Download PDF
Semin Thromb Hemost 2020; 46(08): 865-871
DOI: 10.1055/s-0040-1715793
Review Article

Hormonal Contraceptives and the Risk of Venous Thrombosis

Deeksha Khialani
1   Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
,
Frits Rosendaal
1   Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
2   Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands
,
Astrid van Hylckama Vlieg
1   Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

The risk of venous thrombosis (VT) varies according to the type of progestogen that is found in combined oral contraceptives (COCs). When combined with the estrogen component ethinylestradiol (EE), the androgenic progestogens are better able to counteract the EE-induced stimulation of liver proteins and hence are associated with a twofold decreased risk of VT compared with non- or antiandrogenic progestogens, which exert limited counteraction of EE. Because EE is responsible for the increased risk, novel estrogens such as estradiol were developed and seem to have a lower risk of VT than EE. Besides COCs, there are other methods of hormonal contraceptives, such as progestogen-only contraceptives, which do not increase VT risk, except for injectables. Other nonoral contraceptives are combined vaginal rings and patches. There is insufficient evidence regarding the risk of VT associated with these two methods compared with COCs. The increased risk associated with COCs is more pronounced in women with inherited thrombophilia. In these women, the progestogen levonorgestrel seems to be associated with the lowest risk of VT. Currently, there are no studies that have investigated the risk of VT in women who switch COCs. We hypothesize that switching COCs, even when switching from a high- to a low-risk COC, increases the risk of VT. Finally, risk prediction models in women who use COCs are lacking. Since there is a large number of VT cases associated with COC use, it is important to identify women at risk of VT and advise them on alternative contraception methods.

