Abstract
OBJECTIVE: To evaluate the risks and benefits of third-generation oral contraceptives.
DATA SOURCES: A medline search was done for English language articles published from 1985 through 1998 relating to the side-effect profile of third-generation oral contraceptives or their association with cardiovascular or thromboembolic disease. All articles containing original data were included.
DATA SYNTHESIS: The risk of venous thromboembolism appears to be 1.5- to 2.7-fold greater in users of third-generation, compared with second-generation, oral contraceptives. Compared with nonusers, women who use third-generation oral contraceptives may have a 4.8- to 9.4-fold greater risk of venous thromboembolism. Users of third-generation oral contraceptives do not appear to have an increased risk of myocardial infarction compared with nonusers and may have risk of myocardial infarction of 0.26 to 0.7 compared with second-generation users. Whether third-generation oral contraceptives are associated with a decreased stroke risk is still not clear.
CONCLUSIONS: Although third-generation oral contraceptives most likely increase a user’s risk of venous thromboembolism, their improved side-effect profile and their possible decreased association with myocardial infarction and stroke may make them a useful new class of oral contraceptives for most women except those at increased risk of venous thrombosis.
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References
Stampfer MJ, Willet WC, Colditz GA, Speizer FE, Hennekens CH. A prospective study of past use of oral contraceptive agents and risk of cardiovascular diseases. N Engl J Med. 1988;319:1313–7.
Lewis M, Heinemann A, Spitzer W, MacRae K, Bruppacher R, for the Transnational Research Group on Oral Contraceptives and the Health of Young Women. The use of oral contraceptives and the occurrence of acute myocardial infarction in young women. Contraception. 1997;56:129–40.
Petiti D, Sidney S, Bernstein A, Wolf S, Quesenberry C, Ziel H. Stroke in users of low-dose oral contraceptives. N Engl J Med. 1996;335:8–15.
Schwartz S, Siscovick D, Longstreth WT Jr, Psay B, Beverly K. Use of low-dose oral contraceptives and stoke in young women. Ann Intern Med. 1997;127:596–603.
Runnebaum B, Grunwald K, Rabe T. The efficacy and tolerability of norgestimate/ethinyl estradiol (250 µg of norgestimate/35 µg of ethinyl estradiol): results of an open, multicenter study of 59,701 women. Am J Obstet. 1992;166:1963–8.
Palatsi R, Hirvensalo E, Liukko P, et al. Serum total and unbound testosterone and sex hormone binding globulin (SHBG) in female acne patients treated with two different oral contraceptives. Acta Derm Venereol (Stockh). 1984;64:517–23.
Bilotta P, Favilli S. Clinical evaluation of a monophasic ethinyl estradiol/desogestrel-containing oral contraceptive. Arzneim-Forsch Drug Res. 1988;36:932–4.
Corson SL. Efficacy and clinical profile of a new oral contraceptive containing norgestimate. Acta Obstet Gynecol Scand. 1990;152(suppl):25–31.
Huber J. Clinical experience with a new norgestimate-containing oral contraceptive. Int J Fertil. 1991;36(suppl):25–31.
Chapdelaine A, Desmarais J, Derman RJ. Clinical evidence of the minimal androgenic activity of norgestimate. Int J Fertil. 1989;34:347–52.
Cullberg G, Samsioe G, Andersen RF, et al. Two oral contraceptives, efficacy, serum proteins, and lipid metabolism: a comparative multicentre study on a triphasic and a fixed dose combination. Contraception. 1982;26:229–43.
Walling M. A multicenter efficacy and safety study of an oral contraceptive containing 150 µg desogestrel and 30 µg ethinyl estradiol. Contraception. 1992;46:313–26.
Andolsek KM. Cycle control with triphasic norgestimate and ethinyl estradiol, a new oral contraceptive agent. Acta Obstet Gynecol Scand. 1992;71:22–6.
Hoppe G. Gestodene, an innovative progestogen. Contraception. 1988;37:493–501.
Speroff L, DeCherney A, and The Advisory Board for the New Progestins. Evaluation of a new generation of oral contraceptives. Obstet Gynecol. 1993;81:1034–47.
World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Venous thromboembolic disease and oral contraceptives: results of international multicentre case-control study. Lancet. 1995;346:1575–82.
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;346:1582–88.
