Summary.  Background: Venous thrombosis is one of the leading causes of maternal morbidity and mortality. Objective: In the MEGA study, we evaluated pregnancy and the postpartum period as risk factors for venous thrombosis in 285 patients and 857 control subjects. Patients/methods: Between March 1999 and September 2004, consecutive patients with a first episode of venous thrombosis were included from six anticoagulation clinics. Partners of patients and a random digit dialing group were included as control subjects. Participants completed a questionnaire and DNA was collected. Results: The risk of venous thrombosis was 5‐fold (OR, 4.6; 95% CI, 2.7–7.8) increased during pregnancy and 60‐fold (OR, 60.1; 95% CI, 26.5–135.9) increased during the first 3 months after delivery compared with non‐pregnant women. A 14‐fold increased risk of deep venous thrombosis of the leg was found compared with a 6‐fold increased risk of pulmonary embolism. The risk was highest in the third trimester of pregnancy (OR, 8.8; 95% CI, 4.5–17.3) and during the first 6 weeks after delivery (OR, 84.0; 95% CI, 31.7–222.6). The risk of pregnancy‐associated venous thrombosis was 52‐fold increased in factor V Leiden carriers (OR, 52.2; 95% CI, 12.4–219.5) and 31‐fold increased in carriers of the prothrombin 20210A mutation (OR, 30.7; 95% CI, 4.6–203.6) compared with non‐pregnant women without the mutation. Conclusion: We found an increased risk of venous thrombosis during pregnancy and the postpartum period, with an especially high risk during the first 6 weeks postpartum. The risk of pregnancy‐associated venous thrombosis was highly increased in carriers of factor V Leiden or the prothrombin 20210A mutation.

SummaryIn the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study), body weight, height and body mass index (BMI) were evaluated as risk factors. Additionally, the joint effect of obesity together with oral contraceptive use and prothrombotic mutations on the risk of venous thrombosis were analysed. Three-thousand eight-hundred and thirty-four patients with a first venous thrombosis and 4683 control subjects were included, all non-pregnant and without active malignancies. Relative to those with a normal BMI (<25 kg/m 2 ), overweight (BMI ‡ 25 and BMI < 30 kg/m 2 ) increased the risk of venous thrombosis 1AE7-fold [odds ratio (OR) adj(age and sex) 1AE70, 95% confidence interval (CI) 1AE55-1AE87] and obesity (BMI ‡ 30 kg/m 2 ) 2AE4-fold (OR adj 2AE44, 95% CI 2AE15-2AE78). An increase in body weight and body height also individually increased thrombotic risk. Obese women who used oral contraceptives had a 24-fold higher thrombotic risk (OR adj 23AE78, 95% CI 13AE35-42AE34) than women with a normal BMI who did not use oral contraceptives. Relative to non-carriers of normal BMI, the joint effect of factor V Leiden and obesity led to a 7AE9-fold increased risk (OR adj 7AE86, 95% CI 4AE70-13AE15); for prothrombin 20210A this was a 6AE6-fold increased risk (OR adj 6AE58, 95% CI 2AE31-18AE69). Body height, weight and obesity increase the risk of venous thrombosis, especially obesity in women using oral contraceptives.

The results of studies investigating the relationship of smoking with venous thrombosis are inconsistent. Therefore, in the MEGA study, a large population-based case-control study, we evaluated smoking as a risk factor for venous thrombosis and the joint effect with oral contraceptive use and the factor V Leiden mutation. Consecutive patients with a first venous thrombosis were included from six anticoagulation clinics. Partners of patients were asked to participate and additional controls were recruited using a random digit dialing method. Participants completed a standardized questionnaire. Individuals with known malignancies were excluded from the analyses, leaving a total of 3,989 patients and 4,900 controls. Current and former smoking resulted in a moderately increased risk of venous thrombosis (odds ratio (OR) current 1.43, 95% confidence interval (CI95) 1.28-1.60, OR former 1.23, CI95 1.09-1.38) compared with nonsmoking. Adjustment for fibrinogen levels did not substantially change these risk estimates. A high number of pack-years resulted in the highest risk among young current smokers (OR !20 pack-years 4.30, CI95 2.59-7.14) compared with young nonsmokers. Women who were current smokers and used oral contraceptives had an 8.8-fold higher risk (OR 8.79,) than nonsmoking women who did not use oral contraceptives. Relative to nonsmoking noncarriers, the joint effect of factor V Leiden and current smoking led to a 5.0-fold increased risk; for the prothrombin 20210A mutation this was a 6.0-fold increased risk. In conclusion, smoking appears to be a risk factor for venous thrombosis with the greatest relative effect among young women using oral contraceptives. Am. J. Hematol. 83:97-102, 2008. V

Objective-Carriers of the factor V Leiden mutation (FVL-carriers) have a substantially increased risk of deep venous thrombosis (DVT), whereas the risk of pulmonary embolism (PE) is only mildly increased compared with noncarriers. So far few studies have investigated possible mechanisms for this so-called FVL paradox. Methods and Results-Consecutive patients with a first DVT or PE were included in a large population-based case-control study (MEGA study). Patients, aged 18 to 70 years, provided a questionnaire, DNA (nϭ3313), or plasma (nϭ1474). Surgery, injury, and travel were considered thrombosis-provocative. Of 2063 patients with isolated DVT, 20% were FVL-carrier, as were 8% of the 885 patients with isolated PE. Among DVT patients, FVL-carriers had their thrombi more often proximal and a higher number of affected veins than noncarriers. No differences were observed between FVL-carriers and noncarriers in time between provocation and diagnosis, in vitro coagulation time, and thrombus density. Compared with patients with both DVT and PE, isolated DVT patients more often had thrombi located distally and had a similar number of affected veins. Compared with isolated PE patients, isolated DVT patients had a similar time between provocation and diagnosis, and similar in vitro coagulation time and thrombus density. Conclusion-Although some effects were differential for FVL-carriers and noncarriers, and some were differential for PE and DVT patients, none of the potential mechanisms offered a clear explanation. (Arterioscler Thromb Vasc Biol.

Multiple control groups in case-control studies are used to control for different sources of confounding. For example, cases can be contrasted with matched controls to adjust for multiple genetic or unknown lifestyle factors and simultaneously contrasted with an unmatched population-based control group. Inclusion of different control groups for a single exposure analysis yields several estimates of the odds ratio, all using only part of the data. Here the authors introduce an easy way to combine odds ratios from several case-control analyses with the same cases. The approach is based upon methods used for meta-analysis but takes into account the fact that the same cases are used and that the estimated odds ratios are therefore correlated. Two ways of estimating this correlation are discussed: sandwich methodology and the bootstrap. Confidence intervals for the pooled estimates and a test for checking whether the odds ratios in the separate case-control studies differ significantly are derived. The performance of the method is studied by simulation and by applying the methods to a large study on risk factors for thrombosis, the MEGA Study (1999-2004), wherein cases with first venous thrombosis were included with a matched control group of partners and an unmatched population-based control group.