Unique Characteristics of Stroke in Women and Rehabilitation Considerations

Stroke is the third leading cause of death of women in the United States, and women have a higher lifetime risk of stroke than men. Studies show that women live longer but with poorer functional outcomes and higher rates of disability compared with men. Sex-specific disparities exist between clinical symptoms, medical evaluation, and management after stroke. Stroke rehabilitation strategies specific to women should take into consideration both physiologic and psychosocial demands more common in women to improve functional outcomes. Additional resources for education, clinical research, and implementation of best practices are needed to eliminate gender-related disparities in poststroke care.

Key points

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Gender disparities after stroke have been well-documented and reveal distinct risk factors specific to women.
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Health care must address the various gaps in care for women, with initiatives to eliminate gender disparities.
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Continued education for patients, care partners, and health care providers is imperative to improve clinical awareness of stroke in women and their unique challenges.

Introduction

Each year, an average of 795,000 people are diagnosed with a new or recurrent stroke in the United States. Stroke is the third leading cause of death in women in the United States and is a leading cause of disability. Although the prevalence of stroke increases with advancing age for both men and women, it is estimated that 55,000 more women than men have a stroke, largely because of an average longer life expectancy in women. Overall, women have a higher lifetime risk of stroke than men. In the Framingham Heart Study, the lifetime risk of stroke among those 55 to 75 years of age was 1 in 5 for women (95% confidence interval [CI], 20%–21%) and approximately 1 in 6 for men (95% CI, 14%–17%). As the population ages between 2012 and 2030, nearly 4% of the US population is projected to have had a stroke; estimated total direct medical stroke-related costs are projected to triple, from $71.55 billion to $184.13 billion. While we recognize that there are differences in the rates of stroke between men and women, the etiologies of those differences are being studied by the clinical and research communities.

Risk factors for stroke in women

Gender differences in stroke have been studied extensively, demonstrating gender disparities in clinical presentation and modifiable and nonmodifiable risk factors, revealing distinct unique risk factors specific to women ( Fig. 1 ).

Although women share major nonmodifiable risk factors with men such as age, race, and family history of stroke, their impact differs by gender. For example, the influence of age as a stroke risk factor varies throughout the patient’s lifetime and impacts women more substantially in a bimodal distribution, with women experiencing a higher incidence of stroke than men both at ages under 30 years and when over 70 years old. ^,

Among modifiable risk factors, there are substantial gender disparities, with several factors presenting a more significant risk of stroke in women than in men. The most prevalent modifiable risk factor for stroke, hypertension, has significant gender disparity in prevalence and the risk associated with stroke. Several large cohort studies report a significantly higher risk of stroke associated with hypertension in women compared with men. These results are influenced by factors such as age, race, and ethnicity; nevertheless, it underscores the need for a tailored approach to management and early screening for women. Similarly, the association of diabetes mellitus with ischemic stroke is stronger in women than in men, with large systematic reviews and meta-analyses reporting a 27% higher risk of stroke in women than men, and a twofold increased risk of fatal stroke in women with diabetes mellitus compared with men.

Another dominant modifiable risk factor for stroke is atrial fibrillation (AF), which is an established factor associated with increased risk of stroke, cardiovascular disease, and mortality for men and women. A substantial body of evidence shows that AF has a significantly greater impact on women than men. A large meta-analysis study revealed that AF is associated with twice the relative risk of stroke in women compared with men. In addition, the female gender is identified as an independent risk factor associated with thromboembolism, stroke, cardiovascular diseases, and mortality attributable to AF. ^, As a result, it is considered an independent variable in the stratification of risks such as in the CHA2DS2-VASc score. ^,

Traditional risk factors such as elevated body mass index (BMI) and obesity also have a stronger association in women compared with men. Studies report that obesity increases the risk of ischemic stroke in women by approximately 30% compared with men. ^, Migraines, especially those with aura, increase the risk of stroke for men and women. However, women are more vulnerable to these risks. Among people who experience migraines with aura, the risk of stroke is higher for women, especially those who are under 45 years of age and those who use oral contraceptive pills or smoke.

