The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and  progestogen type: results of the MEGA case-control study

van Hylckama Vlieg A; Helmerhorst FM; Vandenbroucke JP; Doggen CJ; Rosendaal FR

doi:10.1136/bmj.b2921

Contraception Oral Contraceptives

The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study

van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJ, Rosendaal FR

Published August 13, 2009 BMJ (Clinical Research Ed.), 339(aug13 2), b2921

DOI 10.1136/bmj.b2921 PMID 19679614 PMC PMC2726929

RRM Academy Synopsis

Oral contraceptive users had fivefold higher odds of venous clots

A Dutch case-control study of 1524 women with a first clot and 1760 controls found that oral contraceptive users had five times the odds of a venous blood clot compared with non-users. Clot odds were lowest with levonorgestrel pills and highest with desogestrel pills. Higher estrogen dose was also associated with higher odds.

Key Findings

Women currently using oral contraceptives had five times the odds of venous thrombosis compared with non-users (odds ratio 5.0, 95% CI 4.2 to 5.8).
Odds ratios against non-use were 3.6 (95% CI 2.9 to 4.6) for levonorgestrel, 5.6 (3.7 to 8.4) for gestodene and 7.3 (5.3 to 10.0) for desogestrel.
Odds ratios against non-use were 6.8 (95% CI 4.7 to 10.0) for cyproterone acetate and 6.3 (2.9 to 13.7) for drospirenone.
In monophasic pills of three progestogens, odds ratios versus the common estrogen dose were 0.8 (95% CI 0.5 to 1.2) for the lower dose, 1.9 (1.1 to 3.4) for the higher.
The odds ratio peaked in the first three months of use at 12.6 (95% CI 7.1 to 22.4). After one year it fell to the overall fivefold level.

Interpretation

The MEGA study is a population-based case-control study. Women with a first leg or lung clot were compared with partners of patients and with randomly dialed controls, and odds ratios estimate relative risk. Participants were premenopausal Dutch women aged 18 to 50 who were not pregnant, recently postpartum or using other hormonal contraception. Adjusting for smoking and body mass index gave a similar odds ratio of 5.4 (95% CI 4.5 to 6.4). The authors note that no risk estimates can be inferred from the small numbers of progestogen-only pill users.

RRM Context

Oral contraceptives are suppressive medications that stop ovulation. Pills with cyproterone acetate or drospirenone are also used for acne and mild excess hair growth. Restorative reproductive medicine first looks for the cause of those problems and of cycle problems. Cause-based care avoids the clot risk this study measured.

Our editorial summary of this paper, not the article's abstract.

Abstract

Objective

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.

Topics

Contraception › Oral Contraceptives › Metabolic Effects · Therapeutics › Hormonal Agents › Progesterone and Progestins

A van Hylckama Vlieg, Frans M Helmerhorst

F Helmerhorst

PMID 19679614 19679614 DOI 10.1136/bmj.b2921 10.1136/bmj.b2921 van Hylckama Vlieg et al. 2009, van Hylckama Vlieg 2009

Keywords

Contraceptives, Oral, Hormonal, Contraceptives, Oral, Synthetic, Estrogens, Progestins