Keywords

contraceptives - oral - combined oral contraceptives - thrombosis - risk


Publication History

Article published online:
05 October 2020

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 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
    CrossrefPubMedGoogle Scholar
  • 2 Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrøm J. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 2007; 5 (04) 692-699
    CrossrefPubMedGoogle Scholar
  • 3 United Nations. Contraceptive use by method. 2019 Accessed July 28, 2020 at: https://www.un.org/development/desa/pd/sites/www.un.org.development.desa.pd/files/files/documents/2020/Jan/un_2019_contraceptiveusebymethod_databooklet.pdf
    PubMedGoogle Scholar
  • 4 Cohen AT, Agnelli G, Anderson FA. et al; VTE Impact Assessment Group in Europe (VITAE). Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007; 98 (04) 756-764
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Jordan WM. Pulmonary embolism. Lancet 1961; 278 (7212): 1146-1147
    CrossrefPubMedGoogle Scholar
  • 6 Vessey M, Mant D, Smith A, Yeates D. Oral contraceptives and venous thromboembolism: findings in a large prospective study. Br Med J (Clin Res Ed) 1986; 292 (6519): 526
    CrossrefPubMedGoogle Scholar
  • 7 Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, Büller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet 1995; 346 (8990): 1593-1596
    CrossrefPubMedGoogle Scholar
  • 8 Gerstman BB, Piper JM, Tomita DK, Ferguson WJ, Stadel BV, Lundin FE. Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease. Am J Epidemiol 1991; 133 (01) 32-37
    CrossrefPubMedGoogle Scholar
  • 9 Thorogood M, Mann J, Murphy M, Vessey M. Risk factors for fatal venous thromboembolism in young women: a case-control study. Int J Epidemiol 1992; 21 (01) 48-52
    CrossrefPubMedGoogle Scholar
  • 10 Vandenbroucke JP, Koster T, Briët E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344 (8935): 1453-1457
    CrossrefPubMedGoogle Scholar
  • 11 World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 1995; 346 (8990): 1582-1588
    CrossrefPubMedGoogle Scholar
  • 12 Farmer RD, Lawrenson RA, Thompson CR, Kennedy JG, Hambleton IR. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 1997; 349 (9045): 83-88
    CrossrefPubMedGoogle Scholar
  • 13 Vandenbroucke JP, Helmerhorst FM, Bloemenkamp KW, Rosendaal FR. Third-generation oral contraceptive and deep venous thrombosis: from epidemiologic controversy to new insight in coagulation. Am J Obstet Gynecol 1997; 177 (04) 887-891
    CrossrefPubMedGoogle Scholar
  • 14 Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. BMJ 2001; 323 (7305): 131-134
    CrossrefPubMedGoogle Scholar
  • 15 European Medicines Agency. Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks – CHMP endorses PRAC recommendation. EMA/709120/. 2013 Accessed July 28, 2020 at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/11/news_detail_001969.jsp&mid=WC0b01ac058004d5c1
    PubMedGoogle Scholar
  • 16 Stegeman BH, de Bastos M, Rosendaal FR. et al. Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis. BMJ 2013; 347: f5298
    CrossrefPubMedGoogle Scholar
  • 17 Wiegratz I, Kuhl H. Metabolic and clinical effects of progestogens. Eur J Contracept Reprod Health Care 2006; 11 (03) 153-161
    CrossrefPubMedGoogle Scholar
  • 18 Tchaikovski SN, Rosing J. Mechanisms of estrogen-induced venous thromboembolism. Thromb Res 2010; 126 (01) 5-11
    CrossrefPubMedGoogle Scholar
  • 19 Kiley JW, Shulman LP. Estradiol valerate and dienogest: a new approach to oral contraception. Int J Womens Health 2011; 3: 281-286
    CrossrefPubMedGoogle Scholar
  • 20 Burke A. Nomegestrol acetate-17b-estradiol for oral contraception. Patient Prefer Adherence 2013; 7: 607-619
    CrossrefPubMedGoogle Scholar
  • 21 Parke S, Junge W, Mellinger U. , et al. Comparative effects of a four-phasic regimen of estradiol valerate/dienogest versus ethinylestradiol/levonorgestrel on haemostatic parameters. Hum Reprod 2008; 23 (Suppl. 01) i78-i79
    PubMed
  • 22 Parks S, Nauhm G, Mellinger U, Junge W. Metabolic effects of a new four-phasic oral contraceptive containing estradiol valerate and dienogest. Obstet Gynecol 2008; 111: 3-12
    PubMedGoogle Scholar
  • 23 Raps M, Helmerhorst F, Fleischer K. et al. Sex hormone-binding globulin as a marker for the thrombotic risk of hormonal contraceptives. J Thromb Haemost 2012; 10 (06) 992-997
    CrossrefPubMedGoogle Scholar
  • 24 van Vliet HAAM, Frolich M, Christella M. et al. Association between sex hormone-binding globulin levels and activated protein C resistance in explaining the risk of thrombosis in users of oral contraceptives containing different progestogens. Hum Reprod 2005; 20 (02) 563-568
    CrossrefPubMedGoogle Scholar
  • 25 Raps M, Rosendaal F, Ballieux B. et al. Resistance to APC and SHBG levels during use of a four-phasic oral contraceptive containing dienogest and estradiol valerate: a randomized controlled trial. J Thromb Haemost 2013; 11 (05) 855-861
    CrossrefPubMedGoogle Scholar
  • 26 Dinger J, Do Minh T, Heinemann K. Impact of estrogen type on cardiovascular safety of combined oral contraceptives. Contraception 2016; 94 (04) 328-339
    CrossrefPubMedGoogle Scholar
