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On the Association between Human Papillomavirus Vaccine and Primary Ovarian Failure

Dear Sir, We have read the interesting series of case reports recently published by Colafrancesco et al. on your journal. The reports deal with the occurrence of primary ovarian failure occurring in three young girls few days after the vaccination with human papillomavirus vaccine. The reports by Colafrancesco et al., along with a previously reported case, rise an important concern in term of safety for this vaccine. Primary ovarian failure is estimated to affect 1/ 10,000 women under the age of 20 and etiology may include genetic mutations, autoimmune diseases, and environmental causes. However, in a significant amount of cases, no precise cause can be identified. Concerns about supposed adverse effects of vaccine occur regularly, especially after the implementation of a new vaccine in young healthy adolescent. Spontaneous reports of suspected drug reactions represent an important source of new information for monitoring the safety of a newly introduced vaccine, but many of these are simply a coincidence in time with the administration of the vaccine. To define further the association between primary ovarian failure and HPV vaccine, we carried out an analysis using the major national surveillance databases for adverse event following the administration of vaccines or drugs. In this analysis, we considered the adverse event following HPV vaccine coded as ‘premature ovarian failure’, ‘premature ovarian insufficient’, ‘premature menopause’, and ‘primary ovarian failure’. We retrieved four cases from the Vaccine Adverse Event Reporting System (VAERS) database, one case from the Australian database, and two cases from the European database of suspected adverse drug reaction reports. We assessed the reporting rates (RRs) of 0.065/ 1,000,000 doses for this adverse effect considering the number of quadrivalent HPV vaccine doses distributed in United States from June 1, 2006 through July 30, 2012 (46 million) and the VAERS domestic reports in the same time frame (three reports). A similar evaluation of qHPV vaccine doses (7 million of doses) and reports from the Australian TGA database yielded a RRs of 0.14/1,000,000 doses. We also carried out an evaluation of the number of hospital discharges with a diagnosis of premature ovarian failure (ICD-9 code 256.31) or other ovarian failures (ICD-9 code 256.39) using the United States National Inpatient Sample database (NIS). We did not observe any increase in the number of hospital discharge with these diagnoses in patients aged 1–17 years after the introduction of the HPV vaccine. Similarly, we did not observe significant increases in the number of hospital discharges retrieved from the children inpatient database for patients aged 15–17 before and after the introduction of this vaccine. The absence of a significant increase in primary ovarian failure in a population that has been largely exposed to the HPV vaccine, as well as the low number of reports to the regulatory agencies, argues against a causal relationship between the vaccine and this disease. Despite these observations, we cannot exclude that HPV vaccine had a role in the pathogenesis of the condition described by Colafrancesco et al., especially considering the possibility that a rare and unrecognized mutations acted as risk factor in these patients. As correctly stated by the authors, the fact that two of the three patients were blood relatives could indicate the presence of a rare risk factor capable of determining such adverse event following HPV vaccination. Further analysis is required to identify the presence of possible risk factors for this adverse event and define their prevalence among the population exposed to the HPV vaccine.