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Third generation oral contraceptives and risk of venous thrombosis: meta-analysis

BMJ 2001; 323 doi: (Published 21 July 2001) Cite this as: BMJ 2001;323:131
  1. Jeanet M Kemmeren, research fellow,
  2. Ale Algra (A.Algra{at}, associate professor of clinical epidemiology,
  3. Diederick E Grobbee, professor of clinical epidemiology
  1. Julius Centre for General Practice and Patient Oriented Research, University Medical Centre Utrecht, PO Box 85500, 3508 GA Utrecht, Netherlands
  1. Correspondence to: A Algra
  • Accepted 7 June 2001


Objective: To evaluate quantitatively articles that compared effects of second and third generation oral contraceptives on risk of venous thrombosis.

Design: Meta-analysis.

Studies: Cohort and case-control studies assessing risk of venous thromboembolism among women using oral contraceptives before October 1995.

Main outcome measures: Pooled adjusted odds ratios calculated by a general variance based random effects method. When possible, two by two tables were extracted and combined by the Mantel-Haenszel method.

Results: The overall adjusted odds ratio for third versus second generation oral contraceptives was 1.7 (95% confidence interval 1.4 to 2.0; seven studies). Similar risks were found when oral contraceptives containing desogestrel or gestodene were compared with those containing levonorgestrel. Among first time users, the odds ratio for third versus second generation preparations was 3.1 (2.0 to 4.6; four studies). The odds ratio was 2.5 (1.6 to 4.1; five studies) for short term users compared with 2.0 (1.4 to 2.7; five studies) for longer term users. The odds ratio was 1.3 (1.0 to 1.7) in studies funded by the pharmaceutical industry and 2.3 (1.7 to 3.2) in other studies. Differences in age and certainty of diagnosis of venous thrombosis did not affect the results.

Conclusions: This meta-analysis supports the view that third generation oral contraceptives are associated with an increased risk of venous thrombosis compared with second generation oral contraceptives. The increase cannot be explained by several potential biases.

What is already known on this topic

What is already known on this topic Third generation oral contraceptives have been reported to increase the risk of venous thrombosis compared with second generation oral contraceptives

The findings have been vigorously debated, with suggestions that the results can be explained by confounding or bias, or both.

What this study adds

What this study adds Women taking third generation oral contraceptives have a 1.7-fold increased risk of venous thrombosis compared with those taking second generation oral contraceptives

Risk is highest in first time users

The biases were not large enough to account for the observed results


  • Funding None.

  • Competing interests JMK has worked on a study into second and third generation contraceptives sponsored by the Netherlands Thrombosis Foundation.

  • Accepted 7 June 2001
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