  • 27 Fruzzetti F, Cagnacci A. Venous thrombosis and hormonal contraception: what's new with estradiol-based hormonal contraceptives?. Open Access J Contracept 2018; 9: 75-79
    CrossrefPubMedGoogle Scholar
  • 28 Ågren UM, Anttila M, Mäenpää-Liukko K. et al. Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol compared with one containing levonorgestrel and ethinylestradiol on haemostasis, lipids and carbohydrate metabolism. Eur J Contracept Reprod Health Care 2011; 16 (06) 444-457
    CrossrefPubMedGoogle Scholar
  • 29 Gaussem P, Alhenc-Gelas M, Thomas JL. et al. Haemostatic effects of a new combined oral contraceptive, nomegestrol acetate/17β-estradiol, compared with those of levonorgestrel/ethinyl estradiol. A double-blind, randomised study. Thromb Haemost 2011; 105 (03) 560-567
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Tepper NK, Whiteman MK, Marchbanks PA, James AH, Curtis KM. Progestin-only contraception and thromboembolism: a systematic review. Contraception 2016; 94 (06) 678-700
    CrossrefPubMedGoogle Scholar
  • 31 Glisic M, Shahzad S, Tsoli S. et al. Association between progestin-only contraceptive use and cardiometabolic outcomes: a systematic review and meta-analysis. Eur J Prev Cardiol 2018; 25 (10) 1042-1052
    CrossrefPubMedGoogle Scholar
  • 32 Schindler AE. Differential effects of progestins on hemostasis. Maturitas 2003; 46 (Suppl. 01) S31-S37
    CrossrefPubMedGoogle Scholar
  • 33 Cedars MI, Judd HL. Nonoral routes of estrogen administration. Obstet Gynecol Clin North Am 1987; 14 (01) 269-298
    CrossrefPubMedGoogle Scholar
  • 34 Tepper NK, Dragoman MV, Gaffield ME, Curtis KM. Nonoral combined hormonal contraceptives and thromboembolism: a systematic review. Contraception 2017; 95 (02) 130-139
    CrossrefPubMedGoogle Scholar
  • 35 Practice Committee of the American Society for Reproductive Medicine. Electronic address: ASRM@asrm.org; Practice Committee of the American Society for Reproductive Medicine. Combined hormonal contraception and the risk of venous thromboembolism: a guideline. Fertil Steril 2017; 107 (01) 43-51
    CrossrefPubMedGoogle Scholar
  • 36 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 (07) 1393-1403
    CrossrefPubMedGoogle Scholar
  • 37 Spannagl M, Heinemann LA, Schramm W. Are factor V Leiden carriers who use oral contraceptives at extreme risk for venous thromboembolism?. Eur J Contracept Reprod Health Care 2000; 5 (02) 105-112
    CrossrefPubMedGoogle Scholar
  • 38 World Health Organization. Medical eligibility criteria for contraceptive use. 5th ed. Geneva: World Health Organization; 2015
    PubMedGoogle Scholar
  • 39 Hugon-Rodin J, Horellou MH, Conard J, Gompel A, Plu-Bureau G. Type of combined contraceptives, factor V Leiden mutation and risk of venous thromboembolism. Thromb Haemost 2018; 118 (05) 922-928
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Siemiatycki J, Thomas DC. Biological models and statistical interactions: an example from multistage carcinogenesis. Int J Epidemiol 1981; 10 (04) 383-387
    CrossrefPubMedGoogle Scholar
  • 41 Wang X, Elston RC, Zhu X. Statistical interaction in human genetics: how should we model it if we are looking for biological interaction?. Nat Rev Genet 2011; 12 (01) 74
    CrossrefPubMedGoogle Scholar
  • 42 van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJM, Rosendaal FR. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ 2009; 339: b2921
    CrossrefPubMedGoogle Scholar
  • 43 Khialani D, le Cessie S, Lijfering WM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A. The joint effect of genetic risk factors and different types of combined oral contraceptives on venous thrombosis risk. Br J Haematol 2020; (e-pub ahead of print) DOI: 10.1111/bjh.16666.
    CrossrefPubMedGoogle Scholar
  • 44 Khialani D, de Rooij E, le Cessie S, Rosendaal FR, van Hylckama Vlieg A. Thrombosis risk after switching oral contraceptive type. Accessed July 28, 2020 at: http://ecth2019.org/wp-content/uploads/2019/09/ECTH2019-ABSTRACT-BOOK.pdf
    PubMedGoogle Scholar
  • 45 Tans G, Curvers J, Middeldorp S. et al. A randomized cross-over study on the effects of levonorgestrel- and desogestrel-containing oral contraceptives on the anticoagulant pathways. Thromb Haemost 2000; 84 (01) 15-21
    Article in Thieme ConnectPubMedGoogle Scholar
  • 46 Dutch News. Shortage of contraceptive pills set to continue for ‘weeks’. Accessed July 28, 2020 at: https://www.dutchnews.nl/news/2018/11/shortage-of-contraceptive-pills-set-to-continue-for-weeks/
    PubMedGoogle Scholar
  • 47 McDaid A, Logette E, Buchillier V. et al. Risk prediction of developing venous thrombosis in combined oral contraceptive users. PLoS One 2017; 12 (07) e0182041
    CrossrefPubMedGoogle Scholar
  • 48 Bezemer ID, van der Meer FJ, Eikenboom JC, Rosendaal FR, Doggen CJ. The value of family history as a risk indicator for venous thrombosis. Arch Intern Med 2009; 169 (06) 610-615
    CrossrefPubMedGoogle Scholar
  • 49 Cheng Y-J, Liu Z-H, Yao F-J. et al. Current and former smoking and risk for venous thromboembolism: a systematic review and meta-analysis. PLoS Med 2013; 10 (09) e1001515
    CrossrefPubMedGoogle Scholar
  • 50 Ageno W, Becattini C, Brighton T, Selby R, Kamphuisen PW. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation 2008; 117 (01) 93-102
    CrossrefPubMedGoogle Scholar