Two studies published early online in the BMJ have reported that the risk of venous thrombosis varied among different types of hormonal contraceptives.

The first study in a Danish cohort of women (1995 to 2005) aged 15 to 49 years, with no history of cardiovascular or malignant diseases, examined the risk in current users with a focus on regimen, oestrogen dose, type of progestogen, and route of administration. The main outcome measures were adjusted rate ratios for all first time DVT, portal thrombosis, thrombosis of caval vein, thrombosis of renal vein, unspecified DVT, and PE during the study period.  A total of 10.4 million woman years were recorded of which 3.3 million woman years were in receipt of oral contraceptives. The following findings were reported:

• 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 was 6.29 in current users and 3.01 in non-users of oral contraceptives.

• 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% CI, 3.73 to 4.66, 1 to 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 75µg desogestrel 1.12 (0.36 to 3.49), and for hormone releasing intrauterine devices 0.90 (0.64 to 1.26).

The researchers conclude from these findings that “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.” They acknowledge limitations to the registry data used in their study such as not being able to evaluate the validity of each included diagnosis of venous thromboembolism and the lack of information about lifestyle, in addition to the lack of two potential confounders; family predisposition and body mass index.

They advise that for women of normal weight and without known genetic predispositions, a low dose combined pill should be the first choice for contraception, but for women genetically predisposed to venous thrombosis who want to use hormonal contraception, a progestogen only pill or hormone releasing intrauterine device seems to be the appropriate first choice. They add that before firm general clinical recommendations on type of progestogen can be made, data on the effect of drospirenone on arterial end points are needed. However, they suggest that for women with an increased BMI, a low dose combined pill with levonorgestrel should be first choice, noting that if the risk of arterial diseases is the same for the new progestogens as for levonorgestrel then based on their figure, about 7400 women should change from the newer products to oral contraceptives containing levonorgestrel to prevent one case of venous thrombosis.

The second study (MEGA case-control study) was conducted in the Netherlands and examined thrombotic risk associated with oral contraceptive use, focusing on dose of oestrogen and type of progestogen. It was conducted at six anticoagulation clinics and involved premenopausal women < 50 years of age who were not pregnant, not within 4 weeks postpartum, and not using a hormone excreting intrauterine device or depot contraceptive. The main outcome measures were first objectively diagnosed episodes of DVT of the leg or PE.

According to the analysis of 1524 patients and 1760 controls:

• Currently available oral contraceptives increased the risk of venous thrombosis 5-fold vs. non-use (odds ratio 5.0, 95% CI, 4.2 to 5.8) and this risk differed by type of progestogen and dose of oestrogen.

• Use of oral contraceptives containing levonorgestrel was associated with an almost 4-fold increased risk of venous thrombosis (3.6, 2.9 to 4.6) relative to non-users, whereas the risk 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.

• There was a high risk of venous thrombosis during the first months of oral contraceptive use irrespective of the type of oral contraceptives.

The researchers conclude from these findings that “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.” They suggest these results “clearly show that the safest option with regard to the risk of venous thrombosis is an oral contraceptive containing levonorgestrel combined with a low dose of oestrogen.”

In a BBC news report, a spokeswoman for the Family Planning Association and experts said it has long been known that the combined contraceptive pill is associated with an increased risk of venous thrombosis but the overall risk is small, whichever brand is used. Women who are worried are advised not to stop taking the pill but to speak to a doctor.

According to the an assessment by NHS Choices:

• The primary research studies provide reliable estimates of the risk of developing venous thromboembolism in women taking a variety of contraceptive pills, and have been interpreted by the clinical reviewers with care.

• Both of the studies were observational and therefore prone to confounding and bias associated with this type of study.

• There may be good reason why some women have been prescribed pills with higher risks of venous thromboembolism, but those considering changing their contraceptive should consult their doctors to fully discuss these issues.