Third- and second-generation oral contraceptives are associated with similar risk estimates for venous thromboembolism

Abstract

A scientific discussion between 1995 and 1999 addressed the question whether second- and third-generation oral contraceptives (OCs) were associated with different risks of venous thromboembolism (VTE). Results from three epidemiological studies became available in the course of 1995, in which such differences were observed. Although it was unclear at that time whether these observations reflected causality or were induced by bias and/or confounding, some regulatory bodies in Europe restricted the indication for use of third-generation oral contraceptives. Immediate media attention generated a pill scare in those, but also other, countries.

Indications for the influence of bias were observed in the initial studies of 1995 and further substantiated in subsequent utilization and prescribing surveys. The most important bias seemed to be related to differences in age and duration of use between third- and second-generation OC users. A number of new studies as well as new analyses in two of the 1995 databases included measures to limit the effect of the identified biases/confounders. These studies observed similar risks of venous thromboembolism with second- and third-generation oral contraceptives. Two other recently published studies did not or could not include the same level of control for confounding and reported similar results as the 1995 studies, thus reconfirming the relevance of the identified confounders. Population data show that the massive switch in the UK from third-generation OCs to second-generation OCs in 1995 has not resulted in a reduction of the incidence of VTE in OC users after 1995, illustrating that the risk of VTE is not determined by the type of low-dose pill used. In addition, data from trend analyses, spontaneous reporting and studies addressing hemostatic mechanisms in pill-users also do not support a potential difference in risk of VTE between users of second- and third-generation OCs.

KEY WORDS:

• Oral contraceptives
• Desogestrel
• Gestodene
• Levonorgestrel
• Ethinylestradiol
• Venous thromboembolism
• Epidemiological studies
• Bias
• Confounding factors