To assess the thrombotic risk associated with oral contraceptive use with a focus on dose of oestrogen and type of progestogen of oral contraceptives available in the Netherlands.
Design
Population based case-control study.
Setting
Six participating anticoagulation clinics in the Netherlands (Amersfoort, Amsterdam, The Hague, Leiden, Rotterdam, and Utrecht).
Participants
Premenopausal women <50 years old who were not pregnant, not within four weeks postpartum, and not using a hormone excreting intrauterine device or depot contraceptive. Analysis included 1524 patients and 1760 controls.
Main Outcome Measures
First objectively diagnosed episodes of deep venous thrombosis of the leg or pulmonary embolism. Odds ratios calculated by cross-tabulation with a 95% confidence interval according to Woolf's method; adjusted odds ratios estimated by unconditional logistic regression, standard errors derived from the model.
Results
Currently available oral contraceptives increased the risk of venous thrombosis fivefold compared with non-use (odds ratio 5.0, 95% CI 4.2 to 5.8). The risk clearly differed by type of progestogen and dose of oestrogen. The use of oral contraceptives containing levonorgestrel was associated with an almost fourfold increased risk of venous thrombosis (odds ratio 3.6, 2.9 to 4.6) relative to non-users, whereas the risk of venous thrombosis compared with non-use was increased 5.6-fold for gestodene (5.6, 3.7 to 8.4), 7.3-fold for desogestrel (7.3, 5.3 to 10.0), 6.8-fold for cyproterone acetate (6.8, 4.7 to 10.0), and 6.3-fold for drospirenone (6.3, 2.9 to 13.7). The risk of venous thrombosis was positively associated with oestrogen dose. We confirmed a high risk of venous thrombosis during the first months of oral contraceptive use irrespective of the type of oral contraceptives.
Conclusions
Currently available oral contraceptives still have a major impact on thrombosis occurrence and many women do not use the safest brands with regard to risk of venous thrombosis.
PMID 19679614 19679614 DOI 10.1136/bmj.b2921 10.1136/bmj.b2921
Cite this article
van Hylckama Vlieg, A., Helmerhorst, F. M., Vandenbroucke, J. P., Doggen, C. J. M., & Rosendaal, F. R. (2009). The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ (Clinical research ed.), 339(aug13 2), b2921. https://doi.org/10.1136/bmj.b2921
van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJM, Rosendaal FR. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ. 2009;339(aug13 2):b2921. doi:10.1136/bmj.b2921
van Hylckama Vlieg, A., et al. "The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study." BMJ (Clinical research ed.), vol. 339, no. aug13 2, 2009, pp. b2921.
To investigate the association between use of combined oral contraceptives and risk of venous thromboembolism, taking the type of progestogen into account.
Two nested case-control studies.
General practices in the United Kingdom contributing to the Clinical Practice Research Datalink (CPRD; 618 practices) and QResearch primary care database (722 practices). Women aged 15-49 years with a first diagnosis of venous thromboembolism in 2001-13, each matched with up to five controls by age, practice, and calendar year. Odds ratios for incident venous thromboembolism and use of combined oral contraceptives in the previous year, adjusted for smoking status, alcohol consumption, ethnic group, body mass index, comorbidities, and other contraceptive drugs. Results were combined across the two datasets. 5062 cases of venous thromboembolism from CPRD and 5500 from QResearch were analysed. Current exposure to any combined oral contraceptive was associated with an increased risk of venous thromboembolism (adjusted odds ratio 2.97, 95% confidence interval 2.78 to 3.17) compared with no exposure in the previous year. Corresponding risks associated with current exposure to desogestrel (4.28, 3.66 to 5.01), gestodene (3.64, 3.00 to 4.43), drospirenone (4.12, 3.43 to 4.96), and cyproterone (4.27, 3.57 to 5.11) were significantly higher than those for second generation contraceptives levonorgestrel (2.38, 2.18 to 2.59) and norethisterone (2.56, 2.15 to 3.06), and for norgestimate (2.53, 2.17 to 2.96). The number of extra cases of venous thromboembolism per year per 10,000 treated women was lowest for levonorgestrel (6, 95% confidence interval 5 to 7) and norgestimate (6, 5 to 8), and highest for desogestrel (14, 11 to 17) and cyproterone (14, 11 to 17). In these population based, case-control studies using two large primary care databases, risks of venous thromboembolism associated with combined oral contraceptives were, with the exception of norgestimate, higher for newer drug preparations than for second generation drugs.
