Pre-Vaccination Care-Seeking in Females Reporting Severe Adverse Reactions to HPV Vaccine. A Registry Based Case-Control Study

PLoS One. 2016 Sep 9;11(9):e0162520. doi: 10.1371/journal.pone.0162520. eCollection 2016.


Background: Since 2013 the number of suspected adverse reactions to the quadrivalent human papillomavirus (HPV) vaccine reported to the Danish Medicines Agency (DMA) has increased. Due to the resulting public concerns about vaccine safety, the coverage of HPV vaccinations in the childhood vaccination programme has declined. The aim of the present study was to determine health care-seeking prior to the first HPV vaccination among females who suspected adverse reactions to HPV vaccine.

Methods: In this registry-based case-control study, we included as cases vaccinated females with reports to the DMA of suspected severe adverse reactions. We selected controls without reports of adverse reactions from the Danish vaccination registry and matched by year of vaccination, age of vaccination, and municipality, and obtained from the Danish National Patient Registry and The National Health Insurance Service Register the history of health care usage two years prior to the first vaccine. We analysed the data by logistic regression while adjusting for the matching variables.

Results: The study included 316 cases who received first HPV vaccine between 2006 and 2014. Age range of cases was 11 to 52 years, with a peak at 12 years, corresponding to the recommended age at vaccination, and another peak at 19 to 28 years, corresponding to a catch-up programme targeting young women. Compared with 163,910 controls, cases had increased care-seeking in the two years before receiving the first HPV vaccine. A multivariable model showed higher use of telephone/email consultations (OR 1.9; 95% CI 1.2-3.2), physiotherapy (OR 2.1; 95% CI 1.6-2.8) and psychologist/psychiatrist (OR 1.9; 95% CI 1.3-2.7). Cases were more likely to have a diagnosis in the ICD-10 chapters of diseases of the digestive system (OR 1.6; 95% CI 1.0-2.4), of the musculoskeletal system (OR 1.6; 95% CI 1.1-2.2), symptoms or signs not classified elsewhere (OR 1.8; 95% CI 1.3-2.5) as well as injuries (OR 1.5; 95% CI 1.2-1.9).

Conclusion: Before receiving the first HPV vaccination, females who suspected adverse reactions has symptoms and a health care-seeking pattern that is different from the matched population. Pre-vaccination morbidity should be taken into account in the evaluation of vaccine safety signals.

MeSH terms

  • Adolescent
  • Adult
  • Case-Control Studies
  • Child
  • Digestive System / drug effects
  • Digestive System / pathology
  • Female
  • Humans
  • Middle Aged
  • Musculoskeletal System / drug effects
  • Musculoskeletal System / pathology
  • Papillomavirus Infections / prevention & control
  • Papillomavirus Vaccines / adverse effects*
  • Papillomavirus Vaccines / therapeutic use
  • Registries
  • Uterine Cervical Neoplasms / prevention & control
  • Vaccination / adverse effects*
  • Vaccination / statistics & numerical data*
  • Young Adult


  • Papillomavirus Vaccines

Grant support

The study was in part supported by a grant from Innovation Fund Denmark and IBM Denmark (PhD grant to Niels Dalum Hansen). Niels Dalum Hansen is partly employed by IBM Denmark. IBM Denmark provided support in the form of a part of the salary for author Niels Dalum Hansen, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section.