Research
Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study
Cite this as: BMJ 2013;347:f5906
Abstract
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.
Introduction
Since the regulatory approval of first the quadrivalent human papillomavirus (qHPV) vaccine in 2006 and later the bivalent HPV vaccine, as of 2011 about 120 million doses have been distributed worldwide.1 The introduction of a new vaccine invariably puts focus not only on its effectiveness but also on its safety. From experience we know that adverse events, with onset shortly after the receipt of a vaccine, especially if these events are serious (for example, chronic immune mediated and neurological diseases), tend to be attributed to this exposure by pure temporal association.2 3 The likelihood of adverse events occurring in temporal association with exposure to vaccine will increase proportionally with vaccine coverage as a new vaccine is introduced. Concern about vaccine related adverse events has been identified as an important barrier to vaccination and one of the reasons for low HPV vaccine uptake in some settings.4 5 Concerns about autoimmune and neurological conditions being triggered by HPV vaccination may be fueled further by findings related to other vaccines, such as the reported association between adjuvanted influenza A(H1N1)pdm09 vaccine and narcolepsy in Sweden and Finland6 7 as well as a small but significantly increased risk of Guillain-Barré syndrome after influenza A(H1N1)pdm09 vaccination, according to a recent meta-analysis.8 Several potential mechanisms by which vaccines could induce or stimulate autoimmunity have been suggested, including molecular mimicry and bystander activation.2 Consequently, to acquire the best possible evidence of safety, adverse events of newly introduced vaccines such as the HPV vaccines need to be monitored continuously.
Most adverse events occurring after HPV vaccination of adolescent girls have been mild and temporary, such as fever, headache, and injection site reactions.9 10 Pooled analyses of clinical trials have involved almost 12 000 participants exposed to the qHPV vaccine11 and more than 16 000 participants exposed to the bivalent HPV vaccine.12 Although these studies did not identify an increased risk of chronic or autoimmune diseases overall, they were not large enough to study individual conditions. An analysis of 12 424 reports to the Vaccine Adverse Event Reporting System, among which 772 described serious events, identified disproportionate reporting of syncope and venous thromboembolic events but not other events, such as autoimmune conditions.13 However, analysis of data reported to passive surveillance can only identify potential risk signals and can neither estimate the risk relative to an unexposed population nor exclude risks with certainty. Sequential analyses of Vaccine Safety Datalink observational data within seven managed care organisations in the United States (600 558 qHPV vaccine doses) found no increased risk of eight prespecified outcomes, although a non-significantly increased relative risk of venous thromboembolism was observed.14 A cohort study of 189 629 women in two managed care organisations in California explored the risk of 16 autoimmune events and found a significantly increased rate ratio for Hashimoto’s thyroiditis, although further assessment revealed no temporal relation or biological plausibility to support a true association.15 In this same cohort, no new safety concerns emerged when the risk of visits to an emergency department or admissions to hospital were evaluated for a wide range of health outcomes.16
Sweden and Denmark keep population based healthcare registers and thereby have unique opportunities to address the safety of HPV vaccination. In Denmark, we have previously described the incidence rates of anticipated immune mediated adverse events among adolescent girls in the period before the introduction of HPV vaccination.17 In the present study we identified potential safety signals after the introduction of qHPV vaccination in Denmark and Sweden by comparing incidence rates of several autoimmune, neurological, and venous thromboembolic adverse events between adolescent girls exposed and not exposed to the qHPV vaccine.
Methods
Study population
This register based cohort study of serious adverse events associated with the qHPV vaccine was based on individual level data from all 10 to 17 year old adolescent girls in Denmark and Sweden, between 1 October 2006 and 31 December 2010. Every resident in both Denmark and Sweden has a unique personal identification number enabling individual level linkage between multiple registers.18 To define the study cohort in Sweden, we obtained information on birth date and date of death from the total population register and death register, respectively, from Statistics Sweden. To define the study cohort in Denmark, we used the Civil Registration System, which contains daily updated information on vital and demographic variables, such as birth date and place, and loss to follow-up due to emigration or disappearance from the registers, and death.19
Vaccination
The qHPV vaccine (Gardasil; Sanofi Pasteur MSD SNC, Lyon, France (in the United States: Merck, Whitehouse Station, NJ)) was marketed in Europe on 20 September 2006. In Sweden, the qHPV vaccine has been subsidised for 13-17 year old adolescent girls since May 2007 (inclusion of HPV vaccination in the national vaccination programme for 10-12 year old girls was initially planned for January 2010 but was postponed to January 2012 and then coupled with catch-up vaccination of 13-17 year old adolescent girls). In Denmark, the qHPV vaccine has been included in the national vaccination programme since January 2009 for 12 year old girls, with catch-up vaccination of 13-15 year olds from October 2008.
