Oral Contraceptives and Stroke In the 1970s, OC use appeared to be linked to risk of both hemorrhagic and thrombotic stroke, but these studies failed to take into consideration preexisting risk factors (147). A rare form of cerebrovascular insufficiency, moyamoya disease, is linked to OC use, especially among cigarette smokers (148). The present evidence shows no risk of stroke among women who are otherwise healthy and who use low-dose pills. One study identified all Kaiser Permanente Medical Care Program patients aged 15 to 44 years who sustained fatal or nonfatal stroke in California from 1991 to 1994 (149). Hypertension, diabetes, obesity, current cigarette smoking, and black ethnicity were strongly associated with stroke risk, but neither current nor past OC use was associated with stroke. A World Health Organization study of cases from 1989 to 1993 from 17 countries in Europe and the developing world included women taking higher-dose OCs and low-dose OCs. European women using low-dose OCs had no increased risk for either type of stroke, thrombotic or hemorrhagic. Those taking higher-dose OCs did have measurable risk (150,151). Women in developing countries had an apparent modest increase in risk, but this finding was attributed to undetected existing risk factors. Another study from Europe found less stroke risk from low-dose pills than from older, higher-dose pills, and that risk was less if the patient’s blood pressure was checked before starting OCs.
Women who smoke and those who have hypertension and diabetes are at increased risk for cardiovascular disease regardless of whether they use oral contraceptives. The important question is whether risk is further increased if they use low-dose OCs, and if so, by how much. The World Health Organization study described previously provides some insight: smokers taking OCs had seven times the risk of ischemic (thrombotic) stroke when compared with smokers who did not use OCs, and hypertensive women had 10-fold increased risk if they took OCs, but a fivefold risk if they did not (150). Similarly, a study from Denmark found that women with diabetes had a fivefold increase risk for stroke, which increased to 10-fold if they took OCs (152). These data were not limited to low-estrogen OCs. The data suggest that although risk is primarily determined by the predisposing condition—hypertension, diabetes, or cigarette smoking—the risk can be magnified by OC use, even when the OCs are low dose. These observations were confirmed in a recent systematic review (153). Hypertensive women using combination estrogen–progestin oral contraceptives (COCs) had higher risk for ischemic stroke and acute myocardial infarction than hypertensive women not using COCs. The current US practice of limiting hormonal contraceptives containing estrogen by women older than 35 years of age to nonsmokers without other vascular disease risk factors is prudent (7).
Blood Pressure Oral contraceptives have a dose-related effect on blood pressure. With the older high-dose pills, as many as 5% of patients could be expected to have blood pressure levels greater than 140/90 mm Hg. The mechanism is believed to be an estrogen-induced increase in renin substrate in susceptible individuals. Low-dose pills have minimal blood pressure effects, but surveillance of blood pressure is advised to detect the occasional idiosyncratic response.
Glucose Metabolism Oral estrogen alone has no adverse effect on glucose metabolism, but progestins exhibit insulin antagonism (154). Older OC formulations with higher doses of progestins produced abnormal glucose tolerance tests with elevated insulin levels in the average patient. The effect on glucose metabolism, similar to the effect on lipids, is related to androgenic potency of the progestin and to its dose.