Skip to main content
Log in

Fatal Venous Thromboembolism Associated with Different Combined Oral Contraceptives

A Study of Incidences and Potential Biases in Spontaneous Reporting

Drug Safety Aims and scope Submit manuscript

Abstract

Background: Fatal venous thromboembolism (VTE) is a rare complication of combined oral contraceptive (COC) treatment. This study aims to determine incidences of fatal VTE in relation to the type of COC and the percentage of cases reported to the Swedish Adverse Drug Reactions Advisory Committee (SADRAC). A further aim is to compare the characteristics of reported and not reported cases.

Methods: This retrospective study is a separate analysis using data from a larger study that included women aged 15–44 years between 1990 and 1999 with VTE coded as the underlying or contributory cause of death in the Swedish Cause of Death Register. COC use within 2 months of the date of symptom onset or death was identified in 28 cases. Sales data were obtained from the National Corporation of Swedish Pharmacies. Reported cases were identified in the SADRAC database.

Results: After excluding two cases where the type of COC was unknown, the crude incidences of fatal VTE were 5.1 (95% CI 2.3, 9.6), 8.6 (95% CI 4.3, 15.4) and 9.1 (95% CI 3.3, 19.8) cases per million women per year for levonorgestrel-, desogestrel- and norethisterone-containing COCs, respectively. Age-adjusted incidences were approximately twice as high for desogestrel- and norethisterone-containing COCs compared with levonorgestrel-containing COCs, although differences were not statistically significant. Thirty-six percent of cases were reported. Reporting was positively associated with information in medical records relevant to the VTE diagnosis that the patient was a COC user and was significantly higher in northern Sweden.

Conclusion: Results from this study support a higher incidence of fatal VTE with desogestrel-containing COCs than with levonorgestrel-containing COCs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Fig. 1
Table II
Table III
Table IV
Table V
Table VI

Similar content being viewed by others

References

  1. Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353(9159): 1167–73

    Article  PubMed  CAS  Google Scholar 

  2. Turpie AGG, Chin BSP, Lip GYH. ABC of antithrombotic therapy: venous thromboembolism. Pathophysiology, clinical features and prevention. BMJ 2002; 325: 887–90

    Article  PubMed  Google Scholar 

  3. Hägg S, Spigset O. Antipsychotic-induced venous thromboembolism: a review of the evidence. CNS Drugs 2002; 16: 765–76

    Article  PubMed  Google Scholar 

  4. Baglin T. Is smoking a risk factor for venous thromboembolism? Thromb Haemost 2002; 88: 881–2

    PubMed  Google Scholar 

  5. Tosetto A, Frezzato M, Rodeghiero F. Prevalence and risk factors of non-fatal venous thromboembolism in the active population of the VITA project. J Thromb Haemost 2003; 1: 1724–9

    Article  PubMed  CAS  Google Scholar 

  6. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 1995; 346 (8990): 1582–8

    Google Scholar 

  7. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. Lancet 1995; 346 (8990): 1575–82

    Google Scholar 

  8. Parkin L, Skegg DC, Wilson M, et al. Oral contraceptives and fatal pulmonary embolism. Lancet 2000; 355(9221): 2133–4

    Article  PubMed  CAS  Google Scholar 

  9. Jick H, Jick SS, Gurewich V, et al. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995; 346(8990): 1589–93

    Article  PubMed  CAS  Google Scholar 

  10. Farmer RD, Lawrenson RA, Todd JC, et al. A comparison of the risks of venous thromboembolic disease in association with different combined oral contraceptives. Br J Clin Pharmacol 2000; 49(6): 580–90

    Article  PubMed  CAS  Google Scholar 

  11. Nightingale AL, Lawrenson RA, Simpson EL, et al. The effects of age, body mass index, smoking and general health on the risk of venous thromboembolism in users of combined oral contraceptives. Eur J Contracept Reprod Health Care 2000; 5: 265–74

    Article  PubMed  CAS  Google Scholar 

  12. Samuelsson E, Hagg S. Incidence of venous thromboembolism in young Swedish women and possibly preventable cases among combined oral contraceptive users. Acta Obstet Gynecol Scand 2004; 83: 674–81

    PubMed  Google Scholar 

  13. Jick H, Kaye JA, Vasilakis-Scaramozza C, et al. Risk of venous thromboembolism among users of third generation oral contraceptives compared with users of oral contraceptives with levonorgestrel before and after 1995: cohort and case control analysis. BMJ 2000; 321: 1190–5