We obtained information on exposure to HPV vaccine in Denmark from the childhood vaccination database at Statens Serum Institut.20 This database is continually updated from National Health Insurance data obtained from the National Board of Health. General practitioners in Denmark carry out all immunisations in the childhood vaccination programme and are reimbursed for reporting each instance to the National Health Insurance. Reimbursement takes place only after the general practitioner has submitted a form that details the vaccine, the date it was administered, and the personal identification number of the recipient. Therefore the database is thought to be close to complete for vaccines administered through the national programme. Because HPV vaccination was also available outside the national programme in the study period, we retrieved additional vaccination data from the national prescription register, which contains individual level information on all prescriptions filled at all Danish pharmacies. This includes the personal identification number of the recipient, the date the prescription was dispensed, and the Anatomic Therapeutic Chemical (ATC) code.21 The ATC code used to identify the qHPV vaccine was J07BM01. In Sweden, correspondingly, we obtained information on vaccination status from Svevac and the drug prescription register. Svevac is a national HPV vaccination register, established in 2006 and held by the Swedish Institute for Communicable Disease. Healthcare staff who administer the vaccines report to Svevac on a voluntary basis, and the register has an estimated completeness of about 80%.22 The drug prescription register contains all prescription drugs dispensed at pharmacies in Sweden since 1 July 2005.23 Adolescent girls aged between 13 and 17 years received subsidised HPV vaccination and vaccination had to be prescribed and expedited at a pharmacy, thereby generating a register entry in the drug prescription register. The register is held by the National Board of Health and Welfare. For adolescent girls aged 13-17 years it is assumed that almost 100% of administered HPV vaccine doses are registered in the drug prescription register.
Outcomes
We identified data on predefined adverse events from the national patient registers in both countries using ICD-10 codes (international classification of diseases, 10th revision). The patient registers include nationwide individual level information on dates of hospital contact and doctor assigned diagnoses according to the international classification of diseases.24 We did not have information on outcomes from primary healthcare. The Danish patient register was established in 1977, has included both inpatients and outpatients since 1994, and has been using ICD-10 codes since 1995, whereas the Swedish patient register has had nationwide coverage since 1987, has included both inpatients and outpatients since 2001, and has used ICD-10 codes since 1997.25 We predefined several serious adverse outcome events, as identified from records of inpatient admissions and hospital outpatient and emergency department visits, based on our earlier study of autoimmune events,17 and we added several neurological events. We also included venous thromboembolism because it represents a potential adverse event.13 14 The included outcomes are all well defined diseases. In total, we assessed 53 outcomes (see supplementary table 1 for all included outcome events, with ICD-10 codes).
Covariate information
From Statistics Denmark and Statistics Sweden we obtained data on parental educational level, country of birth, and socioeconomic status. We identified the parents from the Danish Civil Registration System and Swedish multigeneration register.
Statistical analyses
Adolescent girls were followed from age 10 years or 1 October 2006, whichever came latest, and until either the occurrence of an adverse event, receipt of bivalent HPV vaccine (Cervarix, GlaxoSmithKline Biologicals; Rixensart, Belgium; ATC code J07BM02), death, disappearance from the registers, emigration (this information was only available for Denmark), 18th birthday, or end of follow-up (31 December 2010). We aggregated the resulting person years of follow-up with counts of outcome events according to qHPV vaccine exposure status and analysed these using Poisson regression (log-linear regression of the counts using the logarithm of follow-up time as offset). This produced incidence rate ratios according to qHPV exposure status. Exposure to the qHPV vaccine was a time varying variable; thus adolescent girls could contribute person time to the study first as unvaccinated and later as vaccinated, but once vaccinated the girls could not be put into the unvaccinated category again. All individual outcomes were treated as separate analyses, and for each specific analysis girls were eligible only if free from the outcome event before entry to the cohort. Estimates were adjusted for country, age in two year categories, calendar year, parental educational level (highest attained level of either parent classified as: primary school (nine years) or shorter; secondary school (12 years); short tertiary education; and medium or long tertiary education), parental country of birth (categories: both parents, one parent, or no parent born in Scandinavia), and paternal socioeconomic status (categories: employment with basic, unknown, or no qualification; employment with medium level or high level qualifications; self employed; and not in labour market).
