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Published: July 1998

The Risk of Venous Thromboembolism with Third Generation Oral Contraceptives

Information on this subject has been updated. Read the most recent information.

Prescriber Update 11, February 1996
July 1998

Medsafe Editorial Team

In October 1995 the Ministry of Health issued a press statement and sent a letter to general practitioners and pharmacists, highlighting a possible increased risk of venous thromboembolism associated with the use of low dose oral contraceptives containing desogestrel or gestodene (that is, the "3rd generation oral contraceptives").

The Ministry's advice at that time was that women using or contemplating the use of oral contraceptives should be made aware of the risks with all oral contraceptives and that there was no need for women to change from their existing choice of contraceptives. December 1995 and January 1996 saw the publication of the five papers from which this preliminary information was derived. All confirm that 3rd generation oral contraceptives produce a greater (up to 2x) relative risk of venous thromboembolism than do low dose oral contraceptives containing levonorgestrel as the progestagen. The overall risk of venous thromboembolism reported in these studies, however, is lower for these 2nd and 3rd generation oral contraceptives than was previously thought.

Prescribers should include this information on the relative risk of venous thromboembolism in the discussion of relative risks and benefits of contraceptive methods, before a contraceptive choice is made or a change is implemented.

The WHO collaborative study of cardiovascular disease and steroid hormone contraception,1 the UK General Practice Research Database (GPRD) study,2 the study conducted by Bloemenkamp in the Netherlands3 and the transnational case-control study by Spitzer et al4 confirm that the use of low dose oral contraceptives containing desogestrel or gestodene is associated with an increased risk of venous thromboembolism (VTE). This increased risk is approximately double that found for low dose oral contraceptives containing levonorgestrel and other 2nd generation oral contraceptives. It should be noted that the overall risk estimates reported in these studies are lower than those demonstrated in most previous research.1 The acknowledged increase in risk estimated for 3rd generation oral contraceptives is close to the previous estimates for all low dose oral contraceptives.5

The approximate doubling of risk remained stable after adjustment for possible confounding factors such as a history of smoking, previous thromboembolism, varicose veins, hypertension and body mass index. The Bloemenkamp study specifically examined cases for Factor V Leiden mutation, a coagulation disorder known to be associated with increased risk of VTE. The increased risk of VTE associated with 3rd generation oral contraceptives, however, could not be explained by a family history of thromboembolism, other factors such as smoking, and/or the presence of Factor V Leiden mutation.3

Absolute risk of VTE Risk per 100,000 women/years
WHO study GPRP study
Never, or past use, of oral contraceptives 3.9 3.8
Current use of low dose oral contraceptives containing levonorgestrel 10.3 16
Current use of low dose oral contraceptives containing desogestrel or gestodene  21  28
Adjusted risk ratio;
desogestrel or gestodene/levonorgestrel
2.5 2.2

The studies conclude that the use of low dose oral contraceptives containing desogestrel or gestodene increases the risk of venous thromboembolism above that found for 2nd generation oral contraceptives. The increase in risk, which appears to be attributable to desogestrel or gestodene, is superimposed on the background risk of VTE for each woman.3

Only 4 independent risk factors for developing VTE were identified in the WHO study, namely, -

The Bloemenkemp study added having a past history of venous thrombosis as a further risk factor.

The authors stress that further independent study is necessary as their results may be due to chance or other unaccounted confounding factors. The interpretation of the small increase in risk of VTE which has been estimated to cause an increase of between 1 and 6 deaths per million users each year, must be weighed against a possible decrease in the risk of other cardiovascular endpoints.4,6 Until the relative risk of other important health outcomes, such as stroke or coronary heart disease, between users of 3rd generation and earlier oral contraceptives is clarified, or a subgroup of women at much higher risk of VTE with 3rd generation products can be identified, there is no sound basis for recommending any change to current contraceptive practices.

  1. WHO collaborative study of cardiovascular disease and steroid hormone contraception. Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control. Lancet 1995;346:1575-1582.
  2. Jick H, Jick S et al. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995;346:1589-1593.
  3. Bloemenkamp KW, Rosendaal FM et al. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet 1995;346:1593-1596.
  4. Spitzer W et al. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. BMJ 1996;312:83-7.
  5. Mills AM, et al. Guidelines for prescribing combined oral contraceptives. BMJ 1996;312:121.
  6. Weiss N. Third-generation oral contraceptives: how risky? Lancet 1995;346:1570.

Note: To assist women become better informed, a fact sheet entitled "Oral Contraceptives and Blood Clots" was included with this issue of Prescriber Update. This patient information fact sheet has been produced by the Women's Health Information Service of the Women's Health Action Trust. Copies were included for medical practitioners, midwives and pharmacists.


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