    Article  PubMed  CAS  Google Scholar 

  14. Farmer RD, Lawrenson RA, Thompson CR, et al. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 1997; 349: 83–8

    Article  PubMed  CAS  Google Scholar 

  15. Hedenmalm K, Samuelsson E, Spigset O. Pulmonary embolism associated with combined oral contraceptives: reporting incidences and potential risk factors for a fatal outcome. Acta Obstet Gynecol Scand 2004; 83: 576–85

    PubMed  Google Scholar 

  16. Samuelsson E, Hedenmalm K, Persson I. Mortality from venous thromboembolism in young Swedish women and its relation to pregnancy and use of oral contraceptives: an approach to specifying rates. Eur J Epidemiol 2005; 20(6): 509–16

    Article  PubMed  Google Scholar 

  17. Fotherby K. A metabolic assessment of different oral contraceptives. J Obstet Gynaecol 1983; 3: S77–82

    Article  Google Scholar 

  18. Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. BMJ 2001; 323: 119–20

    Article  Google Scholar 

  19. Alhenc-Gelas M, Plu-Bureau G, Guillonneau S, et al. Impact of progestagens on activated protein C (APC) resistance among users of oral contraceptives. J Thromb Haemost 2004; 2: 1594–600

    Article  PubMed  CAS  Google Scholar 

  20. Van Rooijen M, Silveira A, Hamsten A, et al. Sex hormonebinding globulin: a surrogate marker for the prothrombotic effects of combined oral contraceptives. Am J Obstet Gynecol 2004; 190: 332–7

    Article  PubMed  Google Scholar 

  21. Odlind V, Milsom I, Persson I, et al. Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills? A discussion based on recent recommendations from the European agency for evaluation of medicinal products regarding third generation oral contraceptive pills. Acta Obstet Gynecol Scand 2002; 81: 482–90

    PubMed  Google Scholar 

  22. Samuelsson E, Hägg S, Bäckstrom M, et al. Thrombosis caused by oral contraceptives: underreporting to the adverse effects registry [in Swedish]. Läkartidningen 1996; 93(37): 3117–24

    PubMed  CAS  Google Scholar 

  23. Skjeldestad FE, Amundsen T, Høibraaten E. Reporting of adverse drug reactions to the Norwegian Drug Control Agency [in Norwegian]. Tidsskr Nor Laegeforen 2000; 120(3): 336–8

    PubMed  CAS  Google Scholar 

  24. Moride Y, Haramburu F, Requejo AA, et al. Under-reporting of adverse drug reactions in general practice. Br J Clin Pharmacol 1997; 43(2): 177–81

    Article  PubMed  CAS  Google Scholar 

  25. Alvarez-Requejo A, Carvajal A, Begaud B, et al. Under-reporting of adverse drug reactions: estimate based on a spontaneous reporting scheme and a sentinel system. Eur J Clin Pharmacol 1998; 54(6): 483–8

    Article  PubMed  CAS  Google Scholar 

  26. Belton KJ. Attitude survey of adverse drug-reaction reporting by health care professionals across the European Union. The European Pharmacovigilance Research Group. Eur J Clin Pharmacol 1997; 52(6): 423–7

    Article  PubMed  CAS  Google Scholar 

  27. Inman WHW, Weber JCP. The United Kingdom. In: Inman WHW, editor. Monitoring for drug safety. 2nd ed. Lancaster: MTP Press Ltd, 1986: 13–48

    Google Scholar 

  28. Bäckstrom M, Mjörndal T, Dahlqvist R, et al. Attitudes to reporting adverse drug reactions in northern Sweden. Eur J Clin Pharmacol 2000; 56 (9–10): 729–32

    Google Scholar 

  29. Ekbom Y, Hedenmalm K, Dalin L, et al. Reporting of sideeffects: a system in need of improvement. Reporting of a physician questionnaire [in Swedish]. Lakartidningen 2002; 99(34): 3290–5

    PubMed  Google Scholar 

  30. Bäckstrom M, Dahlqvist R, Mjörndal T, et al. A regional center for reporting adverse drug reactions in Umea: prompt handling results in quick feedback [in Swedish]. Lakartidningen 1995; 92(3): 148–50

    PubMed  Google Scholar 

Download references

Acknowledgements

The study was supported by grants from the County Council of Jämtland, the Visare Norr (a research venture involving four county councils) and the federation of Swedish County Councils. The authors have no conflicts of interest that are directly relevant to the contents of this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Karin Hedenmalm.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hedenmalm, K., Samuelsson, E. Fatal Venous Thromboembolism Associated with Different Combined Oral Contraceptives. Drug-Safety 28, 907–916 (2005). https://doi.org/10.2165/00002018-200528100-00007

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-200528100-00007

Keywords

Navigation