Contraception/ComparisonGeneral OB/GYN
Open Access
To assess the risk of venous thrombosis in current users of different types of hormonal contraception, focusing on regimen, oestrogen dose, type of progestogen, and route of administration.
National cohort study.
Denmark, 1995-2005. Danish women aged 15-49 with no history of cardiovascular or malignant disease. Adjusted rate ratios for all first time deep venous thrombosis, portal thrombosis, thrombosis of caval vein, thrombosis of renal vein, unspecified deep vein thrombosis, and pulmonary embolism during the study period. 10.4 million woman years were recorded, 3.3 million woman years in receipt of oral contraceptives. In total, 4213 venous thrombotic events were observed, 2045 in current users of oral contraceptives. The overall absolute risk of venous thrombosis per 10 000 woman years in non-users of oral contraceptives was 3.01 and in current users was 6.29. Compared with non-users of combined oral contraceptives the rate ratio of venous thrombembolism in current users decreased with duration of use (<1 year 4.17, 95% confidence interval 3.73 to 4.66, 1-4 years 2.98, 2.73 to 3.26, and >4 years 2.76, 2.53 to 3.02; P<0.001) and with decreasing dose of oestrogen. Compared with oral contraceptives containing levonorgestrel and with the same dose of oestrogen and length of use, the rate ratio for oral contraceptives with norethisterone was 0.98 (0.71 to 1.37), with norgestimate 1.19 (0.96 to 1.47), with desogestrel 1.82 (1.49 to 2.22), with gestodene 1.86 (1.59 to 2.18), with drospirenone 1.64 (1.27 to 2.10), and with cyproterone 1.88 (1.47 to 2.42). Compared with non-users of oral contraceptives, the rate ratio for venous thromboembolism in users of progestogen only oral contraceptives with levonorgestrel or norethisterone was 0.59 (0.33 to 1.03) or with 75 mug desogestrel was 1.12 (0.36 to 3.49), and for hormone releasing intrauterine devices was 0.90 (0.64 to 1.26). The risk of venous thrombosis in current users of combined oral contraceptives decreases with duration of use and decreasing oestrogen dose. For the same dose of oestrogen and the same length of use, oral contraceptives with desogestrel, gestodene, or drospirenone were associated with a significantly higher risk of venous thrombosis than oral contraceptives with levonorgestrel. Progestogen only pills and hormone releasing intrauterine devices were not associated with any increased risk of venous thrombosis.
Identifying breast cancer risk factors is a critical component of preventative strategies for this disease. This study aims to identify modifiable and non-modifiable risk factors of breast cancer in Iranian women. We used international databases (PubMed/Medline, Scopus, Web of Knowledge, and Embase) and national databases (SID, Magiran, and ISC) to retrieve relevant studies until November 13, 2022. The odds ratio (OR) with a 95% confidence interval using the random-effect model was used to estimate the pooled effect. The publication bias was assessed by the Egger and Begg test. A sensitivity analysis was conducted to evaluate the effect of each included study on the final measurement. Of the 30,351 retrieved articles, 24 matched case-control records were included with 12,460 participants (5675 newly diagnosed cases of breast cancer and 6785 control). This meta-analysis showed that of the known modifiable risk factors for breast cancer, obesity (vs normal weight) had the highest risk (OR = 2.17, 95% CI 1.47 to 3.21; I(2) = 85.7) followed by age at marriage (25-29 vs < 18 years old) (OR = 2.00, 95% CI 1.53 to 2.61; I(2) = 0), second-hand smoking (OR = 1.86, 95% CI 1.58 to 2.19; I(2) = 0), smoking (OR = 1.83, 95% CI 1.41 to 2.38; I(2) = 18.9), abortion history (OR = 1.44, 95% CI 1.02 to 2.05; I(2) = 66.3), oral contraceptive use (OR = 1.35, 95% CI 1.11 to 1.63; I(2) = 74.1), age at marriage (18-24 vs < 18 years old) (OR: 1.22, 95% CI 1.02 to 1.47; I(2) = 0). Of non-modifiable risk factors, history of radiation exposure (OR = 3.48, 95% CI 2.17 to 5.59; I(2) = 0), family history of breast cancer (OR = 2.47, 95% CI 1.83 to 3.33; I(2) = 73), and age at menarche (12-13 vs ≥ 14 years old) (OR = 1.67, 95% CI 1.31-2.13; I(2) = 25.4) significantly increased the risk of breast cancer. Since most risk factors related to breast cancer incidence are modifiable, promoting healthy lifestyles can play an influential role in preventing breast cancer. In women with younger menarche age, a family history of breast cancer, or a history of radiation exposure, screening at short intervals is recommended.