For all autoimmune and neurological outcomes, we defined the period at risk as 180 days after exposure to vaccine. This period was chosen to allow for the insidious onset of the diseases studied and because diagnostic investigations may take time; in a recent study of autoimmune outcomes after qHPV vaccination, the median time between first symptoms and diagnosis was 23 days (interquartile range 2-59 days).15 26 For venous thromboembolism, the period at risk was 90 days after vaccination. This was regarded as the maximal period where an acute event could be plausibly related to vaccination; furthermore, the mean time between vaccination and diagnosis of thromboembolism among cases reported to the Vaccine Adverse Event Reporting System was 42 days.13
Because we acquired data on vaccine exposure from two sources that were partly overlapping—that is, some of the girls had both filled prescriptions and were registered in one of the vaccination databases—we applied an algorithm to harmonise the data and define dates of vaccination. Essentially this algorithm removed double data entries and doses appearing beyond the three dose schedule. Furthermore, on the basis of data from girls with both filled prescriptions and register entries in vaccination databases, it was established that the median lag between the dispensing of a prescription and the date of vaccination as registered in the vaccination databases was two days. Consequently, for vaccine doses that were defined by prescriptions alone, the date of exposure was defined as the date of filling the prescription plus two days.
As the recommended qHPV vaccine schedule includes three doses given at 0, 2, and 6 months, any girl could contribute up to three doses in the analyses; we counted exposed person time from the date the vaccine was administered, and each dose contributed up to 180 days (autoimmune and neurological events) of follow-up or up to 90 days (venous thromboembolism) of follow-up (fig 1⇓). We used SAS statistical software version 9.3 (SAS Institute, Cary, NC).
Fig 1 Periods at risk for autoimmune and neurological events in adolescent girls after exposure to quadrivalent human papillomavirus (qHPV) vaccine. For venous thromboembolism, each period at risk was up to 90 days
Analytical strategy
Given that a large number of serious adverse events were assessed and consequently there was a high probability of chance findings, we used the following predefined criteria for the analysis of data. As the first criterion, and in the interest of obtaining relatively reliable rate ratios, for any further assessment to take place we considered only outcomes with at least five vaccine exposed cases during the predefined period at risk. To be regarded as a safety signal, the rate ratio for an outcome with at least five vaccine exposed cases had to be significantly increased (lower bound of 95% confidence interval >1.0). We regarded three criteria as signal strengthening: analysis based on 20 or more vaccine exposed cases (reliability of analysis); a rate ratio of 3.0 or more (strength of association); and significantly increased rate ratios in both countries when analysed separately (consistency). For outcomes where the rate ratio was significantly increased, we additionally assessed clustering of events in time by plotting cases according to time since exposure to the vaccine and estimated rate ratios for a risk period that started on day 181.
Results
Cohort
The study cohort included 997 585 girls of whom 296 826 (29.8%) received at least one dose of the qHPV vaccine (table 1⇓). Among the vaccinated girls, 238 608 (80.4% of vaccinated girls and 23.9% of total study cohort) received the second dose and 160 986 (54.2% of vaccinated girls and 16.1% of total study cohort) received the third. Overall, 696 420 qHPV vaccine doses were administered. During follow-up, 1322 girls received the bivalent HPV vaccine and hence were censored.
Artikeln finns i sin helhet här:
http://www.bmj.com/content/347/bmj.f5906?sid=0ff98b1a-ce3b-4daf-8a53-755d1548b72a
Är det någon mer än jag som tycker att cohort studier är fantastiska. Sverige har ett vaccinregister, det finns tillgång till journaler och här kan forskarna gå igenom dokumentationen för att via dem göra vetenskapliga bedömningar för att sedan kunna kalla det för evidensbaserat.....
Vi skall inte förglömma dokumentationsproblematiken som vi har inom vården. Ett system i en kommun kan inte kommunicera med ett annat. Många vårdcentralen klagar över hur dåligt de nyinköpta datasystemen är och att de är svårarbetade.... hur mycket faller mellan stolarna..... hur många har blivit hemsända med uppmaningen..... ta en panodil så känner du dig snart bättre.
Det finns massor av cohort studier gällande Gardasil men jag har inte hittat en enda obduktionsstudie som förklarar vad man letat efter, eller vad man funnit...... saknas informationen eller vill man inte delge den?
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