Epilepsy in Children After Pandemic Influenza Vaccination
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Siri E. Håberg, MD, PhD, a Kari M. Aaberg, MD, a, b Pål Surén, MD, PhD, a, b Lill Trogstad, MD, PhD,a Sara Ghaderi, MSc, PhD, a EpilepsyCamilla Stoltenberg, MD, PhD, in a, c Per Children Magnus, MD, PhD, a, d Inger JohanneAfter Bakken, MSc, PhDa Pandemic Influenza Vaccination OBJECTIVES: abstract To determine if pandemic influenza vaccination was associated with an increased METHODS: risk of epilepsy in children. Information from Norwegian registries from 2006 through 2014 on all children <18 years living in Norway on October 1, 2009 was used in Cox regression models to estimate hazard ratios for incident epilepsy after vaccination. A self-controlled case series analysis was used to estimate incidence rate ratios in defined risk periods after pandemic RESULTS: vaccination. In Norway, the main period of the influenza A subtype H1N1 pandemic was from October 2009 to December 2009. On October 1, 2009, 1154 113 children <18 years of age were registered as residents in Norway. Of these, 572875 (50.7%) were vaccinated against pandemic influenza. From October 2009 through 2014 there were 3628 new – cases of epilepsy (incidence rate 6.09 per 10000 person-years). The risk of epilepsy was not increased after vaccination: hazard ratio: 1.07; 95% confidence interval: 0.94 1.23. Results from the self-controlled case series analysis supported the finding of no association CONCLUSIONS: between vaccination and subsequent epilepsy. Pandemic influenza vaccination was not associated with increased risk of epilepsy. Concerns about pandemic vaccination causing epilepsy in children seem to be unwarranted. aNorwegian Institute of Public Health, Oslo, Norway; bThe National Center for Epilepsy, Oslo University Hospital, WHT A ’S KNOWN on THIS SUBJECT: Influenza Oslo, Norway; cDepartment of Global Public Health and Community Care, University of Bergen, Bergen, Norway; vaccination has been associated with an increased and dInstitute of Health and Society, University of Oslo, Oslo, Norway risk of febrile seizures in children. There is a link between febrile seizures, particularly complex Dr Håberg conceptualized and designed the study, was responsible for the data collection and the analytics plan, and drafted the initial manuscript; Dr Bakken contributed to the data collection febrile seizures, and an increased risk of later and the analytics plan, conducted the analyses, and reviewed and revised the manuscript; Drs epilepsy. Trogstad, Magnus, and Stoltenberg contributed to the conceptualization and design of the study, WHAT THIS STUDY ADDS: Concerns about pandemic and the interpretation of results, and critically reviewed the manuscript; Drs Ghaderi, Sur n, and é vaccination increasing the risk of epilepsy in Aaberg contributed to the interpretation of results, and critically reviewed the manuscript; and all authors approved the final manuscript as submitted. children seem to be unwarranted. DOI: https:// doi. org/ 10. 1542/ peds. 2017- 0752 Accepted for publication Dec 5, 2017 Address correspondence to Siri E. Håberg, MD, PhD, Norwegian Institute of Public Health, PO Box 4404 Nydalen, 0403 Oslo, Norway. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2018 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. POTENTIAL CONFLICTS OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose. To cite: Håberg SE, Aaberg KM, Surén P, et al. Epilepsy in Children After Pandemic Influenza Vaccination. Pediatrics. 2018;141(3):e20170752 Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 141, number 3, March 2018:e20170752 ARTICLE Seizures, including febrile seizures, including febrile seizures, after 1 are financed through government are the most– commonly reported pandemic influenza vaccination. funding, and health care is free of neurologic1 10complication of influenza Increased seizure risk has also been charge for children up to age 16. infection. Influenza vaccinations described after administration35, 36 Outpatients older than 16 years pay have also been– associated with an of other vaccines, but the a minor fee, whereas hospitalization increased11 risk14 of febrile seizures in association with later epilepsy is less is free of charge for all citizens. children. We have previously clear. In some studies of epilepsy Norway has several nationwide, shown that vaccination against onset after vaccination, genetic or mandatory registries and health pandemic influenza increased the structural etiologies were found in databases with individual-level risk of febrile seizures in children, most children with onset of epilepsy data. The unique identification although to a lower1 