Is Family History of Blood Clots Contraindication for Ocp

Research

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

BMJ 2009; 339 doi: https://doi.org/ten.1136/bmj.b2921 (Published 13 August 2009) Cite this as: BMJ 2009;339:b2921

A van Hylckama Vlieg , inquiry young man1,
F M Helmerhorst , professor of clinical epidemiology of fertility12,
J P Vandenbroucke , professor of clinical epidemiology1,
C J M Doggen , inquiry fellow1,
F R Rosendaal , professor of clinical epidemiology, head of section134

¹Department of Clinical Epidemiology, Leiden University Medical Center, C7-P, PO Box 9600, NL-2300 RC Leiden, Netherlands
²Section of Gynaecology and Reproductive Medicine, Leiden Academy Medical Center
³Department of Thrombosis and Haemostasis, Leiden University Medical Center
^ivEinthoven Laboratory for Experimental Vascular Medicine, Leiden Academy Medical Centre

Correspondence to: F R Rosendaal F.R.Rosendaal{at}lumc.nl

Accustomed 29 May 2009

Abstract

Objective To assess the thrombotic hazard associated with oral contraceptive use with a focus on dose of oestrogen and type of progestogen of oral contraceptives bachelor in the Netherlands.

Pattern Population based example-control report.

Setting Half-dozen participating anticoagulation clinics in kingdom of the netherlands (Amersfoort, Amsterdam, The Hague, Leiden, Rotterdam, and Utrecht).

Participants Premenopausal women <50 years sometime who were not pregnant, not within four weeks postpartum, and not using a hormone excreting intrauterine device or depot contraceptive. Assay included 1524 patients and 1760 controls.

Primary 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; adapted 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 v.0, 95% CI 4.2 to five.viii). 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.vii to 8.4), 7.iii-fold for desogestrel (7.iii, 5.iii to 10.0), 6.viii-fold for cyproterone acetate (vi.8, 4.7 to 10.0), and vi.three-fold for drospirenone (6.3, two.9 to thirteen.seven). The run a risk of venous thrombosis was positively associated with oestrogen dose. We confirmed a loftier risk of venous thrombosis during the showtime months of oral contraceptive apply irrespective of the type of oral contraceptives.

Conclusions Currently bachelor oral contraceptives still have a major affect on thrombosis occurrence and many women do non use the safest brands with regard to chance of venous thrombosis.

Introduction

The offset report of an increased risk of venous thrombosis associated with oral contraceptives appeared in 1961.1 Since then, several big studies have confirmed a twofold to sixfold increased chance of deep venous thrombosis associated with current oral contraceptive utilise.2 iii four five To subtract the risk of thrombosis, the oestrogen dose in combined oral contraceptives was stepwise reduced over the years. A lowering of the oestrogen dose from 100 μg to fifty μg has been associated with a decreased risk of venous thrombosis.6 seven viii There is no articulate evidence that the lowering of the oestrogen dose to 30 μg or 20 μg led to a further decrease of the take chances of deep venous thrombosis.

Oral contraceptives may incorporate unlike types of progestogens. Commencement generation oral contraceptives contained lynestrenol, but these are now little used. Second generation oral contraceptives, which are widely used, comprise levonorgestrel or, less often, norgestrel. Third generation oral contraceptives, containing desogestrel or gestodene, which became available in the 1980s, are also widely used. 2 other types of oral contraceptives are non included in this nomenclature. Preparations containing cyproterone acetate are used for treatment of acne vulgaris, seborrhoea, or mild hirsutism and have anti-ovulatory activeness similar to that of a progestogen.ix x 11 Preparations containing drospirenone, which is an antimineralocorticoid, also inhibit ovulation and have been on the market place since 2001.12 xiii

