Combined oral contraceptives and the risk of venous thromboembolism carriers of antithrombin, protein C or S deficiency: Sub-analysis of a prospective cohort study


Published: 3 November 2022
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Authors

  • Daniela Tormene Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, University of Padua Medical School, Padua, Italy. https://orcid.org/0000-0003-1890-641X
  • Elena Campello Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, University of Padua Medical School, Padua, Italy.
  • Chiara Simion Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, University of Padua Medical School, Padua, Italy.
  • Anna Poretto Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, University of Padua Medical School, Padua, Italy.
  • Paolo Prandoni Arianna Foundation on Anticoagulation, Bologna, Italy.
  • Paolo Simioni Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, University of Padua Medical School, Padua, Italy.

Antithrombin, protein C and S defects are well-recognized inherited risk factors for venous thromboembolism (VTE). Although these defects have been reported to increase the risk of VTE in fertile women under combined oral contraceptives (COCs), the magnitude of this association is uncertain. In a sub-analysis of a prospective cohort study, we evaluated the incidence of VTE occurring during treatment with COCs in fertile women who were family members of a proband with an objectively diagnosed VTE event and a documented defect of antithrombin, protein C or S. Of the 197 women of child-bearing age from 88 families who qualified for this analysis in a 17-year period, 112 (57%) were carriers of an inherited defect (23 antithrombin, 41 protein C and 48 protein S), whereas the remaining 85 were free from these abnormalities. Estrogen-progestin therapy was used by 19 of the 112 (17%) carriers of inherited thrombophilia for an overall period of 276 months, and by 17 of the 85 (20%) non-carriers for an overall period of 992 months. VTE events developed in 12 of the 19 (63%) carriers, leading to a monthly event rate of 4.3% (95% CI: 2.2 to 7.6), and in 2 of the 17 (12%) non-carriers, leading to a monthly rate of 0.2% (95% CI: 0.02 to 0.7), for a relative risk of 21 (95% CI, 4.7 to 92). Among family members of probands with inherited defects of antithrombin, protein C or S defects, the use of estrogen-progestin therapy in carriers of these abnormalities results in a risk of VTE events that is more than 20 times as high as that expected in non-carriers. Accordingly, the systematic screening for thrombophilia in these families has the potential to identify those subjects in whom this kind of hormonal treatment should be strongly discouraged.


Lidegaard A, Lakkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009;339:2890. DOI: https://doi.org/10.1136/bmj.b2890

de Bastos M, Stegeman BH, Rosendaal FR, et al. Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev 2014;3:CD010813. DOI: https://doi.org/10.1002/14651858.CD010813.pub2

Vinogradova Y, Coupland C, Hippisley-Cox J. Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ 2015;350:h2135. DOI: https://doi.org/10.1136/bmj.h2135

van Vlijmen EF, Wiewel-Verschueren S, Monster TB, Meijer K. Combined oral contraceptives, thrombophilia and the risk of venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2016;14:1393-403. DOI: https://doi.org/10.1111/jth.13349

Tormene D, Guerra L, Gavasso S, et al The incidence of VTE in asymptomatic carriers of a deficiency of at PC OR PS: a prospective cohort study. XXV Congress of the International Society on Thrombosis and Haemostasis and 61st Annual SSC Meeting. 20-25 June 2015. Toronto, Canada.

Simioni P, Sanson BJ, Prandoni P, et al. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost 1999;81:198-202. DOI: https://doi.org/10.1055/s-0037-1614442

Simioni P, Tormene D, Manfrin D, et al. Prothrombin antigen levels in symptomatic and asymptomatic carriers of the 20210A prothrombin variant. Br J Haematol 1998;103:1045-50. DOI: https://doi.org/10.1046/j.1365-2141.1998.01112.x

van Vlijmen EF, Brouwer JL, Veeger NJ, et al. Oral contraceptives and the absolute risk of venous thromboembolism in women with single or multiple thrombophilic defects: results from a retrospective family cohort study. Arch Intern Med 2007;167:282-9. DOI: https://doi.org/10.1001/archinte.167.3.282

Jick H, Jick SS, Gurewich V, et al. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995;346:1589-93. DOI: https://doi.org/10.1016/S0140-6736(95)91928-7

Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. BMJ 2001;323:131-4. DOI: https://doi.org/10.1136/bmj.323.7305.131

van Vlijmen EF, Veeger NJ, Middeldorp S, et al. The impact of a male or female thrombotic family history on contraceptive counseling: a cohort study. J Thromb Haemost 2016;14:1741-8. DOI: https://doi.org/10.1111/jth.13393

Hugon-Rodin J, Horellou MH, Conard J, et al. Type of Combined Contraceptives, Factor V Leiden Mutation and Risk of Venous Thromboembolism. Thromb Haemost 2018;118:922-8. DOI: https://doi.org/10.1055/s-0038-1641152

Dinger J. COCs containing dienogest and 30 µg ethinylestradiol may carry a higher VTE_risk compared to corresponding preparations with levonorgestrel: A metaanalysis of four large cohort studies. Front Womens Health 2020;5:175. DOI: https://doi.org/10.15761/FWH.1000175

Vossen CY, Conard J, Fontcuberta J, et al. Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT). J Thromb Haemost 2005;3:459-64. DOI: https://doi.org/10.1111/j.1538-7836.2005.01197.x

Lussana F, Dentali F, Abbate R, et al. Screening for thrombophilia and antithrombotic prophylaxis in pregnancy: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res 2009;124:e19-25. DOI: https://doi.org/10.1016/j.thromres.2009.06.031

Tormene, D., Campello, E., Simion, C., Poretto, A., Prandoni, P., & Simioni, P. (2022). Combined oral contraceptives and the risk of venous thromboembolism carriers of antithrombin, protein C or S deficiency: Sub-analysis of a prospective cohort study. Bleeding, Thrombosis, and Vascular Biology, 1(3). https://doi.org/10.4081/btvb.2022.42

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