The incidence of venous thromboembolism appears to be related to the estrogen but not the progestin content of oral contraceptives and is not related to age, parity, mild obesity, or cigarette smoking. Decreased venous blood flow, endothelial proliferation in veins and arteries, and increased coagulability of blood resulting from changes in platelet functions and fibrinolytic systems contribute to the increased incidence of thrombosis. The major plasma inhibitor of thrombin, antithrombin III, is substantially decreased during oral contraceptive use. This change occurs in the first month of treatment and lasts as long as treatment persists, reversing within a month thereafter.
b. Myocardial infarction—The use of oral contraceptives is associated with a slightly higher risk of myocardial infarction in women who are obese, have a history of preeclampsia or hypertension, or have hyperlipoproteinemia or diabetes. There is a much higher risk in women who smoke. The risk attributable to oral contraceptives in women 30–40 years of age who do not smoke is about 4 cases per 100,000 users per year, as compared with 185 cases per 100,000 among women 40–44 who smoke heavily. The association with myocardial infarction is thought to involve acceleration of atherogenesis because of decreased glucose tolerance, decreased levels of HDL, increased levels of LDL, and increased platelet aggregation. In addition, facilitation of coronary arterial spasm may play a role in some of these patients. The progestational component of oral contraceptives decreases HDL cholesterol levels, in proportion to the androgenic activity of the progestin. The net effect, therefore, will depend on the specific composition of the pill used and the patient’s susceptibility to the particular effects. Recent studies suggest that risk of infarction is not increased in past users who have discontinued oral contraceptives.
c. Cerebrovascular disease—The risk of stroke is concentrated in women over age 35. It is increased in current users of oral contraceptives but not in past users. However, subarachnoid hemorrhages have been found to be increased among both current and past users and may increase with time. The risk of thrombotic or hemorrhagic stroke attributable to oral contraceptives (based on older, higher-dose preparations) has been estimated at about 37 cases per 100,000 users per year.
In summary, available data indicate that oral contraceptives increase the risk of various cardiovascular disorders at all ages and among both smokers and nonsmokers. However, this risk appears to be concentrated in women 35 years of age or older who are heavy smokers. It is clear that these risk factors must be considered in each individual patient for whom oral contraceptives are being considered. Some experts have suggested that screening for coagulopathy should be performed before starting oral contraception.
2. Gastrointestinal disorders—Many cases of cholestatic jaundice have been reported in patients taking progestin-containing drugs. The differences in incidence of these disorders from one population to another suggest that genetic factors may be involved. The jaundice caused by these agents is similar to that produced by other 17-alkyl-substituted steroids. It is most often observed in the first three cycles and is particularly common in women with a history of cholestatic jaundice during pregnancy. Jaundice and pruritus disappear 1–8 weeks after the drug is discontinued.
These agents have also been found to increase the incidence of symptomatic gallbladder disease, including cholecystitis and cholangitis. This is probably the result of the alterations responsible for jaundice and bile acid changes described above.
It also appears that the incidence of hepatic adenomas is increased in women taking oral contraceptives. Ischemic bowel disease secondary to thrombosis of the celiac and superior and inferior mesenteric arteries and veins has also been reported in women using these drugs.
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