Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis

Bernardine H Stegeman, Marcos de Bastos, Frits R Rosendaal, A van Hylckama Vlieg, Frans M Helmerhorst, Theo Stijnen, Olaf M Dekkers, Bernardine H Stegeman, Marcos de Bastos, Frits R Rosendaal, A van Hylckama Vlieg, Frans M Helmerhorst, Theo Stijnen, Olaf M Dekkers

Abstract

Objective: To provide a comprehensive overview of the risk of venous thrombosis in women using different combined oral contraceptives.

Design: Systematic review and network meta-analysis.

Data sources: PubMed, Embase, Web of Science, Cochrane, Cumulative Index to Nursing and Allied Health Literature, Academic Search Premier, and ScienceDirect up to 22 April 2013.

Review methods: Observational studies that assessed the effect of combined oral contraceptives on venous thrombosis in healthy women. The primary outcome of interest was a fatal or non-fatal first event of venous thrombosis with the main focus on deep venous thrombosis or pulmonary embolism. Publications with at least 10 events in total were eligible. The network meta-analysis was performed using an extension of frequentist random effects models for mixed multiple treatment comparisons. Unadjusted relative risks with 95% confidence intervals were reported. The requirement for crude numbers did not allow adjustment for potential confounding variables.

Results: 3110 publications were retrieved through a search strategy; 25 publications reporting on 26 studies were included. Incidence of venous thrombosis in non-users from two included cohorts was 1.9 and 3.7 per 10,000 woman years, in line with previously reported incidences of 1-6 per 10,000 woman years. Use of combined oral contraceptives increased the risk of venous thrombosis compared with non-use (relative risk 3.5, 95% confidence interval 2.9 to 4.3). The relative risk of venous thrombosis for combined oral contraceptives with 30-35 µg ethinylestradiol and gestodene, desogestrel, cyproterone acetate, or drospirenone were similar and about 50-80% higher than for combined oral contraceptives with levonorgestrel. A dose related effect of ethinylestradiol was observed for gestodene, desogestrel, and levonorgestrel, with higher doses being associated with higher thrombosis risk.

Conclusion: All combined oral contraceptives investigated in this analysis were associated with an increased risk of venous thrombosis. The effect size depended both on the progestogen used and the dose of ethinylestradiol.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; BHS was supported by the Netherlands Organization for Scientific Research; MdB was supported by a grant from Capes-Nuffic, Brazil; no other relationships or activities that could appear to have influenced the submitted work.

Figures

https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4793425/bin/steb011344.f1_default.jpg
Fig 1 Flow diagram of included and excluded publications
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4793425/bin/steb011344.f2_default.jpg
Fig 2 Network meta-analysis, per contraceptive plotted on a logarithmic scale. 20LNG=20 μg ethinylestradiol with levonorgestrel; 30LNG=30 μg ethinylestradiol with levonorgestrel; 50LNG=50 μg ethinylestradiol with levonorgestrel; 20GSD=20 μg ethinylestradiol with gestodene; 30GSD=30 μg ethinylestradiol with gestodene; 20DSG=20 μg ethinylestradiol with desogestrel; 30DSG=30 μg ethinylestradiol with desogestrel; 35NRG=35 μg ethinylestradiol with norgestimate; 35CPA=35 μg ethinylestradiol with cyproterone acetate; 30DRSP=30 μg ethinylestradiol with drospirenone; dots (lines)=overall relative risk (95% confidence interval) of venous thrombosis; non-use=reference group

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