Abstract
Around the world, women use oral contraceptive pills for contraceptive as well as many non-contraceptive benefits. Concerns regarding the risks associated with use of hormonal contraceptives have existed since introduction of the first products. Early on, investigators identified the risk of venous thromboembolism (VTE) and attributed this to the estrogen component of the pill as a dose-dependent effect. Although combined hormonal contraception increases the risk of VTE events, the absolute risk remains low, and the same underlying identifiable risk factors exacerbate the risk of thrombosis in both users and nonusers. Over the years, we have seen changes to pill dosing and formulation, including the introduction of new progestins. This has given rise to new questions and concerns regarding risks of specific pills. At the same time, we have improved diagnosis of VTE and gained further insights regarding baseline risk factors, and changes have occurred in both population health and the available options for birth control. Clinical questions and controversies have emerged including risks of progestogens, if screening is indicated, and how to provide patient-centered counseling.
This chapter will:
-
Review the action of combined hormonal contraception.
-
Provide an understanding of estrogens and progestogens used for contraception.
-
Discuss the risk of venous and arterial embolic events, risk factors, and how hormonal contraception modifies these risks.
-
Guide interpretation of the evidence regarding risks of combined hormonal contraception.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
United Nations Department of Economic and Social Affairs PD. Trends in Contraceptive Use Worldwide 2015. 2015.
Kavanaugh ML, Jerman J. Contraceptive method use in the United States: trends and characteristics between 2008, 2012 and 2014. Contraception. 2018;97(1):14–21.
Bureau PR. Most European women use contraceptives. 2001.
Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. Br Med J. 1968;2(5599):199–205.
Jensen JT, et al., editors. Speroff & Darney’s Clinical Guide to Contraception. 6th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2020.
Blackburn S. Maternal, fetal, & neonatal physiology—E-book: a clinical perspective. Amsterdam: Elsevier Health Sciences; 2017.
Coelingh Bennink HJHC, Diczfalusy E. Estetrol review: profile and potential clinical applications. Climacteric. 2008;11(Suppl 1):47–58.
Mashchak CA, Lobo RA, Dozono-Takano R, Eggena P, Nakamura RM, Brenner PF, et al. Comparison of pharmacodynamic properties of various estrogen formulations. Am J Obstet Gynecol. 1982;144(5):511–8.
Dinger J, Mohner S, Heinemann K. Cardiovascular risk associated with the use of an etonogestrel-containing vaginal ring. Obstet Gynecol. 2013;122(4):800–8.
Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ. 2019;364:k4810.
Stanczyk FZ, Roy S. Metabolism of levonorgestrel, norethindrone, and structurally related contraceptive steroids. Contraception. 1990;42(1):67–96.
Foster RH, Wilde MI. Dienogest. Drugs. 1998;56(5):825–33; discussion 34–5.
Han L, Jensen JT. Does the progestogen used in combined hormonal contraception affect venous thrombosis risk? Obstet Gynecol Clin N Am. 2015;42(4):683–98.
Heit JA, Silverstein MD, Mohr DN, Petterson TM, Lohse CM, O’Fallon WM, et al. The epidemiology of venous thromboembolism in the community. Thromb Haemost. 2001;86(1):452–63.
White RH. The epidemiology of venous thromboembolism. Circulation. 2003;107(23 Suppl 1):I4–8.
Sultan AA, West J, Tata LJ, Fleming KM, Nelson-Piercy C, Grainge MJ. Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study. Br J Haematol. 2012;156(3):366–73.
Heinemann LA, Dinger JC. Range of published estimates of venous thromboembolism incidence in young women. Contraception. 2007;75(5):328–36.
Vandenbroucke JP, Rosing J, Bloemenkamp KW, Middeldorp S, Helmerhorst FM, Bouma BN, et al. Oral contraceptives and the risk of venous thrombosis. New Engl J Med. 2001;344(20):1527–35.
Helmrich SP, Rosenberg L, Kaufman DW, Strom B, Shapiro S. Venous thromboembolism in relation to oral contraceptive use. Obstet Gynecol. 1987;69(1):91–5.
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.
Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet. 1995;346(8990):1575–82.
Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet. 1995;346(8990):1589–93.
Inman WH, Vessey MP, Westerholm B, Engelund A. Thromboembolic disease and the steroidal content of oral contraceptives. A report to the committee on safety of drugs. Br Med J. 1970;2(5703):203–9.
Canonico M, Oger E, Plu-Bureau G, Conard J, Meyer G, Levesque H, et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation. 2007;115(7):840–5.
