Skip to main content
SpringerLink
Log in

Thromboembolic Events in Women Exposed to Hormonal Contraception or Cyproterone Acetate in 2012: A Cross-Sectional Observational Study in 30 French Public Hospitals

  • Original Research Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Background

In the context of the European reassessment of the benefit–risk balance of hormonal contraceptives, French data about thromboembolic events were requested.

Objective

The aim of this study was to determine the number of patients exposed to hormonal contraception or cyproterone acetate among hospitalized females diagnosed with a thromboembolic event in 2012, to retrospectively analyze specific risk factors of venous and arterial thromboembolism and to assess the magnitude of the under-reporting of such events to the national pharmacovigilance system.

Methods

This cross-sectional study included 15- to 49-year-old women with pulmonary embolism, venous cerebral thrombosis, ischemic stroke, or myocardial infarction, hospitalized in 2012, and identified within the computerized hospital databases of 30 French teaching hospitals.

Results

Among the 2,966 cases identified, 803 (27.1 %) patients had been exposed to a hormonal contraceptive (747) or to cyproterone acetate (56). Among these, there were 452 venous thromboembolic events (VTEs) and 351 arterial thromboembolic events (ATEs). Age ≥40 years and personal thrombophilia diagnosed after the event were the main VTE risk factors, while current smoking and age ≥40 years were the main ATE risk factors. The mean number of associated risk factors was significantly lower for VTE than for ATE (1.1 vs 2.3). The proportion of cases with no risk factors was higher for third- and fourth-generation than for first- and second-generation combined oral contraceptives. Overall, the under-reporting rate was 92.5 % (95 % CI 70.0–97.3).

Conclusion

This study highlighted the need to strengthen the knowledge of patients and health professionals about thromboembolic risk factors at the first prescription and renewal of hormonal contraceptives.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

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

    Google Scholar 

  2. ANSM. Quelle est la situation actuelle des pilules oestroprogestatives en France? http://ansm.sante.fr/Dossiers/Pilules-estroprogestatives-et-risque-thrombotique/.

  3. Lidegaard Ø, Edstrom B, Kreiner B. Oral contraceptives and venous thromboembolism: a five-year national case-control study. Contraception. 2002;65:187–96.

    Article  CAS  PubMed  Google Scholar 

  4. Jick SS, Kaye JA, Russmann S, et al. Risk of nonfatal venous thromboembolism with oral contraceptives containing norgestimate or desogestrel compared with oral contraceptives containing levonorgestrel. Contraception. 2006;73:566–70.

    Article  CAS  PubMed  Google Scholar 

  5. van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJ, Rosendaal FR. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ. 2009;339:b2921.

  6. Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ. 2009;339:b2890.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Lidegaard Ø, Nielsen LH, Skovlund CW, Skjeldestad FE, Løkkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ. 2011;343:d6423.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Jick SS, Hernandez RK. Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data. BMJ. 2011;342:d2151.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Parkin L, Sharples K, Hernandez RK, Jick SS. Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study based on UK General Practice Research Database. BMJ. 2011;342:d2139.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Gronich N, Lavi I, Rennert G. Higher risk of venous thrombosis associated with drospirenone-containing oral contraceptives: a population-based cohort study. CMAJ. 2011;183:E1319–25.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Plu-Bureau G, Maitrot-Mantelet L, Hugon-Rodin J, Canonico M. Hormonal contraceptives and venous thromboembolism: an epidemiological update. Best Pract Res Clin Endocrinol Metab. 2013;27:25–34.

    Article  CAS  PubMed  Google Scholar 

  12. FDA. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular disease endpoints, final report 111022v2. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf. Accessed 4 Oct 2013.

  13. European Medicines Agency. Safety monitoring of medicines. Combined hormonal contraceptives. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Combined_hormonal_contraceptives/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500151959.pdf. Accessed 30 Oct 2013.

  14. Lidegaard Ø, Løkkegaard E, Jensen A, Skovlund CW, Keiding N. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med. 2012;366:2257–66.

    Article  CAS  PubMed  Google Scholar 

  15. Plu-Bureau G, Hugon-Rodin J, Maitrot-Mantelet L, Canonico M. Hormonal contraceptives and arterial disease: an epidemiological update. Best Pract Res Clin Endocrinol Metab. 2013;27:35–45.

    Article  CAS  PubMed  Google Scholar 

  16. Stegeman BH, de Bastos M, Rosendaal FR, van Hylckama Vlieg A, Helmerhorst FM, Stijnen T, et al. Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis. BMJ. 2013;347:f5298.

