NEW YORK (Reuters Health) – Obese women who take oral contraceptives face a markedly increased risk of cerebral venous thrombosis (CVT), according to results from a case-control study in the Netherlands and Switzerland.

“Physicians should have a lower threshold of suspecting CVT in an obese woman who uses oral contraceptives if they present with symptoms such as severe headache, focal neurological deficits, or seizures,” Dr. Jonathan M. Coutinho, from Academic Medical Center, Amsterdam, the Netherlands, told Reuters Health by email.

The risk of venous thromboembolism (VTE) is doubled or tripled in obese adults, but whether obesity is associated with adult CVT has not been assessed before.

Dr. Coutinho and colleagues examined whether obesity is a risk factor for adult CVT in an unmatched case-control study of two prospective cohorts (186 cases and 6,134 controls) from the Academic Medical Center in Amsterdam and Inselspital University Hospital in Berne, Switzerland.

Overall, the risk of CVT was increased 2.63-fold in patients with obesity (BMI at least 30) vs patients with a normal BMI, but overweight (BMI 25.0-29.99) was not associated with CVT overall.

As a continuous variable, each 1-unit increase in BMI was associated with a 9% increased risk of CVT, according to the March 14 JAMA Neurology online report.

In subgroup analyses, obesity was not significantly associated with the risk of CVT in men.

Among women, overweight and obesity were associated with CVT, but in further analysis, the increased risk of CVT was limited to women who took oral contraceptives: an 11.87-fold increased risk of CVT with overweight and a 29.26-fold increased risk of CVT with obesity.

“For me the most surprising observation was the strength of the association between obesity and CVT, and the fact that this increased risk was fully attributable to the group of women who used oral contraceptives,” Dr. Coutinho said. “I would have expected that there would have been an association in men or women who did not use oral contraceptives.”

“Both obesity and oral contraceptive use lead to increased activated protein C resistance, which leads to higher concentrations of factor VIII, which in turn may cause thrombosis,” he explained. “This mechanism may explain the synergy between obesity and oral contraceptives on the risk of CVT.”

“I think obese women who want to start using oral contraceptives should receive counseling regarding the increased risk of (cerebral) venous thrombosis,” Dr. Coutinho concluded. “Given the low absolute risk of CVT, I do not think that you should always advise against the use of oral contraceptives, but patients should be told the risks and offered alternative forms of contraception.”

Dr. Chirantan Banerjee, from the Department of Neurology at the Medical University of South Carolina, Charleston, who wrote an editorial related to this report, told Reuters Health by email, “Given that this was an unmatched case-control study, further prospective studies are needed to validate these findings. The study was done from data on patients in the Netherlands, and about 90% of the patients were Caucasian. The findings may not generalize to African-American, Hispanic, or Asian patients.”

“Better counseling and education of obese women informing them of the increased risk would be prudent, as would be consideration of alternate nonhormonal oral contraceptive options,” the editorial concluded.

Dr. Diana Aguiar de Sousa, from the University of Lisbon’s department of neurosciences, Lisbon, Portugal, told Reuters Health by email, “The finding that the increased risk of CVT in obese is only evident for women taking oral contraceptives points to the possibility that obesity interacts with the causal pathway of estrogens in the risk of CVT. This is further suggested by the fact that estrogen concentrations are positively associated with BMI in an approximately linear fashion.”

“Therefore, these interesting findings must be confirmed with prospective studies assessing BMI, type and dosage of oral contraceptives, and other related risk factors,” she said. “Further research should also be directed at confirming a possible independent effect of weight in prothrombotic and inhibitory pathways and elucidate if weight loss can be associated with a reduction in the risk of CVT.”

Dr. Thalia Field, from the University of British Columbia and Vancouver Stroke Program, told Reuters Health by email, “Everyone has an intrinsic balance between making and breaking down clots, and I agree with the authors that it is likely that an additional prothrombotic risk factor like oral contraceptives in combination with obesity . . . likely tips the scale toward a prothrombotic state sufficient to drive risk of CVT. CVT is a rare site for venous thrombosis and the authors raise interesting hypotheses about how idiopathic intracranial hypertension, which is well established to be associated with obesity, and CVT may have common mechanisms accounting for the brain as a particular site for thrombosis in these cases.”

“I think the main message that physicians should take away at this point is to continue to keep CVT in mind as a potential diagnosis when they see a patient with a new persistent headache, as the diagnosis is often missed at the beginning as patients tend to be young and otherwise generally healthy,” Dr. Field said.

The Netherlands Organization for Scientific Research, the Dutch Thrombosis Society, the Remmert Adriaan Laan Foundation, and the Swiss Heart Foundation supported this research.

SOURCE: and and

JAMA Neurol 2016.