Clinical Question

Do combined oral contraceptives increase the risk of myocardial infarction (MI) and ischemic stroke?

Evidence-Based Answer

The overall risk of MI and ischemic stroke is increased in women who use combined oral contraceptives. The relative risk of MI and ischemic stroke increases as estrogen dose rises, increasing by 60% with doses of 20 mcg and more than doubling when doses of 50 mcg or more are used. Risk of MI and ischemic stroke does not vary with the type or generation of progestin. Physicians should be cautious when prescribing combined oral contraceptives because of the increased risk of MI and ischemic stroke.¹ (Strength of Recommendation: B, based on limited-quality evidence from observational studies.)

Practice Pointers

Approximately one in six U.S. women of reproductive age uses combined oral contraceptives,² and all formulations are equally effective at preventing pregnancy. Although estrogen doses in combined oral contraceptive formulations have decreased over the past half-century to diminish the risk of thrombotic events, ensuring patient safety remains essential.

This Cochrane review included 24 observational studies in a meta-analysis comparing the risk of fatal or nonfatal MI or ischemic stroke between users and nonusers, 18 to 50 years of age, of combined oral contraceptives of varying generations, types, and doses. The generation and type varied according to the progestin included, and the dose varied according to the estrogen formulation. Studies with progestin-only contraceptives, non-oral contraceptives, and postmenopausal women using hormone therapy were excluded. Both previous combined oral contraceptive users and never-users were considered nonusers. No randomized trials that met inclusion criteria were found.

The overall combined risk of MI and ischemic stroke was increased for users of combined oral contraceptives when compared with nonusers (relative risk [RR] = 1.6; 95% confidence interval [CI], 1.3 to 1.9). The risks of MI alone and ischemic stroke alone were also similarly increased. Furthermore, data from seven studies demonstrated a dose-response for increased risk of MI and ischemic stroke with increasing estrogen dose. For estrogen doses of 20 mcg, the RR was 1.6 (95% CI, 1.4 to 1.8); for estrogen doses between 30 and 49 mcg, the RR was 2.0 (95% CI, 1.4 to 3.0); and for estrogen doses of 50 mcg or more, the RR was 2.4 (95% CI, 1.8 to 3.3). There were no differences in the risk of MI or ischemic stroke based on progestin type or generation. Because the analysis included mostly raw data, confounding by age, body mass index, smoking, and calendar time cannot be ruled out. However, all but one of the studies were case-control designs that employed matching to adjust for age and calendar time.

Previous systematic reviews have found an increased association with MI and ischemic stroke among combined oral contraceptive users. This Cochrane review complements and strengthens these findings with more stringent inclusion criteria. The U.S. Medical Eligibility Criteria for Contraceptive Use (US MEC) provides guidance on safe contraceptive use for women by underlying medical condition.³ The US MEC limits its recommendations for combined oral contraceptive use to formulations containing no more than 35 mcg of ethinyl estradiol and states that combined oral contraceptive use in women with multiple major risk factors for cardiovascular disease may increase health risks to an unacceptable level.³ These guidelines also state that combined oral contraceptive use in patients with a personal history of ischemic heart disease or stroke is contraindicated. Given that unintended pregnancy itself increases the risk of adverse health events among women with these underlying medical conditions, clinicians must consider these risks and may want to offer alternative contraceptive methods for women who cannot take combined oral contraceptives.

The practice recommendations in this activity are available at http://summaries.cochrane.org/CD011054.