The authors of this review observed that all generations of progestogens were associated with an increased risk of venous thrombosis and that third generation users had a slight increased risk compared with second generation users. All individual types of combined oral contraceptives increased thrombosis risk compared with non-use by more than two-fold. The highest risk of venous thrombosis was found among 50LNG (50 μg ethinylestradiol with levonorgestrel) users, and the risk was similar in 30DRSP (30 μg ethinylestradiol with drospirenone), 35CPA (35 μg ethinylestradiol with cyproterone acetate), and 30DSG users (30 μg ethinylestradiol with desogestrel). Users of 30LNG (30 μg ethinylestradiol with levonorgestrel), 20LNG (20 μg ethinylestradiol with levonorgestrel), and 20GSD (20 μg ethinylestradiol with gestodene) had the lowest thrombosis risk.
The authors noted the following limitations with the network meta-analysis:
• Publications had to provide the crude number of users and number of events per type of combined oral contraceptive. A total of 15 studies provided information on combined oral contraceptive use and thrombosis risk without specification of which contraceptive preparations were used. These studies could therefore not be included. Because of the need for crude numbers in the network meta-analysis, adjusted risk estimates were not used for pooling the data.
• Confounding could have influenced the results. Age is a potential confounder for the association between contraceptive use and venous thrombosis. Women using second generation contraceptives are generally older than users of third generation contraceptives. If an analysis is not adjusted for age, the relative risk will then underestimate the risk of venous thrombosis in users of third generation contraceptives compared with users of second generation contraceptives. This implies that the risk of third generation users may be higher than reported here. However, age was often dealt with in the design of the studies.
• There is no generally accepted way to classify oral contraceptives according to generations of progestogens. For instance, norgestimate can be categorised as a second or a third generation progestogen. As a consequence, the classification of these generations was not the same in every publication.
• In the classification of progestogen generations used in this meta-analysis, the dose of ethinylestradiol was not taken into account. The observed increased risk in third generation contraceptives, compared with second generation contraceptives, cannot be explained by a difference in ethinylestradiol dose because a higher dose of ethinylestradiol (50 µg) can be present in a second generation contraceptive but not in a third generation contraceptive.
• In only a few included studies, venous thrombosis was objectively confirmed in all patients. Only about 30% of patients with clinical symptoms of thrombosis are diagnosed with venous thrombosis. Including patients without objectively confirmed venous thrombosis would lead to overestimating the association when oral contraceptives users were more likely to be diagnosed than non-users (diagnostic suspicion bias). However, two studies showed that this bias was independent of type of oral contraceptive. In studies without objective confirmation, women were misclassified irrespective of their contraceptive use, leading to non-differential misclassification. Therefore, results of such studies may underestimate the true association, which was confirmed by this study’s sensitivity analysis where the risk estimates were higher in studies with objectively confirmed venous thrombosis than in those without an objective confirmation.
Two other meta-analyses have evaluated the risk of venous thrombosis comparing third generation contraceptive users with second generation users. Both studies found an increased risk in third generation users (relative risk 1.5, 95% confidence interval 1.2 to 1.8; 1.57, 1.24 to 1.98), which are in line with the results reported for this meta-analysis.
The authors conclude that if a woman prefers using combined oral contraceptives, only contraceptives with the lowest risk of venous thrombosis and good compliance should be prescribed, such as levonorgestrel with 30 µg ethinylestradiol. Current practice is to increase the dose of ethinylestradiol in case of disruptions in bleeding patterns. The results of this analysis indicate that prescribing 50 μg ethinylestradiol with levonorgestrel in case of spotting during the use of 30 μg ethinylestradiol with levonorgestrel might carry a serious risk for venous thrombosis.
In the UK, the MHRA issued information in the June 2013 edition of drug safety update following the Europe-wide review of cyproterone acetate with ethinylestradiol (co-cyprindiol). The Europe-wide review was initiated following concerns in France about the risk of venous thromboembolism (VTE) and off-label use as a contraceptive. The review has concluded that the balance of benefits and risks of co-cyprindiol remains positive; however, some important changes to product information for prescribers and women have been made to further improve this balance. Prescribers and women are advised that the risk of VTE with co-cyprindiol is rare and similar to that associated with the hormonal contraceptive pills. However, use of an additional oral contraceptive with co-cyprindiol is contra-indicated.