Sex differences in stroke risk factors persist

Numerous sex differences exist regarding stroke risk factors, which stress the importance of prevention and treatment in women, according to four reviews published in Stroke.

“Gender influences all aspects of stroke, from risk factors, treatments and outcomes,” Marc Fisher, MD, professor of neurology at Harvard Medical School and editor-in-chief of Stroke, said in a press release. “Highlighting these studies, all led by female researchers, in February, a month when the American Heart Association/American Stroke Association focuses on women’s health with Go Red for Women, is important. For too long, gender influences were not adequately studied.”

Preeclampsia and stroke

Preeclampsia affected up to 5% of pregnancies and increased risk for future stroke.

“Women whose pregnancy is complicated by preeclampsia or eclampsia should be counseled on the signs and symptoms of stroke and monitored closely in the postpartum period,” Mollie McDermott, MD, MS, clinical assistant professor of neurology at University of Michigan in Ann Arbor, and colleagues wrote.

Compared with women without hypertensive disorders during pregnancy, those who had hypertensive disorders related to pregnancy were 5.2 times more likely to have a hemorrhagic or ischemic stroke.

Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) are associated with preeclampsia, according to the review. PRES is a vasogenic cerebral edema that is often diagnosed by MRI in women with severe preeclampsia and eclampsia. This can affect temporal lobes, frontal lobes, brain stem and cerebellum.

Based on available data that show an overlap between eclampsia and PRES, some have suggested that eclampsia signifies obstetric PRES, although PRES caused by preeclampsia or eclampsia may be different than PRES caused by another factor. Patients with PRES and preeclampsia or eclampsia may have less severe outcomes compared with patients with PRES associated with another cause, as they are often younger and have a lower prevalence of CAD, diabetes, alcohol abuse and liver failure.

RCVS is similar to PRES, as it is characterized by a thunderclap headache and can be complicated by brain edema, seizure, ischemic and hemorrhagic strokes and subarachnoid hemorrhage. Angiography is used to diagnose RCVS, which often occurs during the postpartum period.

Cerebral injury and dysfunction caused by preeclampsia is still unknown, but some studies have found that it may be related to decreased cerebral vascular resistance and vasodilation, whereas others have found normal cerebral blood floor and vascular resistance. Regardless, it has been accepted that blood-brain barrier disruption and endothelial dysfunction play a role in cerebral dysfunction in patients with preeclampsia or eclampsia.

MRI is used to see a higher prevalence of white matter lesions, which can help diagnose women with PRES or RCVS. The lesions have been independently associated with current hypertension and onset preeclampsia with less than 37 weeks gestation.

Preeclampsia and eclampsia may be prevented through consistent BP measurements, aspirin and calcium supplements. Delivery, antihypertensives and magnesium may be used to treat both conditions.

Women with preeclampsia have been found to have an estimated 80% increased risk for stroke compared with those without preeclampsia, although the reasons are still uncertain.

“[This suggests] a need to increase awareness among women with this condition and their providers so they can make risk factor modifications and lifestyle changes needed to reduce their risk of stroke,” McDermott and colleagues wrote.

Unique stroke risk factors

Certain stroke risk factors are specific to women, including exogenous hormone therapy, endogenous hormone levels, pregnancy, pregnancy-related complications and peripartum period.

Stacie L. Demel, DO, PhD, assistant professor of neurology and ophthalmology at Michigan State University in East Lansing, and colleagues reviewed available data on women-specific stroke risk factors. There are limited data on the association between endogenous sex hormones and the risk for stroke. One study found that high or low estradiol levels do not increase the risk for ischemic stroke, whereas another study found that women that are in the highest category of free estrogen index had an increased age-adjusted risk for ischemic stroke.

Compared with estrogen levels, testosterone levels remain stable throughout a woman’s life, especially from age 30 to 70 years. Low testosterone has been linked to increased stroke risk in men, but a clear relationship has not been established in women.

The risk for ischemic stroke, increased CV mortality and stroke severity has been linked to dehydroepiandrosterone, which is used for the synthesis of testosterone and estrogen.

Both early age at menarche and early menopause have been associated with an increased CV risk, but this has not been observed in stroke.

Combined oral contraceptives that include progestogen and estrogen increase the risk for CVD and ischemic stroke, although data on progestogen-only contraceptives are limited. The risk for stroke that is associated with combined oral contraceptives is lower compared with the risk for stroke during pregnancy.

The risk for stroke is also increased in patients who have migraines with aura.

 

Oral postmenopausal hormone therapy has consistently been shown to increase the risk for stroke, especially ischemic stroke, in randomized trials and observational studies. Although the association between the timing of hormone therapy and CHD has been shown, this link has not been shown in the time since menopause. Transdermal hormone therapy was not linked to an increased risk for stroke, although some studies have found that high-dose transdermal estrogen was associated with an increased risk for stroke.

 

Hormone therapy for transgender patients often increase the incidence of cerebrovascular disease, although they do not seem to increase the risk for stroke.

The risk for stroke increases with pregnancy and the peripartum period, and both preeclampsia and eclampsia are strong risk factors for intracerebral hemorrhage and ischemic stroke.

“Further research to determine whether risk production models should include risk factors specific to women, including hormonal and reproductive exposures, if needed,” Demel and colleagues wrote.

Impact of risk factors

The risk for ischemic stroke in women increases with the prevalence of atrial fibrillation, diabetes, metabolic syndrome and migraine.

Tracy E. Madsen, MD, ScM, assistant professor of emergency medicine in the division of sex and gender in emergency medicine at Brown University Alpert Medical School, and colleagues identified sex differences in the risk factors for stroke by their review of recent evidence.

