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Statement on combined hormonal contraceptives containing third- or fourth-generation progestogens or cyproterone acetate, and the associated risk of thromboembolism
  1. Johannes Bitzer,
  2. Jean-Jacques Amy1,
  3. Rob Beerthuizen2,
  4. Martin Birkhäuser3,
  5. Teresa Bombas4,
  6. Mitchell Creinin5,
  7. Philip D Darney6,
  8. Lisa Ferreira Vicente7,
  9. Kristina Gemzell-Danielsson8,
  10. Bruno Imthurn9,
  11. Jeffrey T Jensen10,
  12. Andrew M Kaunitz11,
  13. Ali Kubba12,
  14. Medard M Lech13,
  15. Diana Mansour14,
  16. Gabriele Merki15,
  17. Thomas Rabe16,
  18. Katarina Sedlecki17,
  19. David Serfaty18,
  20. Jacques Seydoux19,
  21. Lee P Shulman20,
  22. Regine Sitruk-Ware21,
  23. Sven O Skouby22,
  24. Anne Szarewski23,
  25. James Trussell24,
  26. Carolyn Westhoff25
  1. 1Jean-Jacques Amy, Brussels, Belgium
  2. 2Rob Beerthuizen, Winterswijk, The Netherlands
  3. 3Martin Birkhäuser, Basel, Switzerland
  4. 4Teresa Bombas, Coimbra, Portugal
  5. 5Mitchell Creinin, Sacramento, CA, USA
  6. 6Philip D Darney, San Francisco, CA, USA
  7. 7Lisa Ferreira Vicente, Lisbon, Portugal
  8. 8Kristina Gemzell-Danielsson, Stockholm, Sweden
  9. 9Bruno Imthurn, Zurich, Switzerland
  10. 10Jeffrey T Jensen, Portland, OR, USA
  11. 11Andrew M Kaunitz, Jacksonville, FL, USA
  12. 12Ali Kubba, London, UK
  13. 13Medard M Lech, Warsaw, Poland
  14. 14Diana Mansour, Newcastle upon Tyne, UK
  15. 15Gabriele Merki, Zurich, Switzerland
  16. 16Thomas Rabe, Heidelberg, Germany
  17. 17Katarina Sedlecki, Belgrade, Serbia
  18. 18David Serfaty, Paris, France
  19. 19Jacques Seydoux, Delémont, Switzerland
  20. 20Lee P Shulmann, Chicago, IL, USA
  21. 21Regine Sitruk-Ware, New York, NY, USA
  22. 22Sven O Skouby, Copenhagen, Denmark
  23. 23Anne Szarewski, London, UK
  24. 24James Trussell, Princeton, NY, USA
  25. 25Carolyn Westhoff, New York, NY, USA
  1. Correspondence to Professor Dr Johannes Bitzer, Chief Physician and Chairman Department of Obstetrics and Gynaecology, University Hospital Basel, Basel, Switzerland; Johannes.Bitzer{at}

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The controversy around the combined hormonal contraceptives (CHCs) of the so-called third (containing gestodene or desogestrel) and fourth generation (containing drospirenone, DRSP) has reached a highly emotional political dimension in which all those who are professionally responsible for women's health are involved: the national health authorities, the pharmaceutical companies, the professional organisations, the prescribers, the media and the public (i.e. the current or potential users of CHCs).

The – initially scientific – controversy has now led to a public health dispute that culminated in the decision of the French authorities to withdraw the combination containing ethinylestradiol (EE) and cyproterone acetate (CPA) from the market. The potential impact of this measure, namely the loss of confidence in all CHCs, could be quite serious.


Several registry-based studies published in the British Medical Journal, particularly the one based on the Danish Registry, indicated that there is an increased risk of venous thromboembolism (VTE) associated with the intake of third- and fourth-generation combined oral contraceptives (COCs) compared to preparations containing the progestogen levonorgestrel (LNG).1–,5 The relative risk (RR) was around 2, and the absolute attributable risk was estimated to be (dependent on the background prevalence rate) between 2 to 8 per 10 000 users per year.6

A very recent systematic review and meta-analysis of the possible link between treatment with CHCs and VTE concluded that, in this regard, (1) CHCs containing LNG or norgestimate were the safest, (2) those containing desogestrel, DRSP or CPA were associated with a significantly higher risk than CHCs containing LNG, and (3) the augmented risk of VTE found for pills containing gestodene compared to COCs with LNG appeared to be smaller than in earlier studies.7

These results contrast with those of published prospective cohort studies, sponsored by Bayer HealthCare, at the request of …

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