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The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study

BMJ 2009; 339 doi: (Published 13 August 2009) Cite this as: BMJ 2009;339:b2921
  1. A van Hylckama Vlieg, research fellow1,
  2. F M Helmerhorst, professor of clinical epidemiology of fertility12,
  3. J P Vandenbroucke, professor of clinical epidemiology1,
  4. C J M Doggen, research fellow1,
  5. F R Rosendaal, professor of clinical epidemiology, head of department134
  1. 1Department of Clinical Epidemiology, Leiden University Medical Center, C7-P, PO Box 9600, NL-2300 RC Leiden, Netherlands
  2. 2Department of Gynaecology and Reproductive Medicine, Leiden University Medical Center
  3. 3Department of Thrombosis and Haemostasis, Leiden University Medical Center
  4. 4Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center
  1. Correspondence to: F R Rosendaal F.R.Rosendaal{at}
  • Accepted 29 May 2009


Objective To assess the thrombotic risk associated with oral contraceptive use with a focus on dose of oestrogen and type of progestogen of oral contraceptives available in the Netherlands.

Design Population based case-control study.

Setting Six participating anticoagulation clinics in the Netherlands (Amersfoort, Amsterdam, The Hague, Leiden, Rotterdam, and Utrecht).

Participants Premenopausal women <50 years old who were not pregnant, not within four weeks postpartum, and not using a hormone excreting intrauterine device or depot contraceptive. Analysis included 1524 patients and 1760 controls.

Main outcome measures First objectively diagnosed episodes of deep venous thrombosis of the leg or pulmonary embolism. Odds ratios calculated by cross-tabulation with a 95% confidence interval according to Woolf’s method; adjusted odds ratios estimated by unconditional logistic regression, standard errors derived from the model.

Results Currently available oral contraceptives increased the risk of venous thrombosis fivefold compared with non-use (odds ratio 5.0, 95% CI 4.2 to 5.8). The risk clearly differed by type of progestogen and dose of oestrogen. The use of oral contraceptives containing levonorgestrel was associated with an almost fourfold increased risk of venous thrombosis (odds ratio 3.6, 2.9 to 4.6) relative to non-users, whereas the risk of venous thrombosis compared with non-use was increased 5.6-fold for gestodene (5.6, 3.7 to 8.4), 7.3-fold for desogestrel (7.3, 5.3 to 10.0), 6.8-fold for cyproterone acetate (6.8, 4.7 to 10.0), and 6.3-fold for drospirenone (6.3, 2.9 to 13.7). The risk of venous thrombosis was positively associated with oestrogen dose. We confirmed a high risk of venous thrombosis during the first months of oral contraceptive use irrespective of the type of oral contraceptives.

Conclusions Currently available oral contraceptives still have a major impact on thrombosis occurrence and many women do not use the safest brands with regard to risk of venous thrombosis.


  • We thank the directors of the Anticoagulation Clinics of Amersfoort (MHH Kramer), Amsterdam (M Remkes), Leiden (FJM van der Meer), The Hague (E van Meegen), Rotterdam (AAH Kasbergen), and Utrecht (J de Vries-Goldschmeding) who made the recruitment of patients possible. The interviewers (JCM van den Berg, B Berbee, S van der Leden, M Roosen, and EC Willems of Brilman) performed the blood draws. We also thank I de Jonge, R Roelofsen, M Streevelaar, LMJ Timmers, and JJ Schreijer for their administrative support and data management. The fellows ID Bezemer, JW Blom, ER Pomp, KJ van Stralen, LW Tick took part in every step of the data collection. We express our gratitude to all individuals who participated in the MEGA study.

  • Funding: This research was supported by the Netherlands Heart Foundation (NHS 98.113), the Dutch Cancer Foundation (RUL 99/1992) and the Netherlands Organisation for Scientific Research (912-03-033| 2003). The funding organisations did not play a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript.

  • Competing interests: None declared

  • Ethical approval: All participants gave written informed consent. The study was approved by the Medical Ethics Committee of the Leiden University Medical Center, Leiden, the Netherlands.

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