Since 1995, numerous reports accept been available on the difference in thrombotic risk associated with 2d and third generation oral contraceptives.4 7 14 Most reported an increased risk of venous thrombosis associated with the newer third generation oral contraceptives. Some, all the same, did not ostend this finding or suggested that the risk difference between 3rd and 2d generation oral contraceptives was overestimated because of bias or misreckoning such as referral or prescription bias.5 15 Kemmeren et al performed a meta-analysis on cohort and case-control studies assessing the risk of venous thrombosis among women using oral contraceptives earlier 1995, and found a twofold increased risk of venous thrombosis for tertiary generation oral contraceptives compared with oral contraceptives containing levonorgestrel.sixteen Every bit several authors pointed out, none of the arguments that this finding was acquired by bias stood up to subsequent analyses or reasoning.17 18 19 20

Oral contraceptives containing cyproterone acetate, on the market since 1988, have been associated with a highly increased chance of venous thrombosis in some studies,21 22 23 but not all.24 25 Express data is bachelor for the thrombotic risk associated with the newest oral contraceptives containing drospirenone, but a series of reported cases of venous thrombosis later on its introduction raised business organisation about an increased risk associated with this oral contraceptive.26 27 Two contempo studies sponsored past the manufacturer, however, reported a similar thrombotic risk for drospirenone compared with levonorgestrel.28 29 All these studies included few cases of thrombosis and therefore had considerable uncertainty effectually the adventure estimates.

The aim of the nowadays study was to assess the thrombotic adventure associated with current oral contraceptive use with a focus on dose of oestrogen and type of progestogen. We set out to determine which hormonal contraceptive is safest with regard to the risk of venous thrombosis using data from a big case-command written report of patients with a first deep venous thrombosis and healthy controls.

Methods

Study design

This assay was performed using data from the MEGA written report (multiple environmental and genetic assessment of chance factors for venous thrombosis-study), a big, population based, case-control study on take a chance factors for venous thrombosis.

Between March 1999 and September 2004, consecutive patients aged <70 years with a first episode of deep venous thrombosis (leg or arm) or pulmonary embolism were included from the files of six participating anticoagulation clinics in the Netherlands (Amersfoort, Amsterdam, The Hague, Leiden, Rotterdam, and Utrecht). Data on the diagnostic procedure was obtained from hospital records and general practitioners. A deep venous thrombosis was confirmed with Doppler ultrasonography. A pulmonary embolism was confirmed past a ventilation perfusion lung scan, spiral computed tomography, or angiogram. Exclusion criteria were severe psychiatric issues and the disability to speak Dutch. Of the 6567 eligible patients, 310 died soon after the venous thrombosis. Of the remaining 6257 patients, 5184 participated (83%). Of the not-participants, 86 were in the end stage of fatal disease and 987 refused to participate or could non exist located. Of the participants, 4752 (91.7%) returned a full questionnaire and 431 completed a short questionnaire by telephone.

Partners of patients <70 years onetime were invited to participate every bit controls. Of the 5184 participating patients, 3735 had an eligible partner. One partner died soon afterwards the request for participation. Of the remaining 3734 partners, 3039 participated (81.4%). Of the non-participants, twenty were in the end stage of disease and 675 refused to participate or could not be located. A total questionnaire was returned past 2873 participating partners (94.5%), and 164 completed a brusk questionnaire by telephone.

From January 2002 until September 2004, additional controls were recruited by random digit dialling. Phone numbers were dialled at random inside the geographical inclusion surface area of the patients. The random controls were frequency matched to the patients with respect to historic period and sex. Only controls between the ages of 18 and 70 years with no history of deep venous thrombosis were included and the same exclusion criteria were applied as for the patients.

Of the 4350 eligible random controls, four died earlier they were able to participate. Of the remaining 4346 individuals, 3000 participated (69%). Of the non-participants, 15 were in the finish stage of disease and 1331 refused to participate or could not be located. A questionnaire was returned by 2788 (93%) of the participating random controls.

For the electric current analyses, only women anile 18-l years were included. Women who were postmenopausal, meaning, or within 4 weeks postpartum at the time of the thrombotic event or index engagement (run across below) and women using hormonal contraception other than oral contraceptives were excluded. From the full patient grouping, we included 1524 female patients. From the partner control grouping, we included 712 female partner controls. From the random digit dialling control group, nosotros selected 1048 female controls. Of the total command group described in the current study (n=1760), twoscore.five% were partner controls and 59.v% were random digit dialling controls. For the analyses described in this manuscript, nosotros pooled the two control groups into a unmarried group and adapted for inclusion date.

