Women of reproductive age have a low risk of ischemic stroke, but studies conducted since the introduction of oral contraceptives have produced contradictory results on whether pill use increases that risk. A meta-analysis including 16 of those studies finds that over the last 40 years, the relative risk of stroke among current users of oral contraceptives has been almost three times that among nonusers.1 The omission of studies whose results were found to be biased by aspects of research design--those that did not control for estrogen dosage, smoking and hypertension and those that used hospital controls--reduces the relative risk of ischemic stroke for current users of low-dose pills to 1.9 times the risk among nonusers. This risk represents four additional strokes per 100,000 women annually.

To determine whether stroke risk and oral contraceptive use are related, investigators searched the medical literature for relevant studies and conducted a meta-analysis using the 16 studies that met the following criteria: They included at least 10 cases of ischemic stroke* or cerebral venous sinus thrombosis; clearly differentiated between types of stroke; used a cohort design or a case-control design with controls selected within two years of cases; presented data adequate to calculate the odds ratio or relative risk and confidence interval comparing pill users with non-users; controlled for age; and were not followed by other publications reporting the same data. Overall, women currently using the pill were almost three times as likely as nonusers to have an ischemic stroke (relative risk, 2.8).

Eleven of the 16 studies found a significantly elevated risk of stroke among pill users, while five did not; published relative risks varied from 1.2 to 8.8. Because of the wide range of relative risk estimates from these studies, the investigators examined factors that might have biased the results.

The variation in study results was reduced after stratification by estrogen dosage. The relative risk of stroke rose from 2.1 for women using a pill with less than 50 mcg of the hormone to 2.8 among those using a preparation containing 50 mcg and to 4.5 among those using an oral contraceptive with more than 50 mcg.

The pill-related risk of ischemic stroke in case-control studies was similar to that in cohort studies, which are less susceptible to bias. However, the risk was significantly higher in case-control studies using controls from hospitals than in those using controls from the general population (4.3 vs. 2.3), indicating an underestimation of oral contraceptive use among hospital controls.

Finally, studies that controlled for smoking or for smoking and hypertension yielded significantly smaller risk estimates (2.5-2.6) than did studies that did not control for those factors (3.8-4.3). The investigators note that many studies conducted in the 1960s and 1970s, a period when pill use was positively associated with smoking, did not control for smoking; thus, the elevated stroke risk due to smoking was incorrectly attributed to pill use.

Limiting the analysis to case-control studies that stratified data by estrogen dosage, used controls from the general population, and accounted for the effects of both smoking and hypertension decreased (but did not eliminate) variation in risk estimates. In these five studies, the risk associated with current use of pills containing low doses of estrogen by women who neither smoked nor suffered from hypertension was 1.9, which represents four additional strokes per year per 100,000 women.

According to the investigators, their results suggest that the risk of stroke associated with pill use has declined over the past four decades as the dosage of estrogen contained in oral contraceptives has decreased. They conclude that although women currently using the pill have an elevated risk of ischemic stroke, "the absolute effect is small with current dosages." Moreover, they say, "this additional risk appears to be outweighed by the health benefits of [pill] use in improved birth control."--F. Althaus


1. Gillum LA, Mamidipudi SK and Johnston SC, Ischemic stroke risk with oral contraceptives: a meta-analysis, Journal of the American Medical Association, 2000, 284(1):72-78.