Because diseases can affect men and women differently, the medical community has become concerned about “gender differences” in diseases, including stroke. According to statistics, women account for a higher proportion (3.8 million) of the 6.8 million strokes each year in the United States. In addition, women tend to be older when they have a stroke, tend to live alone, and have a worse premorbid state than men. After stroke, women have poorer levels of recovery and quality of life compared to men.
Many of the risk factors for stroke are specific to the female population, such as pregnancy and pregnancy complications, oral contraceptives and postmenopausal hormone therapy. In addition, there are many risk factors that are more prevalent for women, including hypertension, atrial fibrillation, migraine with aura, depression or psychosocial stress.
Guideline recommendations – Stroke risk factors
Women with hypertension in non-pregnancy
Hypertension is both the most significant independent risk factor for stroke and the greatest risk factor that can be intervened; and the prevalence of hypertension is higher in women compared with men. In addition, hypertension is less well controlled in middle-aged and older women. Men over the age of 80 years account for 38% of those with blood pressure below 140/90 mmHg; women in the same condition account for only 23%. There is no evidence of gender differences in the efficacy of antihypertensive therapy, but many studies of antihypertensive drugs have also not conducted gender-specific analyses of drug efficacy and side effects.
Atrial fibrillation
There are gender differences in atrial fibrillation, such as a higher incidence and associated risk of thromboembolism in women. The epidemiological impact of gender has been mentioned in the development of risk scores for patients with atrial fibrillation-adding female gender as a factor in the CHA2DS2-VASc (congestive heart failure/left heart insufficiency, hypertension, age ≥75 years; diabetes mellitus; history of stroke/transient ischemic attack/thrombosis) score.
Therefore, considering the age-sex differences in stroke events, we recommend the use of a risk stratification tool. Women, especially those older than 75 years, should be actively screened for atrial fibrillation by appropriate pulse rate measurements and ECG monitoring (recommendation category I; level of evidence B). We also recommend antiplatelet therapy for female patients ≤65 years of age with isolated atrial fibrillation.
Migraine with aura
Migraine is 4 times more common in women than in men. Although the absolute risk of developing stroke and migraine are low in correlation, aura migraine is significantly associated with stroke in women <55 years of age. Frequency of migraine attacks was also associated with stroke. We therefore recommend reducing migraine attack frequency as an effective strategy to reduce stroke risk, although there is no clear evidence that it is a specific treatment strategy to reduce stroke risk (e.g., calcium channel blockers, β-blockers, antiplatelet agents).
Considering the synergistic relationship between smoking and migraine with aura, we recommend smoking cessation treatment and counseling for smoking patients with migraine. Finally, we encourage clinicians to remind female migraine patients about oral contraceptives.
Hormonal contraception
Oral contraceptive pills are a risk factor for stroke in young women, with the former having a 1.4-2.0-fold increased risk of stroke compared to women who do not use the drug. According to the results of the recent Denmark study, the absolute risk of stroke was low (about 2/10,000/year) in women who used the lowest prescribed dose. The risk of stroke increases exponentially in the group of women using oral contraceptives: 3.4/10,000/year in the 15-19 age group and 64.4/10,000/year in the 45-49 age group.
Factors that can further increase the risk of stroke include: history of thromboembolism, hypertension, smoking, hyperlipidemia, diabetes mellitus and obesity. Therefore, we recommend that these risk factors be identified in women and that efforts be made to correct and manage interventional risk factors in women taking oral contraceptives.
Coagulation factor mutations and biomarkers act in a synergistic manner to increase stroke risk. Studies have shown that markers of vascular endothelial dysfunction, such as vascular hemophilia factor as well as ADAMTS13 (thrombin-sensitive factor type 1 motif-containing disintegrin-like metalloproteinase), can increase the risk of stroke 10-fold in women on oral contraceptives (compared to women not on the pill).
Although mutations in many coagulation factors can increase the risk of stroke in women taking oral contraceptives, we do not recommend screening for mutations in women before they take oral contraceptives. This is because the chance of mutations is very low in healthy women, especially in women without a positive family history of the disease. Additional trials are needed to study the risk of hemorrhagic stroke in female patients taking oral contraceptives. Studies of available clinical markers, such as vascular hemophilia factor, should also be conducted and need to be initiated in a larger group of women.
Menopause and hormone replacement therapy
Menopause, particularly in women who enter menopause early, is associated with risk of stroke, but the evidence for correlation is inconsistent. Whether both natural and surgical menopause are associated with stroke risk remains unknown. However, hormone therapy in postmenopausal women is a unique risk factor for stroke.
In general, hormone therapy is associated with an increased risk of stroke, but is not mentioned in the context of primary and secondary stroke prevention. There are still many gaps in current research, such as the severity of the damage and the trade-off between benefits and risks after hormone therapy; the optimal timing, dose, type, and route of administration of treatment for perimenopausal or early postmenopausal women, primarily in the subgroup of women at higher risk for stroke after menopause, could be enhanced.
Depression and Psychosocial Stress
Several cohort studies and a meta-analysis have determined that depression and psychosocial stress can increase the risk of stroke – from 25% to 45% in the female population. The ratios in studies including both men and women are similar to those in studies of men or women alone, making it difficult to state with certainty that women in this condition are at higher risk of stroke compared with men. Further studies are needed to clarify the subgroups of women at risk (e.g., treated or untreated groups) and methods that can identify depression or psychosocial stress.