Information drove

All participants filled in a standardised questionnaire on risk factors for venous thrombosis such as family unit history of thrombosis, pregnancy, and oral contraceptive employ in the year before the index engagement. The index date was the date of the thrombotic effect for patients and their partners and the date of filling in the questionnaire for the random controls. The questionnaire was sent to all patients and their partners inside a few weeks afterwards the index date. For the random controls, the questionnaire was sent afterwards their agreement to participate.

At least three months afterwards discontinuation of the oral anticoagulation therapy, patients and their partners were invited to the anticoagulation clinic for a blood sample and an interview. During the interviews (in person or by telephone), details on current oral contraceptive use were verified.

Statistical assay

Relative risks were assessed by calculating odds ratios and 95% confidence intervals. Risk estimates were adjusted past unconditional logistic regression, and confidence intervals were derived from the model. The odds ratios in the overall analysis of the take a chance associated with current oral contraceptive use were adjusted for age. When analysing the thrombotic risk associated with dose of oestrogen or blazon of progestogen, an additional adjustment was fabricated for date of inclusion (divided in a total of 12 periods of 6 calendar months spanning 1999-2004). For levonorgestrel, gestodene, desogestrel, and lynestrenol, preparations can contain dissimilar doses of oestrogen and assay was restricted to one dose—the most frequently used of xxx μg ethinyloestradiol for levonorgestrel, gestodene, and desogestrel and 37.v μg ethinyloestradiol for lynestrenol. In all analyses, we pooled the two control groups into one group and adapted for inclusion date. For current oral contraceptive use, the take a chance of venous thrombosis was calculated for all users of oral contraceptives, and separately for the different types of oral contraceptives, compared with non-users (never users and by users combined). Because a positive family history of venous thrombosis has been hypothesised to pb to preferential prescription of specific types of oral contraceptive, we took a positive family unit history into account. A positive family unit history was defined as a participant having at least ane parent or sibling with a history of venous thrombosis equally reported by the participants. Body mass index (weight (kg)/(height (m)²)), besides a potential confounder in the association between different types of oral contraceptives and the risk of venous thrombosis, was calculated using weight and height as stated by the participants in the questionnaire. Smoking was defined as electric current smoking (compared with never smokers and by smokers combined).

All oral contraceptives were classified according to the dose of oestrogen and the type of progestogen. Comparisons were made relative to non-users, and between users of oral contraceptives containing different oestrogen doses and progestogen types. Because some combinations of oestrogen dose and progestogen type practise not be or were non used in this study population, we also performed stratified analyses, such every bit a comparing between several types of progestogens with the same dose of oestrogen (xxx μg ethinylestradiol) and the effect of oestrogen dose stratified for the different types of progestogens.

Results

Table ane⇓ shows the full general characteristics of the study population. Of all 1524 patients, 859 (56.4%) had a deep venous thrombosis of the leg, 495 (32.5%) had a pulmonary embolism, 111 (7.3%) had both, and 59 (iii.9%) had a deep venous thrombosis of the arm. The hateful age of the 1524 patients was 37.1 years, ranging from 18 to 49. The mean age of the 1760 controls was like to that of patients—namely, 37.4 years (range 18-49). Amongst the controls, women who were using hormonal contraceptives (mean age 33.6) were about six years younger than women who did not use hormonal contraceptives (mean age 39.6, mean difference 6.0, 95% CI v.three to 6.8).

Table 1

General characteristics of report population. Data are number (%) unless otherwise indicated

Of the 1524 patients, 1103 (72.4%) were using oral contraceptives at the fourth dimension of thrombosis, compared with 658/1760 (37.4%) of the controls. The per centum of women using oral contraceptives was college in younger women than in older women (table 1⇑).

Overall, current oral contraceptive use was associated with a fivefold increased chance of venous thrombosis (odds ratio 5.0, 95% CI 4.ii to five.8). Additional adjustment for smoking and body mass index resulted in a relative adventure of 5.4 (95% CI 4.5 to vi.4). Brake to individuals without a positive family history of venous thrombosis resulted in a relative risk of 5.8 (4.7 to 7.two) for all oral contraceptive users combined versus non-users.