degree than around the time of vaccination, numbers given to all residents at influenza infection, and there have supporting the view of vaccinations birth or at immigration enables been concerns about an association as possible precipitating factors of linkage of information. We linked41 with later epilepsy. There has been first seizures in susceptible children, data from the National Registry increasing focus on the role of rather than31, 32 as primary, causal (census information),42 the Norwegian infections and immunologic –factors, factors. Patient Registry (specialist health not only in febrile seizures, but also 15 17 In several studies, authors conclude care data and hospitalizations), in the etiology of epilepsy. that pandemic vaccination may the Norwegian43 Immunization é Register (information on pandemic Epilepsy is defined by the occurrence influence the risk of other neurologic vaccinations), and the national or high risk of recurrent, unprovoked conditions, such– as Guillain-Barr 18 primary care reimbursement seizures. Childhood epilepsy has syndrome, encephalopathies,6 9 and 44 many different causes, but in most narcolepsy, suggesting there is system. The Norwegian Patient cases the causal mechanisms are a potential influence on the brain Registry contains individual-level 19 data from all Norwegian hospitals not identified. However, there when the immune system37, has 38 been is a clear link between febrile triggered by vaccination. and outpatient clinics from 2008 onwards, including dates of discharge seizures, particularly– complex febrile However, no association with seizures, and increased risk of later narcolepsy was found in a study of a fromInternational the hospital Classification or outpatient 20 26 visit, and diagnoses reported epilepsy. The role of influenza nonadjuvanted pandemic influenza39 of Diseases, 10th Revision infection as a causal trigger of vaccine used in the United States. as codes. epilepsy is not clear. In one matched During the 2009 influenza pandemic, Reporting is mandatory and linked case-control study, which included Pandemrix, a monovalent AS03- to the reimbursement system. people of all ages, the authors found adjuvanted influenza A(H1N1) Information from primary care was no increased risk of27 epilepsy after pmd09 vaccine, was offered free of retrieved from the reimbursement influenza infection. In other studies, charge to all citizens in Norway. We system and included dates of authors have found neurologic investigated the risk of epilepsy after International consultation and diagnostic complications– such as meningitis and pandemic influenza vaccination in Classification of Primary Care, Second codes based on the encephalitis3 6, in 8, 9,relation 28, 29 to influenza children by linking individual level Edition infections, and these information from several national complications may in turn increase . health registries that cover the entire Study Population the risk of later epilepsy. Norwegian population. METHODS The role of– vaccination as a causal factor or30 trigger32 of epilepsy is still unclear. In several studies, In Norway, the main wave of the including a study from Sweden on the The study was approved by the pandemic influenza period lasted Pandemrix vaccine (GlaxoSmithKline, Regional Committee for Medical and from October45 2009 to December Brentford, United Kingdom), authors Health Research Ethics, located in 2009. The study population found there was no increased Datasoutheast Sources Norway. included all children registered in the National registry on October 1, risk of epileptic30, 33, seizures 34 after – vaccination. Other studies 2009 who were born after January 1, N conclude that vaccines– may trigger Norway has a nationwide public 1991 (age 0 17 years on October 1, seizures in children30 32 with underlying health care system in which access 2009) ( = 1154113). The National susceptibility. It has previously to specialist care requires referral40 Registry provided information been shown that children were from a general practitioner. on sex, date of birth, and dates of at an increased risk of seizures, Hospitals and outpatient clinics emigrations and deaths. Downloaded from www.aappublications.org/news by guest on September 30, 2021 2 HÅBERG et al Exposure: Pandemic Influenza Vaccination case criteria for incident epilepsy influenza vaccination compared (at least 2 registrations with G40/ with a background period. This G41 during the follow-up period), method eliminates time-independent Dates of vaccination with Pandemrix but with R56 registered before the confounding because children were obtained from the Norwegian start of the follow-up period, were with epilepsy serve as their