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Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis

BMJ 2013; 347 doi: (Published 12 September 2013) Cite this as: BMJ 2013;347:f5298
  1. Bernardine H Stegeman, research associate13,
  2. Marcos de Bastos, research fellow2,
  3. Frits R Rosendaal, professor of clinical epidemiology3,
  4. A van Hylckama Vlieg, research fellow4,
  5. Frans M Helmerhorst, professor of clinical epidemiology of fertility25,
  6. Theo Stijnen, professor of medical statistics6,
  7. Olaf M Dekkers, research fellow7
  1. 1Department of Epidemiology and Public Health, University College London, London, UK
  2. 2Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands
  3. 3Department of Clinical Epidemiology, Department of Thrombosis and Haemostasis, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Netherlands
  4. 4Department of Clinical Epidemiology, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Netherlands
  5. 5Department of Gynaecology and Reproductive Medicine, Leiden University Medical Center, Netherlands
  6. 6Department of Medical Statistics, Leiden University Medical Center, Netherlands
  7. 7Department of Clinical Epidemiology, Department of Endocrinology and Metabolism, Leiden University Medical Center, 2333 ZA Leiden, Netherlands
  1. Correspondence to: O M Dekkers o.m.dekkers{at}
  • Accepted 12 August 2013


Objective To provide a comprehensive overview of the risk of venous thrombosis in women using different combined oral contraceptives.

Design Systematic review and network meta-analysis.

Data sources PubMed, Embase, Web of Science, Cochrane, Cumulative Index to Nursing and Allied Health Literature, Academic Search Premier, and ScienceDirect up to 22 April 2013.

Review methods Observational studies that assessed the effect of combined oral contraceptives on venous thrombosis in healthy women. The primary outcome of interest was a fatal or non-fatal first event of venous thrombosis with the main focus on deep venous thrombosis or pulmonary embolism. Publications with at least 10 events in total were eligible. The network meta-analysis was performed using an extension of frequentist random effects models for mixed multiple treatment comparisons. Unadjusted relative risks with 95% confidence intervals were reported. The requirement for crude numbers did not allow adjustment for potential confounding variables.

Results 3110 publications were retrieved through a search strategy; 25 publications reporting on 26 studies were included. Incidence of venous thrombosis in non-users from two included cohorts was 1.9 and 3.7 per 10 000 woman years, in line with previously reported incidences of 1-6 per 10 000 woman years. Use of combined oral contraceptives increased the risk of venous thrombosis compared with non-use (relative risk 3.5, 95% confidence interval 2.9 to 4.3). The relative risk of venous thrombosis for combined oral contraceptives with 30-35 µg ethinylestradiol and gestodene, desogestrel, cyproterone acetate, or drospirenone were similar and about 50-80% higher than for combined oral contraceptives with levonorgestrel. A dose related effect of ethinylestradiol was observed for gestodene, desogestrel, and levonorgestrel, with higher doses being associated with higher thrombosis risk.

Conclusion All combined oral contraceptives investigated in this analysis were associated with an increased risk of venous thrombosis. The effect size depended both on the progestogen used and the dose of ethinylestradiol.


  • Contributors: BHS, MdB, FMH, and OMD developed the study design. BHS and MdB independently selected the publications and extracted data. BHS, TS, and OMD performed the statistical analysis. All authors interpreted the data and critically reviewed drafts of the manuscript. BHS is guarantor.

  • Funding: This study received no specific funding. BHS was supported by grant 40-00812-98-07-045 from the Netherlands Organization for Scientific Research. MdB was supported by grant from Capes-Nuffic, Brazil. The funding agencies had no role in the study design, implementation, or preparation of results.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: no support from any organisation for the submitted work; BHS was supported by the Netherlands Organization for Scientific Research; MdB was supported by a grant from Capes-Nuffic, Brazil; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not required.

  • Data sharing: No additional data available.

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