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MIAMI BEACH — Patients with some inherited blood clotting disorders that use oral contraceptives may be at increased risk of ischemic stroke, a new study suggests.

If the findings are confirmed, it may someday be advisable to screen patients for the genetic variants – factor V Leiden and methylenetetrahydrofolate reductase (MTHFR) 677T – before prescribing the birth control pill, Dutch researchers said.


Reporting at the AAN Annual Meeting here in April, Arjen J.C. Slooter, MD, PhD, said that the role of inherited prothrombotic conditions, including factor V Leiden, prothrombin G20210A, and the MTHFR 677T genotype, in the pathogenesis of ischemic stroke has been controversial.

It is fairly well established that people who have these genetic variants are at higher than average risk for deep venous thrombosis and pulmonary embolism, he said. However, “it's controversial whether these variants also increase the risk of arterial thrombosis, or ischemic stroke,” said Dr. Slooter, who performed the study while at Utrecht University in the Netherlands.

The researchers hypothesized that the effects of these factors may be potentiated by the use of oral contraceptives, analogous to observations in venous thrombosis, said Dr. Slooter, now a Fellow in the Department of Intensive Care Medicine at Academic Medical Center in Amsterdam.


To test their theory, the researchers studied 193 women −19- to 50 years old – who had suffered an ischemic stroke and 767 women without stroke matched by age and residence.

The analysis showed that women who carried the factor V Leiden variant were 80 percent more likely to have an ischemic stroke than women without the variant. Women who carried the MTHFR 677T genotype were 50 percent more likely to have had arterial thrombosis. However, neither value was statistically significant.

There was no association between the prothrombin G20210A genotype and stroke, Dr. Slooter said.

The researchers then evaluated the subset of women who used oral contraceptives: 52 percent of the women who had suffered an ischemic stroke and 36 percent of the controls.

Women with the factor V Leiden variant who used oral contraceptives had an 11.2-fold higher risk of ischemic stroke, compared with women with neither of these risk factors, the study showed. Women with the MTHFR 677T genotype who used oral contraceptives had a 5.4-fold higher risk of ischemic stroke than women who had neither of these risk factors, Dr. Slooter reported.

There were too few carriers of the prothrombin G20210A genotype who used oral contraceptives to calculate that risk, he said.

The study also showed that current smokers with factor V Leiden were 6.3 times more likely to have an ischemic stroke than women without factor V Leiden who did not smoke.

“If confirmed, the findings could imply that carriers of the factor V Leiden and MTHFR 677T genotypes should not get oral contraceptives,” Dr. Slooter said.


But first a cost-effectiveness analysis should be performed and the pros and cons carefully weighed, he said. At issue is whether genotyping could result in a relatively large number of women being denied good, safe birth control for relatively little potential gain.

On one hand, all women need to see a physician to be prescribed oral contraceptives, “so it would be easy to do a genetic test at that time,” he said, adding that genotyping is relatively inexpensive. On the other hand, such testing could be a burden to offspring and result in an increase in unplanned births, Dr. Slooter said.

“These genotypes are common – about 5 percent of all people carry factor V Leiden and about 10 percent carry MTHFR 677T,” he said. “Ischemic stroke, however, is extremely rare in young women. We need to look at how many strokes would be prevented with genetic screening before the start of oral contraceptives.”


Larry M. Brass, MD, Professor of Neurology at Yale University in New Haven, CT, agreed. “This is an interesting preliminary finding,” he told Neurology Today. Dr. Brass was not involved with the study.

“It appears that oral contraceptives are safe for many women. The challenge and the fear for clinicians is to identify those few patients at increased risk. The exciting part [of this study] is that we may be able to identify and even screen women to find out who is at risk.”


Dr. Arjen J.C. Slooter and colleagues hypothesized that factor V Leiden and MTHFR 677T may be potentiated by the use of oral contraceptives.

While the current trial does not yet provide such a clinical tool, Dr. Brass said it does offer insight into how best to design a study to confirm the findings.

“Obviously we can't do a typical prospective study and put half the women with factor V Leiden on oral contraceptives and wait to see what happens,” he said.

“What we need are observational studies,” he continued. “And this allows us to design observational studies that are less likely to be influenced by bias and appropriately sized to meet the objective. It also provides a rationale for funding.”

Dr. Brass said the findings are also “exciting for offering new insights into what's going on. “There are lots of theories about how estrogen may induce a thrombotic state,” he explained. “It's nice to say, ‘estrogen increases risk a little and factor V Leiden increases risk a little, so both increase risk a little more,’ but that's too simplistic.”

So another next step is to look at what's happening at the molecular level, he said. People with factor V Leiden, for example, have abnormal activity of the clotting protein known as Protein C. There is impaired deactivation of the clotting pathway, easing the way for formation of thromboses, Dr. Brass said.

“If we can understand how Protein C interacts with estrogen [to increase stroke risk], maybe we can design better drugs or maybe a better estrogen,” he said.


  • ✓ Women with genetic variants – factor V Leiden and MTHFR 677T – who also took oral contraceptives were at increased risk for stroke, a team of researchers from the Netherlands reported in a new study.