To show the accented effect of oral contraceptive use among women in different age categories, nosotros estimated the incidence of venous thrombosis in women non using oral contraceptives aged <xxx years, 30-40 years, and twoscore-50 years erstwhile. The overall incidence of venous thrombosis per historic period category (I) can be calculated as I=(p₀×I₀)+(p_one×I₁), relative risk=I₁/I₀, and p_one=1−p₀, where I₁=incidence of venous thrombosis in oral contraceptive users, I₀=incidence of venous thrombosis in non-users, p_i=prevalence of exposure to oral contraceptives in the full general population, and p₀=prevalence of non-exposure in the general population.

From the distribution of oral contraceptive use in the control group, we estimate p₁ and p₀. From our data, we accept estimated the relative risk of venous thrombosis associated with current oral contraceptive use by age category. Using this data, together with the overall incidences of venous thrombosis in women past age category reported by Naess et al,30 nosotros were able to gauge the absolute risk of venous thrombosis in women not using oral contraceptives by age category separately (table 2⇓). Both the relative risk and absolute take a chance of venous thrombosis in women not using oral contraceptives increase with age, which indicates that the absolute risk of venous thrombosis associated with oral contraceptive apply increases with age.

Table 2

Absolute risk of venous thrombosis associated with oral contraceptive use by age category

Most women used a monophasic oral contraceptive, but triphasic oral contraceptives were too used. Eighty 9 patients and 72 controls were using a triphasic oral contraceptive containing levonorgestrel with thirty-xl μg ethinylestradiol. The adventure of venous thrombosis with this triphasic pill was like to that with monophasic oral contraceptives that independent levonorgestrel and 30 μg ethinylestradiol (odds ratio 1.0, 95% CI 0.vii to ane.4); triphasic oral contraceptives increased the take a chance relative to non-users to the same extent every bit monophasic combined contraceptives. The run a risk of venous thrombosis was likewise like for triphasic and monophasic preparations containing gestodene, although the number of users of a triphasic preparation was minor (four patients and five controls).

Progestogen-merely oral contraceptives were used by just 2 patients (lynestrenol) and four controls (desogestrel). No risk estimates tin can be inferred from these minor numbers.

Oestrogen dose and type of progestogen in combined oral contraceptives

Table iii⇓ and the figure⇓ show the risk of venous thrombosis associated with combined oral contraceptives containing different types of progestogens.

Table 3

Take a chance of venous thrombosis associated with unlike types of progestogens in combined oral preparations. Data are numbers (percentages) unless stated otherwise

Oral contraceptives containing levonorgestrel were the nigh frequently used oral contraceptives in the command group (57.0% of all users). Among the thrombosis patients the most frequently used oral contraceptives contained either levonorgestrel (44% of all users) or desogestrel (26.two%).

Compared with non-utilize, use of oral contraceptives was associated with increased chance of venous thrombosis—almost fourfold increment for contraceptives containing levonorgestrel (odds ratio 3.6, 95% CI 2.9 to 4.6), 5.6-fold (95% CI 3.vii to eight.iv) for those containing gestodene, 7.iii-fold (5.3 to ten.0) for desogestrel, 6.8-fold (4.7 to 10.0) for cyproterone acetate, and 6.3-fold (ii.9 to 13.seven) for drospirenone.

When nosotros directly compared different types of oral contraceptives with those containing levonorgestrel (the nearly frequently used progestogen), we found an increased adventure of thrombosis associated with those containing gestodene (odds ratio i.6, 95% CI ane.0 to two.iv), desogestrel (2.0, 1.four to 2.8), cyproterone acetate (2.0, 1.three to 3.0), and drospirenone (1.seven, 0.vii to 3.nine). Amid users of third generation oral contraceptives, the thrombotic run a risk for contraceptives containing desogestrel was mildly increased compared with oral contraceptives containing gestodene (one.3, 0.8 to two.2).

