Oral contraceptive use and cardiovascular disease: is the relationship real or due to study bias?

Epidemiologic studies link oral contraceptive use with several cardiovascular events, but the literature is difficult to summarize, and potential biases remain poorly addressed. This study uses meta-analysis to summarize study results and to analyze the influence of study characteristics, including susceptibility to bias, on study outcome.

Forty-seven case-control and cohort studies of oral contraceptives and four cardiovascular events were coded for relative risk (RR) and study characteristics, including adherence to 14 bias-control standards. Key RRs were pooled to summarize findings for each disease type. Univariate determinants of the magnitude of the relative risks were identified, and partial correlation analysis was performed for each disease type.

Relative risks were significantly greater than 1.0 for venous thromboembolism (RR = 2.8, CI = 2.4 to 3.2), stroke (RR = 1.8, CI = 1.6 to 2.0), and myocardial infarction (RR = 1.6, CI = 1.4 to 1.8), but not for death due to any cardiovascular cause (RR = 1.0, CI = 0.8 to 1.3). Study characteristics were diverse, and potential biases were frequently uncontrolled. For three of ten study characteristics identified as independently influencing relative risk, methodologically stronger studies of venous thromboembolism tended to have higher RRs. The RRs for stroke and myocardial infarction were lower in studies that were methodologically stronger with regard to variables identified as important. In studies of cardiovascular death, bias-control standards identified as important were generally well addressed by the studies.

Oral contraceptive use does not appear to increase overall cardiovascular mortality. The associations noted with stroke and myocardial infarction may be due to methodologic flaws in the studies, while the association with venous thromboembolism is more likely to be valid.