0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Research Letter |

Quadrivalent Human Papillomavirus Vaccine and the Risk of Venous Thromboembolism FREE

Nikolai Madrid Scheller, MB1; Björn Pasternak, MD, PhD1; Henrik Svanström, MSc1; Anders Hviid, DrMedSci1
[+] Author Affiliations
1Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
JAMA. 2014;312(2):187-188. doi:10.1001/jama.2014.2198.
Text Size: A A A
Published online

A potential association between quadrivalent human papillomavirus (HPV) vaccination and venous thromboembolism (VTE) has been reported in 2 postlicensure safety studies.1,2 An analysis of the Vaccine Adverse Event Reporting System database found disproportionately high reporting of VTE following vaccination,1 and a study using the Vaccine Safety Datalink reported a doubling of VTE risk.2

Safety concerns can compromise immunization programs to the detriment of public health, and timely evaluations of such concerns are essential.3 In a self-controlled case-series (SCCS) study, we evaluated the potential link between quadrivalent HPV vaccination and VTE.

Linking individual-level information from Danish national demographic and health care registers, described in detail elsewhere,4 we constructed the source population of all Danish women aged 10 through 44 years from October 1, 2006, through July 31, 2013. The study was approved by the Danish Data Protection Agency. Ethics approval was not required.

Information on vaccination, use of oral contraceptives, use of anticoagulants, and the outcome of a first hospital diagnosis of VTE not related to pregnancy, surgery, or cancer was obtained from Danish registers.4 Because vaccinated and unvaccinated women may differ in ways that are difficult to measure and control for, we used the SCCS method in a population of women with a first diagnosis of VTE.5,6 By taking advantage of within-person comparisons, the SCCS design eliminates confounding by time-independent factors.

Cases were followed up from 10 years of age or October 1, 2006, until emigration, death, 45 years of age, or July 31, 2013. Incidence ratios were derived by conditional Poisson regression (SAS version 9.2, SAS Institute Inc), comparing incidence rates of VTE during predefined risk periods after each vaccine dose with all other observed periods in each individual (control periods). The main risk period was defined as 1 to 42 days from vaccination and was divided into shorter periods for additional analyses (1-14, 15-28, and 29-42 days).

Our first analysis included all VTE cases, both those exposed and unexposed to the quadrivalent HPV vaccine. In the SCCS method, unexposed cases do not contribute to estimates of the association between outcome and exposure but can be included in age adjustment. Second, we performed an analysis including only cases with exposure to the quadrivalent HPV vaccine to ensure that results did not vary.

Third, to increase the validity of VTE diagnosis, we conducted an analysis including only cases receiving anticoagulants at least 4 weeks after diagnosis of VTE. Fourth, we conducted an analysis stratified according to the age groups of 10-24 and 25-44 years because the incidence of VTE varies among women between the ages of 10 and 44 years. Fifth, because oral contraceptives are known to increase the risk of VTE, an analysis with adjustment for oral contraceptive use as a time-dependent variable was included.

A 2-sided 95% confidence interval that did not overlap 1.0 and P < .05 were considered statistically significant.

From a source population of 1 613 798 women, including 500 345 (31%) who received the quadrivalent HPV vaccine, we identified 4375 incident cases of VTE (Figure). Of these, 889 women (20%) were vaccinated during the study period. There was no association between the quadrivalent HPV vaccine and VTE during the 42 days following vaccination (crude incidence rates, 0.126 and 0.159 events/person-year for risk and control periods, respectively; incidence ratio, 0.77 [95% CI, 0.53-1.11]; Table).

Place holder to copy figure label and caption
Figure.
Quadrivalent HPV Vaccine, Venous Thromboembolism, and Cases Included for Analysis
Graphic Jump Location
Table Graphic Jump LocationTable.  Quadrivalent Human Papillomavirus (HPV) Vaccine and Incidence Rate of Venous Thromboembolism

Similarly, no association between the quadrivalent HPV vaccine and VTE was observed in subgroup analyses by age, including only anticoagulant-treated cases, only exposed cases, or when adjusting for oral contraceptive use (Table).

Our results, which were consistent after adjustment for oral contraceptive use and in girls and young women as well as mid-adult women, do not provide support for an increased risk of VTE following quadrivalent HPV vaccination. Two previous studies reported a potential association but one was based on reports from a passive surveillance system1 and the other included few vaccinated cases, many with known risk factors for VTE.2

Limitations of our study include the potential for residual confounding by unmeasured time-varying factors and invalid diagnoses of VTE; however, an analysis restricted to VTE cases with anticoagulant treatment after diagnosis was consistent with our other analyses.

Section Editor: Jody W. Zylke, MD, Senior Editor.

Corresponding Author: Nikolai Madrid Scheller, MB, Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark (nmscheller@gmail.com).

Author Contributions: Mr Scheller had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Scheller.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Scheller, Svanström.

Study supervision: Pasternak, Svanström, Hviid.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Slade  BA, Leidel  L, Vellozzi  C,  et al.  Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA. 2009;302(7):750-757.
PubMed   |  Link to Article
Gee  J, Naleway  A, Shui  I,  et al.  Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink. Vaccine. 2011;29(46):8279-8284.
PubMed   |  Link to Article
Siegrist  CA.  Autoimmune diseases after adolescent or adult immunization: what should we expect? CMAJ. 2007;177(11):1352-1354.
PubMed   |  Link to Article
Arnheim-Dahlström  L, Pasternak  B, Svanström  H, Sparén  P, Hviid  A.  Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study. BMJ. 2013;347:f5906.
PubMed   |  Link to Article
Farrington  CP.  Relative incidence estimation from case series for vaccine safety evaluation. Biometrics. 1995;51(1):228-235.
PubMed   |  Link to Article
Whitaker  HJ, Farrington  CP, Spiessens  B, Musonda  P.  Tutorial in biostatistics: the self-controlled case series method. Stat Med. 2006;25(10):1768-1797.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure.
Quadrivalent HPV Vaccine, Venous Thromboembolism, and Cases Included for Analysis
Graphic Jump Location

Tables

Table Graphic Jump LocationTable.  Quadrivalent Human Papillomavirus (HPV) Vaccine and Incidence Rate of Venous Thromboembolism

References

Slade  BA, Leidel  L, Vellozzi  C,  et al.  Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA. 2009;302(7):750-757.
PubMed   |  Link to Article
Gee  J, Naleway  A, Shui  I,  et al.  Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink. Vaccine. 2011;29(46):8279-8284.
PubMed   |  Link to Article
Siegrist  CA.  Autoimmune diseases after adolescent or adult immunization: what should we expect? CMAJ. 2007;177(11):1352-1354.
PubMed   |  Link to Article
Arnheim-Dahlström  L, Pasternak  B, Svanström  H, Sparén  P, Hviid  A.  Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study. BMJ. 2013;347:f5906.
PubMed   |  Link to Article
Farrington  CP.  Relative incidence estimation from case series for vaccine safety evaluation. Biometrics. 1995;51(1):228-235.
PubMed   |  Link to Article
Whitaker  HJ, Farrington  CP, Spiessens  B, Musonda  P.  Tutorial in biostatistics: the self-controlled case series method. Stat Med. 2006;25(10):1768-1797.
PubMed   |  Link to Article
CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

3,870 Views
1 Citations

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Jobs
×