To assess the risk of venous thrombosis associated with the dose of oestrogen, we restricted the assay to monophasic preparations with levonorgestrel, gestodene, or desogestrel. With an oestrogen dose of 30 μg every bit the reference category, the thrombotic risk was 0.8 (95% CI 0.five to i.2) for an oestrogen dose of twenty μg and i.nine (1.1 to iii.4) for a dose of 50 μg.

In table 4⇓ the run a risk of venous thrombosis associated with different doses of oestrogen are presented by blazon of progestogen of the well-nigh frequently used combined oral contraceptives (monophasic)—that is, levonorgestrel, gestodene, and desogestrel. The oestrogen dose was positively associated with the gamble of venous thrombosis for preparations containing desogestrel and those containing gestodene. Using the most commonly used oestrogen dose (xxx μg) as the reference category, we found oral contraceptives containing 20 μg estradiol were associated with a decreased risk of thrombosis whereas those containing 50 μg estradiol were associated with an increased run a risk of thrombosis. For contraceptives containing levonorgestrel, no reduced thrombotic risk was seen for those containing 20 μg ethinylestradiol compared with 30 μg ethinylestradiol, but very few women used an oral contraceptive containing levonorgestrel combined with twenty μg ethinylestradiol, as shown past the wide confidence interval.

Table 4

The risk of venous thrombosis associated with dissimilar doses of ethinylestradiol in monophasic oral contraceptives. Information are odds ratios adapted for age (95% CI) unless stated otherwise

Risk associated with oral contraceptive use for different types of thrombosis

The take chances of venous thrombosis associated with current oral contraceptive utilize was increased for deep venous thrombosis of the leg and pulmonary embolism (tabular array 5⇓). The relative risk was higher for women with a deep venous thrombosis of the leg (odds ratio vi.6, 95% CI 5.4 to 8.0) than for women with a pulmonary embolism (with or without deep venous thrombosis of the leg) (odds ratio 3.nine, 3.2 to iv.8). The risk differences between types of progestogens which we observed for all types of thromboses combined remained substantially the same for both types of thrombosis separately.

Table v

Risk of different types of venous thrombosis associated with oral contraceptive use by different type of progestogen. Patients with venous thrombosis of the arm omitted from this analysis

Current oral contraceptive utilize was besides associated with a twofold increased risk of deep venous thrombosis of the arm (odds ratio one.9, 95% CI 1.ane to 3.four), but the number of patients with this thrombosis was too small-scale to estimate the chance of venous thrombosis associated with different types of progestogens.

Elapsing of oral contraceptive utilise

For 1005 patients with venous thrombosis and 533 control subjects information on the duration of oral contraceptive use on the alphabetize date was available. The risk of venous thrombosis was conspicuously highest during the showtime three months of use (odds ratio 12.6, 95% CI 7.1 to 22.4) (tabular array 6⇓). Afterward one twelvemonth, the take a chance of venous thrombosis for oral contraceptive users compared with non-users decreased to the overall estimate of a fivefold increased risk. In all time intervals, including those of prolonged use, both 2nd and third generation oral contraceptives were used. When we restricted the assay to women who were using oral contraceptives for more than than two years, the thrombotic hazard with oral contraceptives containing desogestrel remained increased compared with those containing levonorgestrel and was similar to the overall take a chance—for gestodene odds ratio i.5 (95% CI 0.9 to 2.6) and for desogestrel 1.9 (1.3 to 2.9).

Table half-dozen

Gamble of venous thrombosis associated with duration of use of oral contraceptive. Data are number

For the newest types of oral contraceptives, we also assessed the risk of thrombosis restricted to brusk term users, to business relationship for compunction of susceptibles (women at increased gamble of getting deep venous thrombosis). The number of short term users for an individual type of progestogen was low, resulting in wide conviction intervals. However, for women using oral contraceptives for iii months or less, the results back up an increased risk for both drospirenone (odds ratio 1.ix, 95% CI 0.2 to 21.3) and cyproterone acetate (i.6, 0.iii to 9.ix) compared with oral contraceptives containing levonorgestrel.