Ansbacher R. The pharmacokinetics and efficacy of different estrogens are not equivalent. Am J Obstet Gynecol. 2001;184(3):255–63.
Mantha S, Karp R, Raghavan V, Terrin N, Bauer KA, Zwicker JI. Assessing the risk of venous thromboembolic events in women taking progestin-only contraception: a meta-analysis. BMJ. 2012;e4944:345.
The effects of seven monophasic oral contraceptive regimens on hemostatic variables: conclusions from a large randomized multicenter study. Contraception. 2003;67(3):173–85.
Kemmeren JM, Algra A, Meijers JC, Tans G, Bouma BN, Curvers J, et al. Effect of second- and third-generation oral contraceptives on the protein C system in the absence or presence of the factor VLeiden mutation: a randomized trial. Blood. 2004;103(3):927–33.
Odlind V, Milsom I, Persson I, Victor A. Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills? Acta Obstet Gynecol Scand. 2002;81(6):482–90.
Stanczyk FZ, Grimes DA. Sex hormone-binding globulin: not a surrogate marker for venous thromboembolism in women using oral contraceptives. Contraception. 2008;78(3):201–3.
Lidegaard O, Lokkegaard E, Jensen A, Skovlund CW, Keiding N. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med. 2012;366(24):2257–66.
Lidegaard O, Kreiner S. Contraceptives and cerebral thrombosis: a five-year national case-control study. Contraception. 2002;65(3):197–205.
Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet. 1996;348(9026):498–505.
CDC. United States Medical Eligibility Criteria (USMEC) for Contraceptive Use, 2016. Available at https://www.cdc.gov/reproductivehealth/contraception/mmwr/mec/summary.html.
WHO. Medical Eligibility Criteria for Contraceptive Use, 2015. Available at: https://www.who.int/reproductivehealth/publications/family_planning/MEC-5/en/.
Margolis KL, Adami HO, Luo J, Ye W, Weiderpass E. A prospective study of oral contraceptive use and risk of myocardial infarction among Swedish women. Fertil Steril. 2007;88(2):310–6.
Lidegaard O, Milsom I, Geirsson RT, Skjeldestad FE. Hormonal contraception and venous thromboembolism. Acta Obstet Gynecol Scand. 2012;91(7):769–78.
Shapiro S, Dinger J. Risk of venous thromboembolism among users of oral contraceptives: a review of two recently published studies. J Fam Plann Reprod Health Care. 2010;36(1):33–8.
Edelman AB, Jensen JT. Obesity and hormonal contraception: safety and efficacy. Semin Reprod Med. 2012;30(6):479–85.
Rosendaal FR, Van Hylckama Vlieg A, Tanis BC, Helmerhorst FM. Estrogens, progestogens and thrombosis. J Thromb Haemost. 2003;1(7):1371–80.
Blanco-Molina MA, Lozano M, Cano A, Cristobal I, Pallardo LP, Lete I. Progestin-only contraception and venous thromboembolism. Thromb Res. 2012;129(5):e257–62.
Vandenbroucke JP, Koster T, Briet 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):1453–7.
Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, Buller HR, Vandenbroucke JP, Enhancement by factor V. Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen [see comments]. Lancet. 1995;346(8990):1593–6.
Vandenbroucke JP, Bloemenkamp KW, Helmerhorst FM, Rosendaal FR. Handling small relative risks in science and management: the third-generation pill. Ned Tijdschr Geneeskd. 2000;144(6):254–8.
Spitzer WO, Lewis MA, Heinemann LA, Thorogood M, MacRae KD. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. Transnational Research Group on Oral Contraceptives and the Health of Young Women. BMJ. 1996;312(7023):83–8.
Lidegaard O, Lokkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ. 2009;339:b2890.
Farley TM, Meirik O, Poulter NR, Chang CL, Marmot MG. Oral contraceptives and thrombotic diseases: impact of new epidemiological studies. Contraception. 1996;54(3):193–8.
van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJ, 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.
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):83–8.
Jick SS, Hernandez RK. Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data. BMJ. 2011;342:d2151.
Parkin L, Sharples K, Hernandez RK, Jick SS. Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study based on UK General Practice Research Database. BMJ. 2011;342:d2139.
Dinger JC, Heinemann LA, Kuhl-Habich D. The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance Study on oral contraceptives based on 142,475 women-years of observation. Contraception. 2007;75(5):344–54.
Dinger J, Bardenheuer K, Heinemann K. Cardiovascular and general safety of a 24-day regimen of drospirenone-containing combined oral contraceptives: final results from the International Active Surveillance Study of Women Taking Oral Contraceptives. Contraception. 2014;89(4):253–63.