Spitzer WO, Lewis AL, Heinemann LAJ, Thorogood M, MacRae KD, on behalf of the Transnational Research Group on Oral Contraceptives and the Health of Young Women. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. BMJ. 1996;312:83–8.
Bloemenkamp K, Rosendaal FR, Helmerhorst FM, Buller H, Vandenbroucke J. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet. 1995;346:1593–6.
Lidegaard O, Edstrom B, Kreiner S. Oral contraceptives and venous thromboembolism: a case control study. Contraception. 1998;57:291–301.
Bloemenkamp K, Rosendaal F, Buller H, Helmerhorst F, Colly LP, Vandenbroucke J. Risk of venous thrombosis with use of current low-dose oral contraceptives is not explained by diagnostic suspicion and referral bias. Arch Intern Med. 1999;159:65–70.
Jick H, Jick S, Gurewich V, Myers M, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet. 1995;346:1589–93.
Farmer R, Lawrenson R, Thompson C, Kennedy J, Hambleton I. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet. 1997;349:83–8.
Lewis M, Heinemann LA, MacRae K, Bruppacher R, Spitzer W, with the Transnational Research Group on Oral Contraceptives and the Health of Young Women. The increased risk of venous thromboembolism and the use of third generation progestagens: role of bias in observational research. Contraception. 1996;54:5–13.
Lauritzen C. Comments on Desogestrel and Gestodene (third generation progestogens) and the incidence of thromboembolism. Horm Metab Res. 1996;28:225–47.
Jick H, Jick SS, Myers MW, Vasilakis C. Third-generation oral contraceptives and venous thrombosis. Lancet. 1997;349:731–2.
Poulter NR, Change CL, Marmot M, Farley TMM, Meirik O. Third-generation oral contraceptives and venous thrombosis. Lancet. 1997;349:732.
Lidegaard O. The influence of thrombotic risk factors when oral contraceptives are prescribed. Acta Obstet Gynecol Scand. 1997;76:252–60.
Jamin C, de Mouzon J. Selective prescribing of third generation oral contraceptives. Contraception. 1996;54:55–6.
Dahlback, B. Inherited thrombophilia: resistance to activated protein C as a pathogenic factor of venous thromboembolism. Blood. 1995;85:607–14.
Vandenbrouke JP, Koster T, Briet E, Reitsma PH, Brtina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet. 1994;344:1453–7.
Helmerhorst F, Bloemenkamp K, Rosendaal F, Vandenbrouke J. Oral contraceptives and thrombotic disease: risk of venous thromboembolism. Thromb Haemost. 1997;78:327–33.
Farley TM, Meirik O, Poulter NR, Chang CL, Marmot MG. Oral contraceptives and thrombotic diseases: impact of new epidemiological studies. Contraception. 1996;54:193–5.
Rosing J, Tans G, Nicolaes GAF, et al. Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second- and third-generation oral contraceptives. Br J Haematol. 1997;97:233–8.
Darney PD. OC practice guidelines: minimizing side effects. Int J Fertil. 1997;42(suppl 1):158–69.
Lindstedt G, Lundberg PA, Lapidis L, et al. Low sex-hormonebinding globulin concentration as an independent risk factor for the development of non-insulin dependent diabetes: twelve-year follow up of population study of women in Gothenburg. Sweden. Diabetes. 1991;40:123–8.
Rosa JC. The varying effects of progestins on lipid levels and cardiovascular disease. Am J Obstet Gynecol. 1988;158:1621–9.
Kakis G, Powell M, Marshall A, et al. A two-year clinical study of the effects of two triphasic oral contraceptives on plasma lipids. Int J Fertil Menopausal Stud. 1994;39:283–91.
Krauss RM, Burkman RT. The metabolic impact of oral contraceptives. Am J Obstet Gynecol. 1992;167:1177–84.
Greenlund KJ, Webber LS, Srinivasan S, et al. Associations of oral contraceptive use with serum lipids and lipoproteins in young women: the Bogalusa heart study. Ann Epidemiol. 1997;7:561–7.
Notelovitz M, Feldman EB, Gillespy M, Gudat J. Lipid and lipoprotein changes in women taking low-dose, triphasic oral contraceptives: a controlled, comparative, 12-month clinical trial. Am J Obstet Gynecol. 1989;160:1269–80.
