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Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study

BMJ 2013; 347 doi: (Published 09 October 2013) Cite this as: BMJ 2013;347:f5906
  1. Lisen Arnheim-Dahlström, associate professor1,
  2. Björn Pasternak, postdoctoral fellow2,
  3. Henrik Svanström, statistician2,
  4. Pär Sparén, professor1,
  5. Anders Hviid, senior investigator2
  1. 1Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 77, Sweden
  2. 2Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
  1. Correspondence to: L Arnheim-Dahlström lisen.arnheim.dahlstrom{at}
  • Accepted 28 August 2013


Objective To assess the risk of serious adverse events after vaccination of adolescent girls with quadrivalent human papillomavirus (qHPV) vaccine.

Design Register based cohort study.

Setting Denmark and Sweden, October 2006 to December 2010.

Participants 997 585 girls aged 10-17, among whom 296 826 received a total of 696 420 qHPV vaccine doses.

Main outcome measures Incident hospital diagnosed autoimmune, neurological, and venous thromboembolic events (53 different outcomes) up to 180 days after each qHPV vaccine dose. Only events with at least five vaccine exposed cases were considered for further assessment. Rate ratios adjusted for age, country, calendar year, and parental country of birth, education, and socioeconomic status were estimated, comparing vaccinated and unvaccinated person time. For outcomes where the rate ratio was significantly increased, we regarded three criteria as signal strengthening: analysis based on 20 or more vaccine exposed cases (reliability), rate ratio 3.0 or more (strength), and significantly increased rate ratio in country specific analyses (consistency). We additionally assessed clustering of events in time and estimated rate ratios for a risk period that started on day 181.

Results Among the 53 outcomes, at least five vaccine exposed cases occurred in 29 and these were analysed further. Whereas the rate ratios for 20 of 23 autoimmune events were not significantly increased, exposure to qHPV vaccine was significantly associated with Behcet’s syndrome, Raynaud’s disease, and type 1 diabetes. Each of these three outcomes fulfilled only one of three predefined signal strengthening criteria. Furthermore, the pattern of distribution in time after vaccination was random for all three and the rate ratios for these outcomes in the period from day 181 after vaccination were similar to the rate ratios in the primary risk period. The rate ratios for five neurological events were not significantly increased and there were inverse associations with epilepsy (rate ratio 0.66, 95% confidence interval 0.54 to 0.80) and paralysis (0.56, 0.35 to 0.90). There was no association between exposure to qHPV vaccine and venous thromboembolism (0.86, 0.55 to 1.36).

Conclusions This large cohort study found no evidence supporting associations between exposure to qHPV vaccine and autoimmune, neurological, and venous thromboembolic adverse events. Although associations for three autoimmune events were initially observed, on further assessment these were weak and not temporally related to vaccine exposure. Furthermore, the findings need to be interpreted considering the multiple outcomes assessed.


  • We thank Jonas Hällgren for data administration, Karin Sundström for valuable discussion on the findings in this study, and the Swedish Institute for Communicable Diseases for contributing with HPV vaccination data from the Svevac register.

  • Contributors: BP, HS, and AH created the database and performed the statistical analyses. LAD and BP drafted the manuscript. All authors actively participated in study design, interpretation and discussion of the results, revision of the manuscript, and approval of the final version of the manuscript. AH is the guarantor.

  • Funding: This study was supported by a grant from the Swedish Foundation for Strategic Research and the Danish Medical Research Council. The funding bodies had no role in the study design; the collection, analysis, and interpretation of the data; the writing of the article; and the decision to submit it for publication. All authors are independent from the funding agencies.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; LAD and PS are and have been involved in other studies with unconditional grants from GlaxoSmithKline, Sanofi Pasteur MSD, and Merck; and no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: This study was approved by the regional ethical review committee in Stockholm, Sweden, and by the Danish Data Protection Agency. Ethical approval is not required for register based research in Denmark.

  • Declaration of transparency: The lead author affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

  • Data sharing: No additional data available.

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