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Childhood seizures after prenatal exposure to maternal influenza infection: a population-based cohort study from Norway, Australia and Canada
  1. Laura L Oakley1,2,
  2. Annette K Regan3,4,5,
  3. Deshayne B Fell6,7,8,
  4. Sarah Spruin7,9,
  5. Inger Johanne Bakken2,
  6. Jeffrey C Kwong7,10,11,12,13,
  7. Gavin Pereira4,
  8. Natasha Nassar14,
  9. Kari M Aaberg15,
  10. Allen J Wilcox2,16,
  11. Siri E Håberg2
  1. 1Department of Non-communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
  2. 2Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
  3. 3School of Nursing and Health Professions, University of San Francisco, San Francisco, California, USA
  4. 4School of Public Health, Curtin University, Perth, Western Australia, Australia
  5. 5Fielding School of Public Health, University of California Los Angeles, Los Angeles, California, USA
  6. 6School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
  7. 7ICES, Toronto, Ontario, Canada
  8. 8Children's Hospital of Eastern Ontario (CHEO) Research Institute, Ottawa, Ontario, Canada
  9. 9Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  10. 10Division of Epidemiology, University of Toronto Dalla Lana School of Public Health, Toronto, Ontario, Canada
  11. 11Public Health Ontario, Toronto, Ontario, Canada
  12. 12Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada
  13. 13University Health Network, Toronto, Ontario, Canada
  14. 14Child Population and Translational Health Research, Children's Hospital at Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia
  15. 15The National Center for Epilepsy, Oslo University Hospital, Oslo, Norway
  16. 16Epidemiology Branch, National Institutes of Health/National Institute of Environmental Health Sciences, Durham, North Carolina, USA
  1. Correspondence to Dr Laura L Oakley, Non-communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK; laura.oakley{at}lshtm.ac.uk

Abstract

Objective To assess whether clinical and/or laboratory-confirmed diagnosis of maternal influenza during pregnancy increases the risk of seizures in early childhood.

Design Analysis of prospectively collected registry data for children born between 2009 and 2013 in three high-income countries. We used Cox regression to estimate country-level adjusted HRs (aHRs); fixed-effects meta-analyses were used to pool adjusted estimates.

Setting Population-based.

Participants 1 360 629 children born between 1 January 2009 and 31 December 2013 in Norway, Australia (New South Wales) and Canada (Ontario).

Exposure Clinical and/or laboratory-confirmed diagnosis of maternal influenza infection during pregnancy.

Main outcome measures We extracted data on recorded seizure diagnosis in secondary/specialist healthcare between birth and up to 7 years of age; additional analyses were performed for the specific seizure outcomes ‘epilepsy’ and ‘febrile seizures’.

Results Among 1 360 629 children in the study population, 14 280 (1.0%) were exposed to maternal influenza in utero. Exposed children were at increased risk of seizures (aHR 1.17, 95% CI 1.07 to 1.28), and also febrile seizures (aHR 1.20, 95% CI 1.07 to 1.34). There was no strong evidence of an increased risk of epilepsy (aHR 1.07, 95% CI 0.81 to 1.41). Risk estimates for seizures were higher after influenza infection during the second and third trimester than for first trimester.

Conclusions In this large international study, prenatal exposure to influenza infection was associated with increased risk of childhood seizures.

  • epidemiology
  • neurology

Data availability statement

Data may be obtained from a third party and are not publicly available. The Ontario dataset from this study was linked using unique encoded identifiers and analysed at ICES, where they are held securely in coded form. While data sharing agreements prohibit ICES from making the dataset publicly available, access may be granted to those who meet prespecified criteria for confidential access, available at www.ices.on.ca/DAS. The full dataset creation plan and underlying analytical code are available from the authors upon request, understanding that the computer programs may rely upon coding templates or macros that are unique to ICES and are, therefore, either inaccessible or may require modification. The NSW dataset is stored securely at the Curtin University School of Public Health and access is restricted to named investigators in Australia. The Norwegian dataset contains personal data and cannot be made public due to confidentiality requirements according to Norwegian legislation. However, researchers who are interested in analysing data from the registries used in this study may apply to the appropriate registry owners after having obtained all necessary approvals according to Norwegian legislation.

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Data availability statement

Data may be obtained from a third party and are not publicly available. The Ontario dataset from this study was linked using unique encoded identifiers and analysed at ICES, where they are held securely in coded form. While data sharing agreements prohibit ICES from making the dataset publicly available, access may be granted to those who meet prespecified criteria for confidential access, available at www.ices.on.ca/DAS. The full dataset creation plan and underlying analytical code are available from the authors upon request, understanding that the computer programs may rely upon coding templates or macros that are unique to ICES and are, therefore, either inaccessible or may require modification. The NSW dataset is stored securely at the Curtin University School of Public Health and access is restricted to named investigators in Australia. The Norwegian dataset contains personal data and cannot be made public due to confidentiality requirements according to Norwegian legislation. However, researchers who are interested in analysing data from the registries used in this study may apply to the appropriate registry owners after having obtained all necessary approvals according to Norwegian legislation.

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Footnotes

  • Contributors The study was initiated by SEH. SEH, IJB, LO, AR, DBF and AJW contributed to the study design; while SEH, LO, AR and DBF developed the analysis plan. IJB extracted data in Norway, LO prepared and analysed the Norwegian data. AR extracted, prepared and analysed the Australian data. DBF and SS extracted, prepared and analysed the Canadian data. LO performed the pooled meta-analyses. LO, SEH, AR, DBF, SS, IJB, JCK, GP, NN, KMA and AJW were all involved in interpreting the results. LO led the drafting of the manuscript and all coauthors contributed to revising the manuscript. All coauthors approved the final version.

  • Funding This work was funded by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700 and by the Norwegian Institute of Public Health. In Ontario, this research was supported by an Operating Grant from the Canadian Institutes of Health Research (AO1-151541), and supported by ICES, a non-profit research institute funded by an annual grant from the Ontario Ministry of Health (MOH) and Ontario Ministry of Long-Term Care (MLTC). In NSW, this research was supported by a National Health and Medical Research Council project grant (GNT 1099655). This research was supported in part by the Intramural Program of the National Institute of Environmental Health Sciences, NIH.

  • Disclaimer The opinions, results, and conclusions reported in this article are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOH or Ontario MLTC is intended or should be inferred. This study is based in part on data provided by Better Outcomes Registry and Network (BORN), part of the Children’s Hospital of Eastern Ontario. The interpretation and conclusions contained herein do not necessarily represent those of BORN Ontario. Parts of this material are based on data and/or information compiled and provided by the Canadian Institute for Health Information (CIHI). However, the analyses, conclusions, opinions and statements expressed in the material are those of the author(s), and not necessarily those of CIHI (Ontario data). Data from the Norwegian Patient Registry have been used in this publication. The interpretation and reporting of these data are the sole responsibility of the authors, and no endorsement by the Norwegian Patient Registry is intended nor should be inferred.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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