Among both sexes, hypertension is the dominant modifiable risk factor for stroke. Compared with men, women have a lower prevalence of hypertension up to the sixth decade of life, when there is a higher prevalence thereafter. Black women have a higher prevalence of hypertension compared with men and women from other racial and ethnic groups. The risk for stroke is similarly affected by hypertension in men and women.

Limited data are available on potential sex-specific BP targets for the primary and secondary prevention of stroke. A study found that more women have controlled their hypertension compared with men, although it varied with age.

The leading cause of mortality and CVD is AF, and it is 1.5 to two times more likely in men than women. As women live longer and its prevalence increases with age, the absolute number of women with AF is higher compared with men. The risk for stroke increases with AF in both men and women. Female sex is an independent risk factor for stroke, death and CVD caused by AF.

Women with AF who had a stroke have an increased risk for recurrence and dependency at 36 months after their event. Strokes caused by AF are often more severe. Compared with men, women are less likely to undergo cardiac ablation and receive oral anticoagulation treatment.

Diabetes is a stroke risk factor in both men and women. Although patients with incident stroke have similar incidences of diabetes, women have a higher occurrence of stroke associated with diabetes compared with men.

Women with diabetes may have an increased risk for fatal stroke. This risk is similar in women with and without diabetes. Some data have shown that HbA1c control is less likely to be achieved in women compared with men.

The decline in the rate of stroke in women is slowing down, which has caused rates in men and women to be equal.

Dyslipidemia has been shown to increase the risk for ischemic stroke, but guidelines have not been updated to include information on how to manage it in both sexes for stroke prevention.

The data are mixed regarding dyslipidemia rates. Some show that more men have dyslipidemia compared with women, whereas other studies show similar rates. It is unknown whether there are sex differences in the links between stroke risk and non-HDL total cholesterol, LDL, HDL and triglycerides.

Women are more likely to not receive statin therapy or achieve cholesterol goals, although some data conflict. One study found that the use of lipid-lowering medications increased in men and women.

In the general population and in those with stroke, women are an estimated three times more likely to have migraines vs. men. Migraines with aura also increase the risk for stroke, although the mechanism is unknown. Women have a stronger association between migraine and cryptogenic stroke compared with men.

Cognitive impairment is linked to an elevated risk for stroke, although it is not currently included in U.S. guidelines for the primary prevention of stroke. Women are more likely to have dementia, Alzheimer’s disease and cognitive impairment, which may be caused by women living longer than men.

“Greater attention to sex-specific risks and treatment strategies has the potential to improve the effectiveness of stroke prevention in women and ultimately reduce stroke-related death and disability,” Madsen and colleagues wrote.

Outcomes after stroke

Women were more likely to have worse health-related quality of life, more activity limitations and more depression after stroke compared with men.

Seana Gall, BSc (Hons), PhD, senior research fellow in cardiovascular epidemiology at the Menzies Institute for Medical Research at the University of Tasmania in Hobart, Australia, and colleagues reviewed studies that focused on sex differences in stroke outcomes.

In eight studies, activity limitations after ischemic and hemorrhagic strokes were seen more in women than men. Women also had worse outcomes compared with men.

Women with ischemic stroke had worse outcomes vs. men, and common covariates included stroke severity, age and comorbidities. For intracerebral hemorrhage, activity limitations were more common in women compared with men.

Some studies that analyzed sex differences in health-related quality of life found that women had a lower mean quality of life compared with men. In another study, the magnitude of the sex differences was reduced at 3 months and 12 months after adjusting for sociodemographics, age, function and stroke severity at 3 months. One study found that women had a better quality of life compared with men, and significantly poorer quality of life was found in women in five studies. Others found that there was no link between sex and health-related quality of life.

Women were more likely to have depression after stroke vs. men after adjusting for stroke severity, age and activity limitations.

Data on sex differences in cognitive impairment were inconsistent.

“These differences in outcomes are at least partially explained by women’s advanced age, greater stroke severity and poorer health at the time of stroke,” Gall and colleagues wrote. “There is a pressing need for high-quality population-based studies of sex differences in [patient-reported outcome measures] after stroke. Studies exploring potential modifiable contributors to these differences are needed, so effective interventions to reduce sex disparities in outcome can be designed.”

 

In a related editorial, Eric Kaplovitch, MD, of the department of medicine at University of Toronto, and Sonia S. Anand, MD, PhD, FRCPC, professor in the division of cardiology, associate member of the department of clinical epidemiology and biostatistics and director of the population genomics program at McMaster University, in Hamilton, Ontario, wrote: “Sex-specific risk factors for stroke exist at all ages and stages of the life course. Whether mediated by the unique physiological stress of pregnancy, endogenous or exogenous hormones or the ubiquitous nature of traditional stroke risk factors, understanding the epidemiology of stroke in women is integral to prevention and treatment. Underpinning all associations between biological sex and stroke is the need for risk factor identification and management. Aggressive treatment of obesity (even before pregnancy), hypertension, hyperlipidemia, diabetes mellitus, smoking and atrial fibrillation in women should be emphasized.” – by Darlene Dobkowski

References:

Demel SL, et al. Stroke. 2018;doi:10.1161/STROKEAHA.117.018415.
Gall S, et al. Stroke. 2018;doi:10.1161/STROKEAHA.117.018417.

Kaplovitch E, et al. Stroke. 2018;doi:10.1161/STROKEAHA.117.020354.
Madsen TE, et al. Stroke. 2018;doi:10.1161/STROKEAHA.117.018418.
McDermott M, et al. Stroke. 2018;doi:10.1161/STROKEAHA.117.018416.

Disclosures: Gall, Madsen, McDermott, Kaplovitch and Anand report no relevant financial disclosures. Demel reports she receives compensation for serving as a member of the speakers bureau for Genentech. Please see the studies for all other authors’ relevant financial disclosures.