatients were included in the latter period only. confidence interval.21 In fact. 95% CI. Overall.70 (0. We believe it is unlikely that MMR vaccination status influences the threshold for hospitalization or the coding of febrile seizures.38-3.60 4. 2.55) 3.79. of Children 10 541 973 6472 No. and current vaccination status.02) compared with the period 1995 to 1998 (2.59 Vaccinated 2.
Hviid. Olsen. children Study concept and design: Vestergaard. and the rarely long-term rate of epilepsy was not inobserved today in countries with creased in children who had febrile seihigh zures following MMR vaccination comvaccination coverage.32 Our study pared with children who had febrile showed that the transient increased seizures of a different etiology. Downloaded from jama. 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. July 21.31.ama-assn. JAMA. 2004—Vol 292. No. the risk the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data difference was small even in analysis. Madsen. All rights reserved.org by guest on November 18. Wohlfahrt. 3 (Reprinted) ©2004 American Medical Association. Melbye.change in the estimate of interest. MMR vaccination is an effective health intervention. The 3 diseases and 356 their neurological sequelae are at high risk of febrile seizures. rate of febrile seizures was restricted to 2 Author Contributions: Dr Melbye had access to all of weeks following vaccination. However. 2011 .
Thorsen. 30. 1987. 22-02-0207 from the Danish Medical Research Coun. cination and autism.79: 340-349. 32. theria/tetanus/pertussis and measles/mumps/ Administrative. Madsen. Nuorti JP. Madsen. Bossuyt PM. Melbye. MSci. Neurologic disorders after measles-mumps-rubella vaccination. Stafstrom CE. Vestergaard M. 1996. 28. and precautions: recommendations of the Advisory Committee on Immunization Practices (ACIP). beneficial effect of measles immunisation: analysis of Analysis and interpretation of data: Vestergaard.243:1337-1340. et al. family history of convulsions and use of antipyretics: supplementary ACIP statement. Lanof data for modern health sciences. 2002.284: 2643-2647. Peltola H. Hviid A. May 31. Melbye. Lancet. 1993. et al. Epidemiology. JAMA.16. Greenland S. Wohlfahrt. Peltola H. Olsen. and rubella juries. Pertussis immunization. et al. tion did not participate in the design and conduct of 11. Thorsen. 10. contraindications. The risk Critical revision of the manuscript for important inof seizures after receipt of whole-cell pertussis or tellectual content: Vestergaard. mumps. Madsen. New York. 1996. 1980. Manual of the International Statistical Classification of Diseases. 17. 1989. Aarhus. 1995.345:656-661. Melbye.MMR VACCINATION AND RATE OF FEBRILE SEIZURES Acquisition of data: Vestergaard. 1993. Acknowledgment: We thank Lars Pedersen. Practhe activities of the Danish Epidemiology Science titioner. N Engl Anders Riis. Risk of seizures after measles-mumpsFunding/Support: This study was supported by grant rubella immunization. The incidence and prevalence of febrile seizures. 5. 2002. Griffin MR. Mortimer EA. 1989. Watson JC. A new method Obtained funding: Vestergaard. 2002.47(RR-8):1-57. 2. eds. 27. Genetic and Prenatal Epidemiology of Febrile Convulsions [PhD thesis]. 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