Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen

Lancet. 1995 Dec 16;346(8990):1593-6. doi: 10.1016/s0140-6736(95)91929-5.


Recent concern about the safety of combined oral contraceptives (OCs) with third-generation progestagens prompted an examination of data from a population-based case-control study (Leiden Thrombophilia Study). We compared the risk of deep-vein thrombosis (DVT) during use of the newest OCs, containing a third-generation progestagen, with the risk of "older" products. We also investigated the influence of family history of thrombosis, previous pregnancy, age, and the thrombogenic factor V Leiden mutation. We selected 126 women with DVT and 159 controls aged 15-49 (mean age 34.9) and premenopausal and found, as compared with non-users, the highest age-adjusted relative risks to be that for an OC containing desogestrel and 30 micrograms ethinyloestradiol (relative risk [RR] 8.7, 95% CI 3.9-19.3). We found lower relative risks for all other types of OC, ranging from 2.2 to 3.8. In a direct comparison, users of the desogestrel-containing oral contraceptive had a 2.5-fold higher risk (95% CI 1.2-5.2) than users of all other OC types combined. The relative risk for the desogestrel-containing OC was similar among women with and without a family history--ie, preferential prescription because of family history cannot explain our findings. Nor could the excess risk be explained by previous pregnancy, and it was highest in the youngest age categories, where we would expect most new users. The age-adjusted RR for the desogestrel-containing contraceptive was 9.2 (3.9-21.4) among non-carriers of the factor V Leiden mutation and 6.0 (1.9-19.0) among carriers of the mutation. This latter risk is superimposed on the 8-fold increased risk of venous thrombosis for carriers of the factor V Leiden mutation. The risk of carriers using the desogestrel-containing OC as compared with noncarrier non-users will therefore be increased almost 50-fold. Use of low-dose OCs with a third-generation progestagen carries a higher risk of DVT than the previous generation of OCs. The absolute risk of DVT associated with these OCs seems to be especially high among carriers of the factor V Leiden mutation and among women with a family history of thrombosis. However, the higher risk associated with OC with a third-generation progestagen compared with previous generations was also present in women without factor V Leiden and with no family history.

PIP: In the Netherlands, researchers compared data on 126 women with deep-vein thrombosis (DVT) with data on 159 premenopausal women aged 15-49 to examine the risk of DVT during use of oral contraceptives (OCs) containing a third generation progestogen as well as the influence of the thrombogenic factor V Leiden mutation, family history of thrombosis, age, and previous pregnancy. The desogestrel-containing monophasic OC had the highest relative risk for DVT (8.7 vs. 2.2-3.8). There were too few women using OCs containing gestodene or norgestimate to draw substantial conclusions. The OC with 30 mcg ethinyl estradiol (E2) and desogestrel increased the risk of DVT 2.2 times when compared with the levonorgestrel-containing OC with the same amount of E2. When compared with all other OCs, desogestrel-containing OCs had a 2.5 higher risk. When the researchers compared carriers of the factor V Leiden mutation with non-carriers, the risk of DVT increased about 50 times among women using desogestrel-containing OCs. The age-adjusted relative risk of DVT for desogestrel-containing OCs was 7.2. Even though a positive family history of DVT and factor V Leiden mutation enhanced the effect of desogestrel-containing Ocs, neither could account for all the excess risk of the desogestrel-containing OC since the risk of DVT increased in women with and without a family history of DVT and those with and without factor V Leiden. These findings suggest that the OCs containing a third-generation progestogen (i.e., desogestrel) contribute to a reverse of the gains achieved in reducing the thrombotic risk by decreasing the dose of E2.

Publication types

  • Comment
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Contraceptives, Oral, Combined / adverse effects*
  • Desogestrel / adverse effects
  • Ethinyl Estradiol / adverse effects
  • Factor V / genetics*
  • Factor V / physiology
  • Female
  • Humans
  • Middle Aged
  • Mutation*
  • Progestins / adverse effects*
  • Risk Factors
  • Thrombophlebitis / chemically induced*


  • Contraceptives, Oral, Combined
  • Progestins
  • Ethinyl Estradiol
  • Desogestrel
  • Factor V