Little absolute risk of stroke, heart attack in hormonal contraceptives

Most have acceptable increased risk, given their multiple benefits

Add new information to your contraceptive counseling databank: Findings from a just-published study indicate the absolute risk of increased thrombotic stroke and myocardial infarction (MI) associated with the use of hormonal contraception is low, although the relative risks vary depending on whether higher doses of estrogen are used.1

While several studies have assessed the risk of venous thromboembolism (VTE) associated with the use of hormonal contraceptives, few studies have examined thrombotic stroke and myocardial infarction.2-9 While complications are less frequent than venous complications among young women, the short- and long-term consequences of arterial complications often are more serious. The risks for MI increase with age, but they are greatly magnified by the combination of age, smoking, and hypertension.10

The current research paper, a 15-year historical cohort study, followed nonpregnant Danish women ages 15-49 with no history of cardiovascular disease or cancer. Researchers pulled data from four national registries on hormonal contraception, clinical end points, and potential confounders to perform the analysis.

The researchers looked at data from some 1.6 million Danish women, all of whom were free of thrombotic disease at baseline, from 1995 to 2009. The reference group included nonusers, defined as women who had never used hormonal contraception, as well as former users.

Risks of arterial thrombotic events were assessed, with stratification according to estrogen dose (50 mcg, 30 to 40 mcg, or 20 mcg of ethinyl estradiol or progestin-only contraceptive), progestin type, route of administration, and duration of use. Estimates of relative risk were adjusted for age, calendar year, education, smoking, and status with respect to hypertension, heart disease, diabetes, and hyperlipidemia, with conditions defined by the use or nonuse of medications for such treatment.

The analysis indicates there were 3,311 strokes (21.4 per 100,000 person years) and 1,725 myocardial infarctions (10.1 per 100,000 person-years) over the course of the study.

Researchers state the relative risks of stroke and myocardial infarctions were increased by a factor of 1.3 to 2.3 among users of estrogen-progestin oral contraceptives using a low dose of ethinyl estradiol (30 to 40 mcg), with only small differences according to the progestin (which included norethindrone, levonorgestrel, norgestimate, desogestrel, drospirenone, and cyproterone acetate), as compared with nonuse.

For combined oral contraceptives containing 20 mcg of ethinyl estradiol, the analysis indicates relative risks of stroke and acute MI increased by a factor of 0.9 to about 1.7, with only small differences according to progestin, compared with nonuse. The respective relative risks for stroke and MI respectively, by progestin were desogestrel, 1.5 (95% confidence interval [CI], 1.3 to 1.9) and 1.6 (95% CI, 1.1 to 2.1); gestodene, 1.7 (95% CI, 1.4 to 2.1) and 1.2 (95% CI, 0.8 to 1.9); and drospirenone, 0.9 (95% CI, 0.2 to 3.5) and 0.0.

Other methods, smoking eyed

For the levonorgestrel intrauterine device and subcutaneous implant, the relative risk of thrombotic stroke and MI were not significantly increased for any of the progestin-only formulations studied. For the transdermal patch, the relative risk was 3.2 for stroke (95% CI, 0.8 to 12.6); for the vaginal ring, the relative risk was 2.5 for stroke (95% CI, 1.4 to 4.4) The number of myocardial infarctions was too low among patch and ring users to provide reliable estimates, investigators state.1

In looking at women who smoked compared with those who did not, the relative risks of thrombotic stroke and MI were 1.57 (95% CI, 1.31 to 1.87) and 3.62 (95% CI, 2.69 to 4.87), respectively.

The current study describes the well-established association of combined hormonal contraception and arterial thrombosis, which are rare events in healthy young women, notes Jeffrey Jensen, MD, MPH, Leon Speroff Professor & Vice Chair, Research, in the Department of Obstetrics & Gynecology at Portland-based Oregon Health & Science University. "The limitations of the database design used in this research have been previously described," says Jensen. "Large prospective studies have not shown an increase in relative risk with vaginal ring users."11

Women, clinicians, and the public should be reassured not only by the current study, but by the "vast body" of evidence from epidemiologic studies of hormonal contraception that have been done over the past five decades, states Diana Petitti, MD, MPH, professor of biomedical informatics at Phoenix-based Arizona State University, in an editorial accompanying the current study.12

This wealth of evidence documents the small magnitude of the problem of arterial thrombotic events in women using combined hormonal contraceptives, notes Petitti. Such risk could be minimized or eliminated by abstaining from smoking and by checking blood pressure, with avoidance of hormonal contraceptive use if blood pressure is raised, Petitti states in the editorial.

"Decades of research shows that we have not been able to eliminate entirely the risk of thrombotic disease in users of combined estrogen-progestin hormonal contraceptives, and then the issue becomes how safe is safe enough and whether or not we have information that allows us to bound the magnitude of those risks and to identify the people in whom the risks are the highest," observes Petitti. "I don't think we need any more research in order to do either of those two things."


  1. Lidegaard Ø, Løkkegaard E, Jensen A, et al. Thrombotic stroke and myocardial infarction with hormonal contraception. NEJM 2012; 366(24):2,257-2,266.
  2. Parkin L, Skegg DCG, Wilson M, et al. Oral contraceptives and fatal pulmonary embolism. Lancet 2000; 355:2,133-2,134.
  3. Van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, et al. The venous thrombotic risk of oral contraceptives, effects of estrogen dose and progestagen type: results of the MEGA case-control study. BMJ 2009; 339:b2921.
  4. Lidegaard Ø, Løkkegaard E, Svendsen AL, et al. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009; 339:b2890.
  5. Parkin L, Sharples K, Hernandez RK, et al. 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.
  6. Jick SS, Hernandez RK. Risk of nonfatal 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.
  7. Lidegaard Ø, Nielsen LH, Skovlund CW, et al. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and estrogen doses: Danish cohort study 2001-9. BMJ 2011; 343:d6423.
  8. Food and Drug Administration Office of Surveillance and Epidemiology. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular disease endpoints. Accessed at
  9. Gronich N, Lavi I, Rennert G. Higher risk of venous thrombosis associated with drospirenone-containing oral contraceptives: a population-based cohort study. CMAJ 2011; 183(18):E1,319-E1,325.
  10. Nelson, AL, Cwiak C. Combined oral contraceptives. In: Hatcher RA, Trussell J, Nelson AL, et al. Contraceptive Technology: 20th revised edition. New York: Ardent Media; 2011.
  11. Dinger J, Pineda AA. Risk of VTE in users of an etonogestrel-containing vaginal ring and combined oral contraceptives. Presented at the American College of Obstetricians and Gynecologists Annual Clinical Meeting. New Orleans; May 7, 20122.
  12. Petitti DB. Hormonal contraceptives and arterial thrombosis — not risk-free but safe enough. NEJM 2012; 366(24):2,316-2,318.