Stroke prevention measures
Healthy lifestyle
We recommend maintaining a normal weight, a healthy diet, smoking cessation, moderate alcohol consumption, physical activity, and interventions aimed at achieving or maintaining normal blood pressure, cholesterol, and blood glucose levels. The guidelines highlight several risk factors for stroke, including obesity, physical inactivity, and metabolic syndrome, but there is little evidence that these factors disproportionately increase the risk of stroke in women.
However, a recent meta-study that included more than 750,000 subjects and more than 12,000 stroke patients found that the risk of stroke was 27% higher in women with diabetes compared to men with diabetes. The exact mechanism involved in the results is unclear, but women with diabetes may have more adverse cardiovascular risk factors compared to men.
The results of this meta-analysis provide further evidence that identifying stroke risk factors, especially those that may disproportionately increase stroke risk in women, has implications for stroke prevention. Healthy lifestyles, including regular exercise, a blood pressure-lowering diet, smoking cessation, moderate alcohol consumption, and identification and treatment of diabetes are critical. Recommendations for healthy lifestyles that can prevent stroke will remain the same in male and female populations until gender-specific measures are validated.
Carotid artery stenosis
Fewer women than men may undergo carotid endarterectomy in patients with symptomatic carotid stenosis. It remains unknown whether the benefits and risks of carotid stenting differ between male and female patients. From the CREST study (Carotid Endarterectomy for Arterial Revascularization versus Stenting Trial), it was shown that women were randomly assigned to angioplasty and stenting at a higher rate than men, and that there may be an interaction between treatment placement and gender.
There were clear gender differences in carotid plaques (less inflammatory features in women) and a higher risk of perioperative complications with endarterectomy for asymptomatic stenosis. However, evidence on whether women with symptomatic or asymptomatic carotid stenosis should receive medical or surgical treatment (carotid endarterectomy or stent formation) or differ from men remains scarce. Therefore, the current recommendations in the guidelines are the same for men and women. Little is known about gender-specific treatment in carotid artery disease, so future studies are needed to determine whether surgical therapy is preferable to aggressive medical therapy for women with symptomatic carotid stenosis.
Stroke prevention with aspirin
There is no clear evidence to suggest that a unique antiplatelet therapy or therapeutic dose will have a different effect in men or women, but aspirin-specific vasoprotective effects may be gender-based. For example, the WHS (Women’s Health Study) showed that daily use of 100 mg aspirin did not reduce the risk of heart attack or vascular death compared with placebo, but did reduce the risk of stroke, especially ischemic stroke.
A meta-analysis of aspirin and primary prevention showed that aspirin prevented stroke risk in women, but in men, aspirin prevented heart attacks. However, the ATT (Antithrombotic Clinical Trials) Collaborative Study showed no evidence of any sex differences in vascular prognosis after correction for multiple comparisons.
Therefore in line with recommendations published by other organizations, we would recommend that aspirin be considered for use in female patients over 65 years of age if the patient’s blood pressure is well controlled and the benefit of preventing ischemic stroke or heart attack far outweighs the risk of gastrointestinal bleeding or hemorrhagic stroke. The question of whether women younger than 65 years of age could benefit from aspirin would also be addressed if gender-specific risk scores were available.
New Guideline Recommendations
Pregnancy and pregnancy complications
The risk of stroke is fairly low during pregnancy (34/100,000 births) but highest during the postpartum period. Although the traditional postpartum period is 6 weeks, a recent study showed that thrombotic events can become apparent at 12 weeks postpartum. Postpartum women with new headaches, blurred vision, seizures, or any new neurological signs or symptoms should be highly suspicious of postpartum stroke or vascular disease (reversible posterior encephalopathy syndrome or reversible cerebral vasoconstriction syndrome), or cerebral venous thrombosis.
Pre-eclampsia and eclampsia
Pre-eclampsia occurs in nearly 5% of pregnant women. It is defined as hypertension, proteinuria (urinary protein excretion ≥300 mg/24h) or thrombocytopenia, hepatic impairment, progressive renal insufficiency, pulmonary edema, and cerebral or optic nerve disorders that occur during pregnancy. An updated guideline published by the American College of Obstetricians and Gynecologists includes women without proteinuria but with one or more other systemic features in the criteria for preeclampsia.
With evidence that women with a history of preeclampsia will have a 2-fold increased risk of stroke and a 4-fold increased risk of hypertension in later life, we recommend that preeclampsia be classified as a risk factor (Class IIa, Level C). Our aim is to increase awareness that women with a history of preeclampsia can benefit from lifestyle changes and interventions for early cardiovascular risk factor assessment.
Although the evidence linking pre-eclampsia to late hypertension and stroke is known, the current deficit is how to identify women who will develop these pre-eclampsia complications. More studies are therefore needed to identify relevant biomarkers or other indicators that can help identify female patients at risk.
Hypertension in pregnancy
Another new study is considering the treatment of women with new-onset systolic blood pressure of 150-159 mmHg or diastolic blood pressure of 100-109 mmHg in pregnancy (Class IIa, Level B). This recommendation differs from that of the American College of Obstetricians and Gynecologists guidelines: treatment at blood pressures above 160/110 mmHg is indicated. We base this new recommendation on the evidence that treatment of mild to moderate blood pressure elevation during pregnancy can reduce the risk associated with severe hypertension by 50%.
The new study is either a re-analysis of existing data that can be used to assess the benefit of treating mild to moderate blood pressure elevation during pregnancy. Despite the safety and efficacy of antihypertensive medications used during pregnancy, the risks to the fetus should be carefully considered.