Combined oral contraceptives, thrombophilia and the risk of venous thromboembolism: a systematic review and meta-analysis

J Thromb Haemost. 2016 Jul;14(7):1393-403. doi: 10.1111/jth.13349. Epub 2016 Jun 16.


Essentials We performed a meta-analysis on thrombosis risk in thrombophilic oral contraceptive (COC)-users. The results support discouraging COC-use in women with a natural anticoagulant deficiency. Contrary, additive risk of factor V Leiden (FVL) or prothrombin-G20210A (PT) mutation is modest. Women with a FVL/PT-mutation as single risk factor can use COCs if alternatives are not tolerated.

Summary: Background Combined oral contraceptives (COCs) are associated with an increased risk of venous thromboembolism (VTE), which is shown to be more pronounced in women with hereditary thrombophilia. Currently, WHO recommendations state that COC-use in women with hereditary thrombophilias (antithrombin deficiency, protein C deficiency, protein S deficiency, factor V Leiden and prothrombin-G20210A mutation) is associated with an unacceptable health risk. Objective To perform a meta-analysis evaluating the additional risk of VTE in COC-users with thrombophilia. Methods The MEDLINE and EMBASE databases were searched on 10 February 2015 for potential eligible studies. A distinction was made between 'mild' (factor V Leiden and prothrombin-G20210A mutation) and 'severe' thrombophilia (antithrombin deficiency, protein C deficiency, protein S deficiency, double heterozygosity or homozygosity of factor V Leiden and prothrombin-G20210A mutation). Results We identified 12 case-control and three cohort studies. In COC-users, mild and severe thrombophilia increased the risk of VTE almost 6-fold (rate ratio [RR], 5.89; 95% confidence interval [CI], 4.21-8.23) and 7-fold (RR, 7.15; 95% CI, 2.93-17.45), respectively. The cohort studies showed that absolute VTE risk was far higher in COC-users with severe thrombophilia than in those with mild thrombophilia (4.3 to 4.6 vs. 0.49 to 2.0 per 100 pill-years, respectively), and these differences in absolute risks were also noted in non-affected women (0.48 to 0.7 vs. 0.19 to 0.0), but with the caveat that absolute risks were estimated in relatives of thrombophilic patients with VTE (i.e. with a positive family history). Conclusion These results support discouraging COC-use in women with severe hereditary thrombophilia. By contrast, additive VTE risk of mild thrombophilia is modest. When no other risk factors are present, (e.g. family history) COCs can be offered to these women when reliable alternative contraceptives are not tolerated.

Keywords: combined oral contraceptives; hereditary; meta-analysis; thrombophilia; venous thromboembolism.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Anticoagulants / adverse effects
  • Anticoagulants / therapeutic use
  • Case-Control Studies
  • Cohort Studies
  • Contraceptives, Oral, Combined / adverse effects*
  • Contraceptives, Oral, Combined / therapeutic use
  • Factor V / genetics
  • Female
  • Heterozygote
  • Humans
  • Middle Aged
  • Mutation
  • Protein C Deficiency / complications
  • Protein S Deficiency / complications
  • Prothrombin / genetics
  • Risk Factors
  • Thrombophilia / complications
  • Thrombophilia / etiology*
  • Thrombophilia / genetics
  • Thrombophilia / prevention & control
  • Venous Thromboembolism / etiology
  • Venous Thromboembolism / genetics
  • Venous Thromboembolism / prevention & control*
  • Young Adult


  • Anticoagulants
  • Contraceptives, Oral, Combined
  • factor V Leiden
  • Factor V
  • Prothrombin

Supplementary concepts

  • Thrombophilia, hereditary