Human papillomavirus vaccination and all-cause morbidity in adolescent girls: a cohort study of absence from school due to illness.

BACKGROUND: A growing body of evidence supports the safety of the human papillomavirus (HPV) vaccines. However, concerns about autonomic dysfunction syndromes and non-specific symptoms continue to linger. These conditions are not easily captured by traditional diagnostic classification schemes and call for innovative approaches to the study of vaccine safety which take more general measures of all-cause morbidity into account. METHODS: Taking advantage of the unique Danish registers, including regional registration of absence from school, we conducted a cohort study of 14 068 adolescent Danish girls attending 5th through 9th grade in public schools in the municipality of Copenhagen during 1 August 2013-23 January 2018. We obtained time-varying HPV vaccination status and demographic information from nationwide registers. Using Poisson regression with random effects, we estimated rate ratios (RRs) of absence due to illness, comparing HPV-vaccinated girls with unvaccinated girls with adjustment for grade, season, calendar period, demographic factors and random effects at the individual, class and school levels. RESULTS: Our study included 6 206 188 school days with 213 221 days of absence from school due to illness (absence rate, 3.4%). Comparing absence rates due to illness in HPV-vaccinated and unvaccinated girls yielded an adjusted RR of 1.00 (95% confidence interval [CI], 0.98-1.03). CONCLUSIONS: Our study provides an important and novel contribution to HPV vaccine safety. Using absence from school records, we were able to address important safety concerns without relying on medical diagnoses. We conclude that HPV vaccination does not increase the risk of morbidity in any manner that manifests as absence from school due to illness.

Association between quadrivalent human papillomavirus vaccination and selected syndromes with autonomic dysfunction in Danish females: population based, self-controlled, case series analysis.

OBJECTIVE: To evaluate the association between quadrivalent human papillomavirus vaccination and syndromes with autonomic dysfunction, such as chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome. DESIGN: Population-based self-controlled case series. SETTING: Information on human papillomavirus vaccinations and selected syndromes with autonomic dysfunction (chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome) identified using ICD-10 (international classification of diseases, revision 10) diagnostic codes from Danish nationwide registers. PARTICIPANTS: 869 patients with autonomic dysfunction syndromes from a cohort of 1 375 737 Danish born female participants aged 10 to 44 years during 2007-16. MAIN OUTCOME MEASURES: Self-controlled case series rate ratios (95% confidence intervals) of the composite outcome of chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome, adjusted for age and season, comparing female participants vaccinated and unvaccinated with the quadrivalent human papillomavirus vaccine. Chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome were also considered separately in secondary analyses. RESULTS: During 10 581 902 person years of follow-up, 869 female participants with syndromes of autonomic dysfunction (136 with chronic fatigue syndrome, 535 with complex regional pain syndrome, and 198 with postural orthostatic tachycardia syndrome) were identified. Quadrivalent human papillomavirus vaccination did not statistically significantly increase the rate of a composite outcome of all syndromes with autonomic dysfunction in a 365 day risk period following vaccination (rate ratio 0.99, 95% confidence interval 0.74 to 1.32) or the rate of any individual syndrome in the risk period (chronic fatigue syndrome (0.38, 0.13 to 1.09), complex regional pain syndrome (1.31, 0.91 to 1.90), or postural orthostatic tachycardia syndrome (0.86, 0.48 to 1.54)). CONCLUSIONS: When vaccination is introduced, adverse events could occur in close temporal relation to the vaccine purely by chance. These results do not support a causal association between quadrivalent human papillomavirus vaccination and chronic fatigue syndrome, complex regional pain syndrome, or postural orthostatic tachycardia syndrome, either individually or as a composite outcome. An increased risk of up to 32% cannot be formally excluded, but the statistical power of the study suggests that a larger increase in the rate of any syndrome associated with vaccination is unlikely.