Seeger JD, Loughlin J, Eng PM, Clifford CR, Cutone J, Walker AM. Risk of thromboembolism in women taking ethinylestradiol/drospirenone and other oral contraceptives. Obstet Gynecol. 2007;110(3):587–93.
Heinemann K, Heinemann LA. Comparative risks of venous thromboembolism among users of oral contraceptives containing drospirenone and levonorgestrel. J Fam Plann Reprod Health Care. 2011;37(3):132–5.
Lewis MA, Heinemann LA, MacRae KD, Bruppacher R, Spitzer WO. The increased risk of venous thromboembolism and the use of third generation progestagens: role of bias in observational research. The Transnational Research Group on Oral Contraceptives and the Health of Young Women. Contraception. 1996;54(1):5–13.
Bird ST, Hartzema AG, Brophy JM, Etminan M, Delaney JA. Risk of venous thromboembolism in women with polycystic ovary syndrome: a population-based matched cohort analysis. CMAJ. 2013;185(2):E115–20.
Okoroh EM, Hooper WC, Atrash HK, Yusuf HR, Boulet SL. Is polycystic ovary syndrome another risk factor for venous thromboembolism? United States, 2003–2008. Am J Obstet Gynecol. 2012;207(5):377 e1–8.
Bloemenkamp KW, Helmerhorst FM, Rosendaal FR, Vandenbroucke JP. Thrombophilias and gynaecology. Best Pract Res Clin Obstet Gynaecol. 2003;17(3):509–28.
Suissa S, Blais L, Spitzer WO, Cusson J, Lewis M, Heinemann L. First-time use of newer oral contraceptives and the risk of venous thromboembolism [see comments]. Contraception. 1997;56(3):141–6.
Speroff L. A clinician’s response to the oral contraceptive thrombosis controversy. Hum Reprod Update. 1999;5(6):654–63.
Suissa S, Spitzer WO, Rainville B, Cusson J, Lewis M, Heinemann L. Recurrent use of newer oral contraceptives and the risk of venous thromboembolism. Hum Reprod. 2000;15(4):817–21.
Jensen JT, Burke AE, Barnhart KT, Tillotson C, Messerle-Forbes M, Peters D. Effects of switching from oral to transdermal or transvaginal contraception on markers of thrombosis. Contraception. 2008;78(6):451–8.
Farmer RD, Lawrenson RA. Oral contraceptives and venous thromboembolic disease: the findings from database studies in the United Kingdom and Germany. Am J Obstet Gynecol. 1998;179(3 Pt 2):S78–86.
Herings RM, Urquhart J, Leufkens HG. Venous thromboembolism among new users of different oral contraceptives. Lancet. 1999;354(9173):127–8.
Heinemann LA, Lewis MA, Assmann A, Gravens L, Guggenmoos-Holzmann I, Working Group for Pharmacoepidemiology B-B, editors. Could preferential prescribing and referral behaviour of physicians explain the elevated thrombosis risk found to be associated with third generation oral contraceptives? Pharmacoepidemiol Drug Saf. 1996;5(5):285–94.
Ademi Z, Sutherland CS, Van Stiphout J, Michaud J, Tanackovic G, Schwenkglenks M. A systematic review of cost-effectiveness analysis of screening interventions for assessing the risk of venous thromboembolism in women considering combined oral contraceptives. J Thromb Thrombolysis. 2017;44(4):494–506.
London A, Jensen JT. Rationale for eliminating the hormone-free interval in modern oral contraceptives. Int J Gynaecol Obstet. 2016;134(1):8–12.
Baerwald AR, Pierson RA. Ovarian follicular development during the use of oral contraception: a review. J Obstet Gynaecol Can. 2004;26(1):19–24.
Fritz M, Speroff L. Clinical gynecologic endocrinology and infertility. 8th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011.
Pomp ER, Lenselink AM, Rosendaal FR, Doggen CJ. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost. 2008;6(4):632–7.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Reid, J.A., Jensen, J.T. (2021). Venous and Arterial Risks Associated with Combined Hormonal Contraception. In: Meriggiola, M.C., Gemzell-Danielsson, K. (eds) Female and Male Contraception. Trends in Andrology and Sexual Medicine. Springer, Cham. https://doi.org/10.1007/978-3-030-70932-7_9
Download citation
DOI: https://doi.org/10.1007/978-3-030-70932-7_9
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-70931-0
Online ISBN: 978-3-030-70932-7
eBook Packages: MedicineMedicine (R0)