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Original Investigation
October 7, 2019

Evaluation of Long-term Risk of Epilepsy, Psychiatric Disorders, and Mortality Among Children With Recurrent Febrile Seizures: A National Cohort Study in Denmark

Author Affiliations
  • 1National Centre for Register-Based Research, Department of Economics and Business Economics, Aarhus University, Aarhus, Denmark
  • 2Centre for Integrated Register-Based Research, Centre for Integrated Register-Based Research, Aarhus University, Aarhus University, Aarhus, Denmark
  • 3Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark
  • 4Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
JAMA Pediatr. Published online October 7, 2019. doi:10.1001/jamapediatrics.2019.3343
Key Points

Question  Are long-term consequences associated with recurrent febrile seizures?

Findings  In this cohort study of 2 103 232 children between the ages of 3 months and 5 years born in Denmark, recurrent febrile seizures were assessed. The cumulative risk of recurrent febrile seizures in 75 593 children with a first febrile seizure was 22.7%. The risk of epilepsy and psychiatric disorders increased with the number of hospital admissions with febrile seizures.

Meaning  Recurrent febrile seizures appear to be associated with a risk of developing epilepsy and psychiatric disorders, but excessive mortality was observed only in those who later developed epilepsy.

Abstract

Importance  Febrile seizures occur in 2% to 5% of children between the ages of 3 months and 5 years. Many affected children experience recurrent febrile seizures. However, little is known about the association between recurrent febrile seizures and subsequent prognosis.

Objective  To estimate the risk of recurrent febrile seizures and whether there is an association over long-term follow-up between recurrent febrile seizures and epilepsy, psychiatric disorders, and death in a large, nationwide, population-based cohort in Denmark.

Design, Setting, and Participants  This population-based cohort study evaluated data from all singleton children born in Denmark between January 1, 1977, and December 31, 2011, who were identified through the Danish Civil Registration System. Children born in Denmark who were alive and residing in Denmark at age 3 months were included (N = 2 103 232). The study was conducted from September 1, 2017, to June 1, 2019.

Exposures  Hospital contacts with children who developed febrile seizures between age 3 months and 5 years.

Main Outcomes and Measures  Children diagnosed with epilepsy were identified in the Danish National Patient Register and children diagnosed with psychiatric disorders were identified in the Psychiatric Central Research Register. Competing risk regression and Cox proportional hazards regression were used to estimate the cumulative and relative risk of febrile seizures, recurrent febrile seizures, epilepsy, psychiatric disorders, and death.

Results  Of the 2 103 232 children (1 024 049 [48.7%] girls) in the study population, a total of 75 593 children (3.6%) were diagnosed with a first febrile seizure between 1977 and 2016. Febrile seizures were more common in boys (3.9%; 95% CI, 3.9%-4.0%) than in girls (3.3%; 95% CI, 3.2%-3.3%), corresponding to a 21% relative risk difference (hazard ratio, 1.21; 95% CI, 1.19-1.22). However, the risks of recurrent febrile seizures, epilepsy, psychiatric disorders, and death were similar in boys and girls. The risk of (recurrent) febrile seizures increased with the number of febrile seizures: 3.6% at birth, 22.7% (95% CI, 22.4%-23.0%) after the first febrile seizure, 35.6% (95% CI, (34.9%-36.3%) after the second febrile seizure, and 43.5% (95% CI, (42.3%-44.7%) after the third febrile seizure. The risk of epilepsy increased progressively with the number of hospital admissions with febrile seizures. The 30-year cumulative risk of epilepsy was 2.2% (95% CI, (2.1%-2.2%) at birth compared with 15.8% (95% CI, 14.6%-16.9%) after the third febrile seizure, while the corresponding estimates for risk of psychiatric disorders were 17.2% (95% CI, 17.2%-17.3%) at birth and 29.1% (95% CI, 27.2%-31.0%) after the third febrile seizure. Mortality was increased among children with recurrent febrile seizures (1.0%; 95% CI, 0.9%-1.0% at birth vs 1.9%; 95% CI, 1.4%-2.7% after the third febrile seizure), although this risk was associated primarily with children who later developed epilepsy.

Conclusions and Relevance  A history of recurrent febrile seizures appears to be associated with a risk of epilepsy and psychiatric disorders, but increased mortality was found only in individuals who later developed epilepsy.

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