Give-and-take

Main findings of the study

Nosotros constitute that currently available oral contraceptives were associated with a fivefold increased chance of venous thrombosis. This event confirms the results of previous studies reporting a twofold to sixfold increased gamble of deep venous thrombosis associated with oral contraceptive apply.2 3 4 5 Several older studies written report a slightly lower risk, which is probably because nowadays different types of oral contraceptives containing newer progestogens with higher risks are being used. The take a chance clearly differed by blazon of progestogen and dose of oestrogen. Oral contraceptives containing desogestrel were associated with a twofold increased risk of venous thrombosis compared with oral contraceptives containing levonorgestrel, which persisted among women who had used these oral contraceptives for many years.

The chance of thrombosis associated with oral contraceptives containing cyproterone acetate or drospirenone was like to that associated with oral contraceptives containing desogestrel—a sixfold to sevenfold increased risk compared with non-users.

Comparing with other studies

In contrast to our findings, a large prospective cohort report found an equal risk of thrombosis associated with oral contraceptives containing drospirenone or levonorgestrel.28 Nonetheless, our results of an excess risk for drospirenone are supported by previous data from laboratory studies in good for you users, where an excess in thrombin generation (endogenous thrombin potential) was found for oral contraceptives containing desogestrel, cyproterone acetate, and drospirenone that exceeded the event of oral contraceptives containing levonorgestrel.31 Previous studies have also shown that this global exam predicts risk of thrombosis, even in women non using the pill and in men.32

The size of our study allowed split up risk estimation for both desogestrel and gestodene, whereas most previous studies either included just one type or grouped these two progestogens together. The run a risk of deep venous thrombosis with oral contraceptives containing desogestrel was slightly higher than that with oral contraceptives containing gestodene (odds ratio 1.three, 95% CI 0.viii to 2.ii). This confirmed the findings of a previous instance-control written report of oral contraceptives containing gestodene or desogestrel.24 Furthermore, oral contraceptives containing desogestrel have been associated with a more pronounced activated poly peptide C resistance and higher levels of sex hormone binding globulin than those containing gestodene, which are likely to indicate thrombotic chance.33 Results of a crossover report in healthy users, including 33 women, showed different effects on the haemostatic system for third and 2nd generation oral contraceptives.34 35 Oral contraceptives containing desogestrel were associated with more pronounced changes in both the procoagulation and anticoagulation systems compared with oral contraceptives containing levonorgestrel and activated protein C resistance (in both the activated partial thromboplastin time too as the endogenous thrombin potential test) was more pronounced.34 35 36

We plant the risk of venous thrombosis was positively associated with oestrogen dose. Lidegaard et al also showed a positive association between oestrogen dose and the risk of venous thrombosis for oral contraceptives with oestrogen doses lower than fifty μg.24 The same tendency was shown earlier for oral contraceptives with higher doses of oestrogen (50-100 μg).6 7 8

Strengths and limitations of this report

This written report was performed more a decade later on the introduction of oral contraceptives containing desogestrel or gestodene in the netherlands, and data were collected ten years after those that led to our showtime report on the increased thrombogeneity of tertiary generation progestogens. Some women have used oral contraceptives containing desogestrel or gestodene for a considerable fourth dimension. The big study size allowed us to study the duration of oral contraceptive use in detail. Clearly the chance of thrombosis was highest in the offset twelvemonth of oral contraceptive use, with a peak in the commencement three months of apply (odds ratio 12.6, 95% CI 7.1 to 22.iv). This high risk of venous thrombosis during the first months of oral contraceptive use was non the result of differences in the type of oral contraceptives, nor was the loftier risk conferred by third generation oral contraceptives or oral contraceptives containing cyproterone acetate the result of recent use of item brands ("compunction of susceptibles"). We confirmed the latter in an analysis limited to women who had used oral contraceptives for more than two years. These results clearly signal that "recent introduction" bias cannot have affected our results. Oral contraceptives containing drospirenone have been available in the Netherlands since 2002. Here nosotros countered potential "recent introduction" bias by restricting the analysis to brusk term users, and we yet institute a similar excess risk in comparison with brusque term utilise of oral contraceptives containing levonorgestrel (1.vi-fold increased hazard for drospirenone).

