Hospital Records of Pain, Fatigue, or Circulatory Symptoms in Girls Exposed to Human Papillomavirus Vaccination: Cohort, Self-controlled Case Series, and Population Time Trend Studies.

Human papillomavirus (HPV) vaccination has been associated with subsequent diffuse symptoms in girls, reducing public confidence in the vaccine. We examined if girls have nonspecific outcomes of HPV vaccination, using triangulation from a cohort, self-controlled case series (SCCS), and population time trend study in entire Denmark between 2000-2014. The study population consisted of 314,017 vaccinated girls and 314,017 age-matched unvaccinated girls (cohort analyses); 11,817 girls with hospital records (SCCS analyses); and 1,465,049 girls and boys (population time trend analyses). Main outcome measures were hospital records of pain, fatigue, or circulatory symptoms. The cohort study revealed no increased risk among HPV vaccine-exposed girls, with incidence rate ratios close to 1.0 for abdominal pain, nonspecific pain, headache, hypotension/syncope, tachycardia (including the postural orthostatic tachycardia syndrome), and malaise/fatigue (including the chronic fatigue syndrome). In the SCCS analyses, we observed no association between HPV vaccination and subsequent symptoms. In time trend analyses, we observed a steady increase in these hospital records in both girls and (HPV-unvaccinated) boys, with no relation to the 2009 HPV vaccine introduction in Denmark's vaccination program. This study with nationwide coverage showed no evidence of a causal link between HPV vaccination and diffuse autonomic symptoms leading to hospital contact.