Obesity, Oral Contraceptive Use, and Cerebral Venous Thrombosis in Women

Cerebral venous thrombosis (CVT) is an uncommon cause of stroke that primarily affects young adults. A unique risk factor profile and plurality of presenting features make it an elusive diagnosis unless a high index of suspicion is maintained. It comprises approximately 0.5% to 1% of all strokes,1 and widespread availabil ity of magnetic resonance imaging has made recognition easier. The International Study on Cerebral Vein and Dural Sinus Thrombosis is the largest prospective, multinational, observational study2 of patients with CVT to date, including 624 consecutive patients with symptomatic CVT at 89 centers between May 1998 and May 2001. Of these patients, 465 were women (74.5%), and they tended to be younger than men at diagnosis (median age, 34 vs 42 years). A total of 301 (65.0%) of these women had an identified sex-specific risk factor, such as oral contraceptive (OC) use, pregnancy, puerperium, or hormonal therapy. It was also observed that women with sex-specific risk factors who develop CVT tend to have better outcomes than women without sex-specific risk factors, which was thought to be owing to younger age and shorter onset to diagnosis period. ThepathophysiologicmechanismsofCVTarenotwell understood because of a lack of appropriate animalmodels,3 but CVT is very distinct from arterial stroke. Pathogenesis of venous thromboembolism (VTE) is closely linked to the Virchow triadof stasis, endothelial damage, andhypercoagulable state. In theVTE literature,OCuse inwomen isawell-recognized risk factor.4 Initially,estrogen inOCpillswas thought to increase the clot risk. However, a study5 has also linked progestins, such as drospirenone and desogestrel, to VTE risk. The discovery of increased rates of asymptomatic atherosclerosis in patients with VTE6 led to the systematic study of cardiovascular risk factors, such as obesity, in VTE. Data from several cohorts, including the Framingham Study, the Atherosclerosis Risk in Communities, and the Cardiovascular Health Study, found an increased risk of VTE with obesity. Obesity also increases the risk of VTE along with OC use, smoking, factor V Leiden, prothrombin gene mutation, and air travel.7 The increased risk of VTE in obese individuals is postulated to be mediated by factor VIII–related activated protein C resistance.8 To date, the association between obesity and CVT in adults had not been studied. In this issue of JAMA Neurology, Zuurbier et al9 study obesity as a risk factor for CVT in an unmatched case-control study. Cases include 192 patients with CVT admitted to the Academic Medical Center, Amsterdam, the Netherlands, and Inselspital University Hospital, Berne, Switzerland, from July 1, 2006 (Amsterdam), and October 1, 2009 (Berne), through December 31, 2014. The authors use 6297 healthy historical controls from the Dutch Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis study, which was a Dutch case-control study that included patients with a first deep vein thrombosis of the leg or pulmonary embolism from March 1, 1999, to September 31, 2004. Obesity is defined as a body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) greater than 30, with individuals with a normal BMI (<25) used as reference. The authors use multivariate logistic regression modeling adjusted for potential confounders, including age, sex, history of cancer, ethnicity, smoking status, and OC use. Given the known association between sex and OC use on VTE risk, they also perform predefined subgroup analyses to study the effect of sex and OC use on the association between obesity and CVT. Caseswere younger, weremore often female,more often usedOCs, andmore frequentlyhadahistoryof cancer.Theauthors found an increased risk of CVT among obese women (odds ratio, 2.63; 95%CI, 1.53-4.54),with a strong association in women, but only for those using OCs, and not inmen. The risk is30-foldhigher inobesewomenusingOCscomparedwith normal-weight women not using OCs. These findings are novel and in concordance with prior studies7,10 on obesity and OC use as risk factors for VTE. The authors also demonstrate a dose-response relationship in the risk of CVTamongwomenusingOCs,with obesewomenhaving ahigher risk comparedwithoverweightwomen.Given the lackof prospectivedata thus far, this is an important studybecauseof theuseof appropriate controls, predefinedconfounders, and appropriate subgroups. It does, however, have limitations, namely, a small number of men and women without OC use, unmatched historical controls, andmissing BMI data in 15.9% of cases. Future prospective studies on the association of obesity, OC use, and CVT in women are needed to corroborate and validate these findings. Studies investigating the effect of inherited thrombophilia on the association between obesity and CVT would also be important because the current study did not have this data. Other potential confounders, such as obstructive sleep apnea and anemia, should be included in future studies. There are clinical and public health implications of the findings because they demonstrate an association of obesity, OC use, and CVT in women. The authors correctly point out that despite the manifold increased relative risk, the absolute risk of CVT in obese women taking OCs still remains low and should not preclude OC use among them. Use of OCs has also been associated with increased risk of arterial ischemic stroke in obese women.11 Better counseling and education of obese women informing them of the increased risk would be prudent, as would be consideration of alternate nonhormonal OC options. Related article page 579 Opinion Editorial