Many Women May Not Be Using the Safest Brands of Oral Contraceptives

Laurie Barclay, MD

August 13, 2009

August 13, 2009 — Many women are using brands of oral contraceptives that have been linked to greater risk for venous thrombosis, according to the results of 2 studies reported in the August 14 issue of the BMJ.

"The first report of an increased risk of venous thrombosis associated with oral contraceptives appeared in 1961," write A. van Hylckama Vlieg, from Leiden University Medical Center, the Netherlands, and colleagues from the Multiple Environmental and Genetic Assessment (MEGA) case-control study. "Since then, several large studies have confirmed a twofold to sixfold increased risk of deep venous thrombosis associated with current oral contraceptive use. To decrease the risk of thrombosis, the oestrogen dose in combined oral contraceptives was stepwise reduced over the years."

Dutch Population-Based Study Findings

The goal of this population-based case-control study by A. van Hylckama Vlieg PhD, and colleagues was to determine the thrombotic risk associated with the use of oral contraceptives that are available in the Netherlands and that vary in dose of estrogen and type of progestogen.

At 6 participating anticoagulation clinics in the Netherlands (Amersfoort, Amsterdam, The Hague, Leiden, Rotterdam, and Utrecht), this study looked at premenopausal women younger than 50 years who were not pregnant, had not delivered within 4 weeks, and were not using a hormone-excreting intrauterine device or depot contraceptive. Patients with a first objectively diagnosed episode of deep venous thrombosis of the leg or pulmonary embolism (n = 1524) were compared with 1760 healthy control patients.

Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by cross tabulation and use of Woolf's method, adjusted ORs were estimated using unconditional logistic regression, and standard errors were derived from the model.

Compared with nonuse of oral contraceptives, use of currently available oral contraceptives was associated with a 5-fold increase in the risk for venous thrombosis (OR, 5.0; 95% CI, 4.2 – 5.8). Type of progestogen affected thrombotic risk, and the risk for venous thrombosis was positively associated with estrogen dose. During the first months of oral contraceptive use, risk for venous thrombosis was high regardless of the type of oral contraceptives used.

Compared with other progestogens, levonorgestrel was associated with the lowest thrombotic risk (with a nearly 4-fold increased risk for venous thrombosis vs nonusers of oral contraceptives; OR, 3.6; 95% CI, 2.9 – 4.6). In contrast, the risk for venous thrombosis compared with nonuse was increased 5.6-fold for gestodene (95% CI, 3.7 – 8.4), 7.3-fold for desogestrel (95% CI, 5.3 – 10.0), 6.8-fold for cyproterone acetate (95% CI, 4.7 – 10.0), and 6.3-fold for drospirenone (95% CI, 2.9 – 13.7).

"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," the study authors write.

Limitations of this study include potential "recent introduction" bias and recall bias, both of which the investigators consider to be unlikely.

Danish National Follow-Up Study Results

The second study, by Øjvind Lidegaard, MD, DrMSci, from Rigshospitalet, Copenhagen University, Denmark, and colleagues was a national cohort follow-up study taking place in Denmark from 1995 to 2005. The goal was to determine the risk for venous thrombosis in current users of hormonal contraception based on regimen, estrogen dose, type of progestogen, and route of administration.

The study cohort consisted of Danish women aged 15 to 49 years with no history of cardiovascular or malignant disease, and the primary endpoints were adjusted RRs for all first-time deep venous thrombosis, portal thrombosis, caval vein thrombosis, renal vein thrombosis, unspecified deep vein thrombosis, and pulmonary embolism during the study period.

During a total of 10.4 million woman-years, there were 3.3 million woman-years in receipt of oral contraceptives. Of 4213 venous thrombotic events observed during follow-up, 2045 were in current users of oral contraceptives. Overall absolute risk for venous thrombosis per 10,000 woman-years was 6.29 in current users of oral contraceptives compared with 3.01 in nonusers.

The RR of venous thromboembolism in current users of combined oral crontraceptives vs nonusers decreased with decreasing dose of estrogen and with duration of use (< 1 year, 4.17; 95% CI, 3.73 – 4.66; 1 – 4 years, 2.98; 95% CI, 2.73 – 3.26; and > 4 years, 2.76; 95% CI, 2.53 – 3.02; P < .001).

Compared with oral contraceptives containing levonorgestrel and with the same dose of estrogen and duration of use, the rate ratios (RRs) were as follows:

  • oral contraceptives containing norethisterone, 0.98 (95% CI, 0.71 – 1.37);

  • norgestimate, 1.19 (95% CI, 0.96 – 1.47);

  • desogestrel, 1.82 (95% CI, 1.49 – 2.22);

  • gestodene, 1.86 (95% CI, 1.59 – 2.18);

  • drospirenone, 1.64 (95% CI, 1.27 – 2.10); and

  • oral contraceptives containing cyproterone, 1.88 (95% CI, 1.47 – 2.42).

Compared with women who did not use oral contraceptives, the RR for venous thromboembolism in women who used progestogen-only oral contraceptives with levonorgestrel or norethisterone was 0.59 (95% CI, 0.33 – 1.03); for progestogen-only oral contraceptives with 75-μg desogestrel, the RR was 1.12 (95% CI, 0.36 – 3.49). For women who used hormone-releasing intrauterine devices, the RR for venous thromboembolism was 0.90 (95% CI, 0.64 – 1.26).

"The risk of venous thrombosis in current users of combined oral contraceptives decreases with duration of use and decreasing oestrogen dose," the study authors write. "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."

Limitations of this study were lack of data on 2 potential confounders (family predisposition and body mass index), inability to evaluate the validity of each included diagnosis of venous thromboembolism, and lack of data on lifestyle.

Safest Oral Contraceptives to Use

"For women of normal weight and without known genetic predispositions, we recommend a low dose combined pill as first choice for contraception," the study authors conclude. "For women genetically predisposed to venous thrombosis who still want hormonal contraception, however, a progestogen only pill or hormone releasing intrauterine device seems to be the appropriate first choice."

In an accompanying editorial, Nick Dunn, MD, from the University of Southampton, United Kingdom, notes that both studies were observational and were therefore prone to confounding and bias, but also that both studies produced remarkably similar results. Dr. Dunn agrees with the conclusions of a clinical review of all methods of female contraception also published in the same issue of the BMJ:

"When discussing oral contraceptives it recommends those containing levonorgestrel or norethisterone, with as low a dose of oestrogen as possible. All of the more recent progestogens, possibly except norgestimate, now seem to be at a disadvantage with regard to venous thromboembolism. However, the absolute risk of having venous thromboembolism is low — the baseline risk is five per 100 000 person years, and this increases to about 15-25 per 100 000 person years when taking the pill."

The Netherlands Heart Foundation, the Dutch Cancer Foundation, and the Netherlands Organisation for Scientific Research supported the MEGS case control study, and the authors have disclosed no relevant financial relationships. The Gynaecological Clinic, Rigshospitalet, covered the expenses for the Danish national follow-up study. Dr. Lidegaard has received grants from pharmaceutical companies to cover research expenses and has received fees for speeches on pharmacoepidemiological topics. Dr. Dunn has disclosed no relevant financial relationships.

BMJ. 2009;339:b2890, b2921, b3164.

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