    Google Scholar 

  17. Gourdy P, Bachelot A, Catteau-Jonard S, Chabbert-Buffet N, Christin-Maître S, Conard J, et al. Hormonal contraception in women at risk of vascular and metabolic disorders: guidelines of the French Society of Endocrinology. Ann Endocrinol (Paris). 2012;73:469–87.

    Article  CAS  Google Scholar 

  18. Holst AG, Jensen G, Prescott E. Risk factors for venous thromboembolism: results from the Copenhagen city heart study. Circulation. 2010;121:1896–903.

    Article  PubMed  Google Scholar 

  19. Beck F, Guignard R, Richard JB, Wilquin JL, Peretti-Watel P. Increasing trends in smoking in France: main results of the French Health Barometer, France 2010. BEH. Special issue—World No Tobacco Day, 2011;20–21:230–33.

  20. Department of Reproductive Health and Research, World Health Organization. Medical eligibility criteria for contraceptive use. 4th ed. 2009. A WHO family planning cornerstone. Geneva: World Health Organization, 2010. http://whqlibdoc.who.int/publications/2010/9789241563888_eng.pdf. Accessed 4 Oct 2013.

  21. Centers for Disease Control. US. Medical Eligibility Criteria for Contraceptive Use, 2010: adapted from the World Health Organization Medical Eligibility Criteria for Contraceptive Use, 4th ed. MMWR Recomm Rep 2010 June 18;59 (RR-4), p. 1–86.

  22. Cnamts-DSES-DESP. [Combined oral contraceptives and risk of pulmonary embolism, stroke and myocardial infarction: a cohort study of 4 million French women]. http://ansm.sante.fr/Dossiers-thematiques/Pilules-estroprogestatives-et-risque-thrombotique/Quelles-sont-les-donnees-sur-le-risque-thromboembolique-veineux-issues-des-etudes-de-pharmacoepidemiologie/(offset)/5. Accessed 4 Oct 2013.

  23. Hazell L, Shakir SA. Under-reporting of adverse drug reactions: a systematic review. Drug Saf. 2006;29:385–96.

    Article  PubMed  Google Scholar 

  24. ANSM. Quelle est la situation actuelle des pilules estroprogestatives en France? http://ansm.sante.fr/Dossiers-thematiques/Pilules-estroprogestatives-et-risque-thrombotique/Quelle-est-la-situation-actuelle-des-pilules-estroprogestatives-en-France/(offset)/1. Accessed 4 Oct 2013.

  25. Dahlbäck B. Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood. 2008;112:19–27.

    Article  PubMed  Google Scholar 

  26. Dykes AC, Walker ID, McMahon AD, Islam SI, Tait RC. A study of Protein S antigen levels in 3788 healthy volunteers: influence of age, sex and hormone use, and estimate for prevalence of deficiency state. Br J Haematol. 2001;113:636–41.

    Article  CAS  PubMed  Google Scholar 

  27. HAS. Stratégies de choix des méthodes contraceptives chez la femme. Recommandations pour la pratique clinique. Service des recommandations professionnelles de l’Anaes. Décembre 2004. http://www.choisirsacontraception.fr/pdf/contraception_recommandations_has.pdf. Accessed 4 Oct 2013.

  28. Contraceptifs oraux combinés et risque de thrombose veineuse : prescription des pilules de 2e génération contenant du lévonorgestrel en première intention—Point d’information. Octobre 2012. http://ansm.sante.fr/content/download/43790/568981/version/2/file/pi-121001-COC.pdf.

  29. Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks—CHMP endorses PRAC recommendation. November 2013. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/11/WC500155455.pdf.

Download references

Acknowledgments

Collaborators from the French Network of Pharmacovigilance Centres:

Guillaume Drablier (Angers), Christian Riché (Brest), Marie Blanche Valnet Rabier (Besançon), Hélène Géniaux (Bordeaux), Marie Zenut (Clermont-Ferrand), Sophie Fedrizzi (Caen), Edith Schir (Grenoble), Marine Auffret (Lille), Marie Laure Laroche (Limoges), Franck Rouby (Marseille), Véronique Pinzani (Montpellier), Bernadette Baldin (Nice), Anne Lise Ruellan (Nantes), Dominique Swiegot (Nancy), Sylviane HOROWICZ (Paris), Christine Le Beller (Paris), Laure Thomas (Creteil), Bénédicte Lebrun-Vignes (Paris), Joelle Michot (Paris), Caroline Pecriaux (Paris), Malak Abou Taam (Reims), Marie-Noëlle Osmont (Rennes), Aude Lambert (Strasbourg), Isabelle Lacroix (Toulouse), Annie Pierre Jonville-Bera (Tours).