London RS, Chapdelaine A, Upmalis D, Olson W, Smith J. Comparative contraceptive efficacy and mechanism of action of the norgestimate-containing triphasic oral contraceptive. Acta Obstet Gynecol Scand. 1992;71:9–14.
Becker H. Supportive European data on a new oral contraceptive containing norgestimate. Acta Obstet Gynecol Scand. 1990;152(suppl):33–9.
Mann JI, Inman WH. Oral contraceptives and death from myocardial infarction. BMJ. 1975;2:245–8.
Mann JI, Inman WH, Thorogood M. Oral contraceptive use in older women and fatal myocardial infarction. BMJ. 1976;2:445–7.
Rosenberg L, Hennekens CH, Rosner B. Oral contraceptive use in relation to nonfatal myocardial infarction. Am J Epidemiol. 1980;111:59–66.
Shapiro S, Slone D, Rosenberg L, et al. Oral-contraceptive use in relation to myocardial infarction. Lancet. 1979;1:743–7.
Ory HW. Association between oral contraceptives and myocardial infarction. JAMA. 1977;237:2619–22.
Slone D, Shapiro S, Kaufman D, et al. Risk of myocardial infarction in relation to current and discontinued use of oral contraceptives. N Engl J Med. 1981;305:420–4.
Croft P, Hannaford PC. Risk factors for acute myocardial infarction in women: evidence from the Royal College of General Practitioners’ oral contraception study. BMJ. 1989;298:165–8.
Rosenberg L, Kaufman DW, Helmrich SP. Myocardial infarction and cigarette smoking in women younger than 50 years of age. JAMA. 1985;253:2965–9.
Rosenberg L, Palmer JR, Lesko SM, Shapiro S. Oral contraceptive use and the risk of myocardial infarction. Am J Epidemiol. 1990;131:1009–16.
Thorogood M, Mann J, Murphy M, Vessey M. Is oral contraceptive use still associated with an increased risk of fatal myocardial infarction? Report of a case-control study. Br J Obstet Gynaecol. 1991;98:1245–53.
Sidney S, Petitti DB, Quesenberry CP, Klatsky AR, Ziel HK, Wolf S. Myocardial infarction in users of low-dose oral contraceptives. Obstet Gynaecol. 1996;88:939–44.
Sidney S, Siscovick DS, Petitti DB, et al. Myocardial infarction and use of low-dose oral contraceptives: a pooled analysis of 2 US studies. Circulation. 1998;98:1058–63.
WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone contraception. Acute myocardial infarction and combined oral contraceptives. Results of and international multicentre case-control study. Lancet. 1997;349:1202–9.
Jick H, Jick S, Myers M, Vasilakis C. Risk of acute myocardial infarction and low-dose combined oral contraceptives. Lancet. 1996;347:627–8.
WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Ishaemic stroke and combined oral contraceptives. Results of an international, multicentre, case-control study. Lancet. 1996;348:498–505.
Heinemann LA, Lewis MA, Thorogood M, et al., and the Transnational Research Group on Oral Contraceptives and the Health of Young Women. Case-control study of oral contraceptives and risk of thromboembolic stroke: results from international study on oral contraceptives and health of young women. BMJ. 1997;315:1502–4.
WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Hemorrhagic stroke, overall stroke risk, and combined oral contraceptives. Results of an international, multicentre, case-control study. Lancet. 1996;348:505–10.
Heinemann LA, Lewis MA, Thorogood M, et al., and the Transnational Research Group on Oral Contraceptives and the Health of Young Women. Thromboembolic stroke in young women: a European case-control study on oral contraceptives. Contraception. 1998;57:29–37.
Lewis MA, Sitzer WO, Heinemann LA, MacRae KD, Bruppacher R. Lowered risk of dying of heart attack with third generation pill may offset risk of dying of thromboembolism. BMJ. 1997;315:679–80.
Schwing PJ, Shelton J. Modeled estimates of myocardial infarction and venous thromboembolic disease in users of second and third generation oral contraceptives. Contraception. 1997;55:125–9.
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LeBlanc, E.S., Laws, A. Benefits and risks of third-generation oral contraceptives. J GEN INTERN MED 14, 625–632 (1999). https://doi.org/10.1046/j.1525-1497.1999.08108.x
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DOI: https://doi.org/10.1046/j.1525-1497.1999.08108.x