Importantly, in addition to traditional modifiable and nonmodifiable risk factors that affect both genders, women face unique female-specific risk factors that substantially elevate the risk of stroke ( Fig. 1 ). During pregnancy, the risk of stroke is 3 times higher than the rate for age-matched adults, with studies demonstrating that 30 out of every 100,000 pregnancies are affected by stroke. Furthermore, women with adverse pregnancy outcomes, preterm delivery, gestational hypertension, placental abruption, and stillbirth are at increased risk for cerebrovascular and cardiovascular morbidity and mortality. Additionally, a large population cohort study suggests that a history of 5 or more births is associated with an increased risk of stroke, coronary heart disease, and myocardial infarction. ^, ^, Another pregnancy-related risk factor is pre-eclampsia, which significantly increases the risk of stroke in women. Systematic review and meta-analysis studies demonstrated that pre-eclampsia was associated with an approximately twofold higher risk of stroke and future cardiovascular and cerebrovascular disease-related mortality compared to women with no history of pre-eclampsia. Clinical recommendations advise the use of low-dose aspirin to decrease the risk of pre-eclampsia during pregnancy.

The use of oral contraceptive pills (OCPs) poses a significant risk of stroke, with data showing an increased risk for ischemic and hemorrhagic stroke. ^, The risk of stroke is directly associated with the dose of estrogen, with OCPs that contain a lower dose of estrogen potentially contributing to a lower stroke risk compared to those with a higher dose of estrogen. Progestin-only pills, on the other hand, have not shown any correlation with an increased risk of ischemic stroke. ^, Crucially, the risk of stroke further increases by additional factors such as smoking, hypertension, history of migraines, or age older than 35 for women taking OCPs. ^,

Additionally, the administration of oral hormone therapy for menopause increases the risk of ischemic stroke in women, regardless of whether it is estrogen alone or in combination with progestin. ^, As an alternative, studies have demonstrated that low-dose transdermal estrogen delivery formulations may offer a safer alternative for managing menopausal symptoms without increasing the risk of stroke.

Furthermore, according to a recent meta-analysis, women who have a reduced reproductive life span of less than 30 years are at a 75% higher risk of stroke, compared to those with a reproductive life span of 36 to 38 years. Women with a reproductive life span of 32 to 35 years are also at a higher risk of stroke although to a lesser extent. ^, Additionally, age at menarche presents a U-shaped association with increased risk of stroke in women who experience early menarche (age ≤10) or late menarche (age ≥16) at higher risk of stroke, Moreover, early menopause (age ≤44) is also associated with at an increased risk of stroke.

Clinical presentations and symptoms of stroke in women

Regrettably, the diagnosis of stroke within the emergency department continues to be a persistent challenge, with studies reporting stroke being the fourth most common misdiagnosis. ^, The early recognition of stroke symptoms is critical to confirm diagnosis and to initiate treatments promptly to maximize recovery and prevent long-term disability. Recent studies estimated that approximately 9% to 12% of all strokes are not recognized in the emergency department at initial presentation. ^, Misdiagnosis of stroke leads to significantly worse outcomes, including severe disability and death. ^,

Women encounter distinct challenges compared with men. A recent large cross-sectional study demonstrated that women have 25% higher odds of misdiagnosis than men. Additionally, numerous studies have reported considerable gender disparities in clinical presentation, received in-hospital services, and poor functional outcomes for women compared with men. One of the major factors influencing the misdiagnosis of stroke in women is the manifestation of nontraditional symptoms in addition to conventional stroke symptoms ( Fig. 2 ). Women often present with atypical symptoms such as dizziness, headaches, nausea, confusion, fatigue, disorientation, and generalized weakness, posing challenges in differentiating actual strokes from stroke-like mimics. ^, ^, ^, Additionally, several studies reported that women often present with non-neurological symptoms such as chest pain and palpitations.

Women face an increased risk of not identifying strokes at initial presentation because of often exhibiting nontraditional symptoms and signs. A large multiregional population-based study analyzing emergency department misdiagnosis revealed that headaches and dizziness were the 2 most common symptoms leading to stroke hospital readmissions. Other studies demonstrated that patients presenting with motor symptoms have the lowest rates for misdiagnosis, at about 4%, whereas 35% of patients presenting with dizziness and 50% of those presenting with isolated dizziness with no other neurologic symptoms are misdiagnosed. ^, ^, An international multicenter cohort study demonstrated that early MRI within 1 week of presentation led to a change in the diagnosis for 30% of cases such as transient ischemic attack and stroke mimic, based on the results of MRI.