Collaborators from the Medical Record Units of the participating hospitals:

Elisabeth Lewandowski (Amiens), Nathalie Andreu (Angers), Jean Michel Cauvin (Brest), Marie-Claude Antraigue (Besançon), Aude Kostrzewa (Bordeaux), Emeline Duroy (Caen), Bruno Aublet-Cuvelier (Clermont-Ferrand) Hervé Aubé (Dijon), Jérome Fauconnier (Grenoble), Amelie Bruandet (Lille), Sandra Yonnet (Limoges), Sandrine Couray-Targe (Lyon), Vanessa Pauly (Marseille), Philippe Mailhe (Montpellier), Yves Gendreike (Nice), Nathalie Surer (Nantes), Haritina El Adssi (Nancy), Pavla Vicente (Paris), Paul Avillach (Paris), François Hemery (Creteil), Pierre Rufat (Paris), Jeanne Marty (Paris), Jerome Frenkiel (Paris), Danièle Blanc (Reims), Loetizia Froment (Rouen), Annie Fresnel (Rennes), Béatrice Trombert-Paviot (St Etienne), Hassina Lefevre (Strasbourg), Laurent Bieler (Toulouse), Florence Fourquet (Tours).

Contributorship statement

MG designed data collection tools, collected, cleaned and analyzed the data, drafted and revised the draft paper.

AG designed data collection tools, collected, cleaned and analyzed the data, drafted and revised the draft paper.

MNB collected and analyzed the data, drafted and revised the draft paper.

NM collected and analyzed the data, drafted and revised the draft paper.

VG collected and analyzed the data, drafted and revised the draft paper.

AD designed data collection tools.

GMS collected and analyzed the data, drafted and revised the draft paper.

NP initiated the collaborative project, designed data collection tools, collected, cleaned and analyzed the data, drafted and revised the draft paper.

All members of the Regional Pharmacovigilance Centres and all members of the Medical Record Units of the participating hospitals collected the data.

Funding and Conflicts of Interest

No sources of funding were used to conduct this study or prepare this manuscript. Mathilde Gourbil, Aurélie Grandvuillemin, Marie-Noëlle Beyens, Nathalie Massy, Valérie Gras, Andréa D’Amico, Ghada Miremont-Salamé and Nadine Petitpain have no conflicts of interest that are directly relevant to the content of this study.

Author information

Authors and Affiliations

  1. Regional Pharmacovigilance Centre, University Hospital, 69424, Lyon, France

    Mathilde Gourbil & Andréa D’Amico

  2. Regional Pharmacovigilance Centre, University Hospital, 21079, Dijon, France

    Aurélie Grandvuillemin

  3. Regional Pharmacovigilance Centre, University Hospital, Hôpital de Bellevue, 42055, Saint-Étienne, France

    Marie-Noëlle Beyens

  4. Regional Pharmacovigilance Centre, University Hospital, Hôpital Charles Nicolle, 76031, Rouen, France

    Nathalie Massy

  5. Regional Pharmacovigilance Centre, University Hospital Sud, 80054, Amiens, France

    Valérie Gras

  6. Regional Pharmacovigilance Centre, University Hospital, Hôpital Pellegrin, 33076, Bordeaux, France

    Ghada Miremont-Salamé

  7. Regional Pharmacovigilance Centre, University Hospital of Nancy, 29 av de Lattre de Tassigny, 54035, Nancy, France

    Nadine Petitpain

Authors
  1. Mathilde Gourbil
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aurélie Grandvuillemin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marie-Noëlle Beyens
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nathalie Massy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Valérie Gras
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andréa D’Amico
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ghada Miremont-Salamé
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nadine Petitpain
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

The French Network of Regional Pharmacovigilance Centres

Corresponding author

Correspondence to Nadine Petitpain.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gourbil, M., Grandvuillemin, A., Beyens, MN. et al. Thromboembolic Events in Women Exposed to Hormonal Contraception or Cyproterone Acetate in 2012: A Cross-Sectional Observational Study in 30 French Public Hospitals. Drug Saf 37, 269–282 (2014). https://doi.org/10.1007/s40264-014-0149-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40264-014-0149-8

Keywords

Search

Navigation