The relative risk associated with oral contraceptive apply was higher for deep venous thrombosis of the leg than for pulmonary embolism. Oral contraceptive use was also associated with a twofold increased hazard of a deep venous thrombosis of the arm, as previously reported from this study.37

Information technology could be argued that recall bias may take occurred in our study. Nonetheless, patients fill in the questionnaire within a few weeks after the thrombotic event. For controls, current utilize of oral contraceptives is filled in on the questionnaire. The brusque fourth dimension between thrombosis and filling in the questionnaire, equally well as the fact that the questionnaire is sent to the participants' home, where the package of the oral contraceptive is readily available, makes the occurrence of recall bias very unlikely.

Conclusions and policy implications

All currently used oral contraceptives are equally effective in preventing pregnancy. However, especially the preparations containing cyproterone acetate or drospirenone also have other indications, such as handling of acne vulgaris, seborrhoea, or balmy hirsutism. A recent Cochrane review assessed the event of different combined oral contraceptives for the treatment of acne.38 It concluded that only minor differences were institute in the effectiveness of preparations containing cyproterone acetate, desogestrel, or levonorgestrel in the treatment of acne. As well with regard to weight gain while using oral contraceptives, no major differences were found between preparations containing drospirenone or levonorgestrel.39 The effectiveness of alleviation of premenstrual symptoms by oral contraceptives containing drospirenone compared with placebo or other oral contraceptives has non been demonstrated.40

Thus, available evidence suggests that, fifty-fifty for acne or weight gain, there is no clear divergence between most commonly used oral contraceptives. This indicates that the choice of oral contraceptive should be based on the smallest increase of side effects, such every bit chance of venous thrombosis. Information technology is estimated that 100 million women utilize an oral contraceptive worldwide.41 With such a large number of women using oral contraceptives, even the smallest increase of side furnishings volition affect many. Noesis of these risks and efforts to reduce them are of crucial importance. Our results conspicuously 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.

What is already known on this topic

Current oral contraceptive use is associated with a twofold to sixfold increased take a chance of venous thrombosis
Limited information is available on the risk associated with the newest type of oral contraceptives containing drospirenone

What this study adds

The venous thrombotic risk clearly differed by type of progestogen and was positively associated with dose of oestrogen
The risk of thrombosis associated with oral contraceptives containing cyproterone acetate or drospirenone was similar to that associated with oral contraceptives containing desogestrel; a sixfold to sevenfold increased risk compared with non-users
The safest option with regard to the risk of venous thrombosis is an oral contraceptive containing levonorgestrel combined with a low dose of oestrogen

Notes

Cite this as: BMJ 2009;339:b2921

Footnotes

We thank the directors of the Anticoagulation Clinics of Amersfoort (MHH Kramer), Amsterdam (M Remkes), Leiden (FJM van der Meer), The Hague (E van Meegen), Rotterdam (AAH Kasbergen), and Utrecht (J de Vries-Goldschmeding) who fabricated the recruitment of patients possible. The interviewers (JCM van den Berg, B Berbee, S van der Leden, M Roosen, and EC Willems of Brilman) performed the claret draws. We also give thanks I de Jonge, R Roelofsen, 1000 Streevelaar, LMJ Timmers, and JJ Schreijer for their authoritative support and information management. The fellows ID Bezemer, JW Blom, ER Pomp, KJ van Stralen, LW Tick took part in every footstep of the data collection. We express our gratitude to all individuals who participated in the MEGA study.
Funding: This enquiry was supported past the Netherlands Middle Foundation (NHS 98.113), the Dutch Cancer Foundation (RUL 99/1992) and holland Organisation for Scientific Research (912-03-033| 2003). The funding organisations did not play a role in the design and conduct of the study; collection, management, assay, and estimation of the data; preparation, review, or approving of the manuscript.
Competing interests: None declared
Ethical approval: All participants gave written informed consent. The study was approved by the Medical Ethics Committee of the Leiden Academy Medical Center, Leiden, the Netherlands.

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