Nontraditional risk factors shed light on unexplained strokes in adults younger than 50

Previous research indicates the rate of ischemic (clot-caused) stroke among adults 18-49 years old is increasing and propelled by a corresponding rise in cryptogenic strokes (strokes of unknown cause) in adults without traditional risk factors, including high blood pressure, smoking, obesity, high cholesterol and Type 2 diabetes.

"Up to half of all ischemic strokes in younger adults are of unknown causes, and they are more common in women. For effective prevention, careful and routine assessment of both traditional and nontraditional risk factors in younger people is critical," said lead study author Jukka Putaala, M.D., Ph.D., M.Sc., head of the stroke unit at the Neurocenter, Helsinki University Hospital in Helsinki, Finland. "We should also carefully screen people after they have a stroke to prevent future strokes."

Researchers analyzed data for more than 1,000 adults aged 18-49 in Europe, with a median age of 41 years. Half of the participants had experienced a cryptogenic ischemic stroke, while half had no history of stroke. The study examined the associations of 12 traditional risk factors, 10 nontraditional risk factors and five risk factors specific to women (such as gestational diabetes or pregnancy complications). Researchers also closely reviewed participants with a heart defect called patent foramen ovale (PFO), a hole between the heart's upper chambers. A PFO is usually harmless yet is known to increase the odds of stroke. The study aimed to determine which risk factors contribute the most to unexplained strokes.

The analysis found:

• Traditional risk factors were more strongly associated with stroke in men and women without a PFO.
• In contrast, nontraditional risk factors, such as blood clots in the veins, migraine with aura, chronic kidney disease, chronic liver disease or cancer, were more strongly associated with stroke among study participants with a PFO.
• In those without a PFO, each additional traditional risk factor increased stroke risk by 41%, while each nontraditional risk factor increased stroke risk by 70%.
• Risk factors related to women also increased stroke risk by 70% independent of traditional and nontraditional risk factors.
• Among participants with a PFO, each traditional risk factor increased the risk of stroke by 18%. However, after considering individual demographic factors, such as age, sex and level of education, nontraditional risk factors more than doubled the odds of having an ischemic stroke.

Researchers also analyzed the study population's attributable risk (determining how a disease would be impacted if a certain risk factor were eliminated). To calculate population-attributable risk, researchers analyzed each risk factor and their contribution to the increased risk separately and found:

• For strokes that occur without a PFO, traditional risk factors accounted for about 65% of the cases, nontraditional risk factors contributed 27% and risk factors specific to women made up nearly 19% of the cases.
• In contrast, for strokes associated with a PFO, traditional risk factors contributed about 34%, nontraditional risk factors accounted for 49% and female-specific risk factors represented about 22%.
• Notably, migraine with aura was the leading nontraditional risk factor associated with strokes of unknown origin, with a population-attributable risk of about 46% for strokes among people with a PFO and about 23% for those without a PFO, indicating a higher risk for people with PFO.

"We were surprised by the role of non-traditional risk factors, especially migraine headaches, which seems to be one of the leading risk factors in the development of strokes in younger adults," Putaala said. "Our results should inform the health professional community to develop a more tailored approach to risk factor assessment and management. We should be asking young women if they have a history of migraine headaches and about other nontraditional risk factors."

American Heart Association chair of the Clinical Cardiology (CLCD)/Stroke Women's Health Science Committee, Tracy E. Madsen, M.D., Ph.D., FAHA, said, "This study is helpful because the authors present data by sex and age group. We know that stroke risk changes based on sex and age. For instance, recent data shows that younger women may have a higher risk of stroke than younger men. However, during middle age, men usually have a higher risk. Recognizing specific risks that affect women and those not commonly seen, such as migraine with aura and pregnancy complications as significant contributors to stroke risk in younger women, could change our approach to screening for these risks and educating our patients throughout their lives." Madsen, who was not involved in the study, is also an associate professor, vice chair of research in emergency medicine and director of the EpiCenter at the Robert Larner, M.D. College of Medicine at the University of Vermont in Burlington, Vermont.

The study's limitations include being an observational study, meaning that it was a review and analysis of existing health data on patients enrolled in another trial or database; therefore, this study's findings cannot prove cause and effect. The study also relied on patient-reported risk factors, which may impact accuracy. In addition, 95% of participants were self-reported to be white adults of European descent, which limits the applicability of the findings to other populations.

Study details, background and design:

• The study included 523 adults aged 18-49 (median age 41 years; 47.3% female; 37.5% with PFO) who had suffered a cryptogenic ischemic stroke and 523 peers of similar age with no history of stroke.
• The purpose of the review was to evaluate traditional and nontraditional risk factors associated with an increased risk of cryptogenic ischemic stroke.
• Participants were enrolled in Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Triggers, Causes, and Outcome (SECRETO) study at 19 centers in 13 European nations (Estonia, Finland, Germany, Greece, Italy, Lithuania, Netherlands, Norway, Portugal, Spain, Sweden, Turkey and the United Kingdom) between November 2013 and January 2022.