It is crucial to raise awareness among health care professionals of the nontraditional symptoms of stroke in women to enable early diagnosis and timely intervention. This highlights the critical need and importance of developing and implementing standardized diagnostic approaches for identifying stroke symptoms, especially understanding gender-specific manifestations of stroke symptoms.

Differences in stroke rehabilitation and outcomes for women

Sex disparities exist for women starting in the early stages of the medical evaluation and carry through their course of recovery, negatively influencing their overall clinical outcomes. Women are more likely to present nontraditional stroke symptoms and may have a delayed clinical presentation to the acute care hospital. Women have higher intracerebral hemorrhage scores than men at initial emergency department presentation and have a significantly shorter acute care hospital length of stay (median 3 days) even when controlled for age compared with men (median 4 days). While hospitalized, they are less likely to receive a comprehensive medical evaluation and diagnostic studies (eg, carotid imaging and echocardiography) required to adequately diagnose and treat acute stroke. Studies have shown that women may be as much as 30% less likely to be treated with thrombolytics when presenting with acute stroke compared with men, despite considering patient eligibility, geographic/regional location, and after controlling for age, stroke severity, and comorbidities. Female patients undergoing endovascular therapy are more likely to have prestroke disability, and to live alone, which results in delays between symptom onset and activation of the emergency response system compared with men. Even after controlling for age, women with intracerebral hemorrhage were significantly more likely to die or enter hospice. Upon hospital discharge, a study reviewing Medicare Advantage poststroke discharge patterns revealed that women were more likely to be discharged to a skilled nursing facility rather than an inpatient rehabilitation facility, ^, while men were more likely to be discharged to home.

Concerning clinical outcomes, women have lesser functional recovery and inferior quality of life compared with men after stroke. ^, Studies show that women live longer but with poorer functional outcomes and higher rates of disability compared with men. ^, Older women are generally more prone to physical disability than men and tend to survive longer with disability. This may be partially explained, because older female patients may experience greater socioeconomic disadvantage than men and be more affected by changes in social networks and support. In addition to functional outcomes, women are more likely to experience poststroke depression (78%) and other mental health symptoms like anxiety, compared with men. After multivariable adjustment for stroke severity, age at stroke onset, and functional activity limitations, women were still more likely to have a significantly higher prevalence, incidence, or symptoms of depression than men. Furthermore, preliminary data from a cohort study of community-dwelling adults in the United States found that women endure more cognitive deficits after stroke, even after controlling for prestroke cognitive measures, predominantly during the early poststroke period.

Factors that may contribute to sex-specific differences with a less favorable outcome for women after stroke include more severe strokes at symptom onset, disparities in acute stroke treatment, advanced age, poorer prestroke function, more serious medical comorbidities, less social support, and higher likelihood of being a widow without a care partner to help during the recovery process. ^, ^, Despite psychosocial factors, preclinical and clinical evidence demonstrates that the combination of factors including exposure to sex hormones and the microenvironment of the brain and vasculature may contribute to sex differences in cellular mechanisms of stroke injury.

Stroke rehabilitation strategies for women

Stroke rehabilitation strategies should be tailored for the individual and be an integral part of a comprehensive treatment plan. Several subgroups of women have additional needs that should factor into developing a comprehensive approach to rehabilitation. Women who are pregnant and/or breastfeeding should consult with their health care provider regarding the risks and benefits when considering certain treatment options used for the treatment of stroke-related disability including neurostimulants for cognitive and attention deficits, medication for neuropathic pain, and medication for the treatment of mood disorders after stroke. Causes of self-reported increasing spasticity include the menstrual cycle, mental stress, and bowel/bladder dysfunction. Pelvic floor muscle training has proven beneficial for the management of urinary incontinence in female stroke survivors. The use of physical activity is foundational to neurorehabilitation, but also for a reduced risk of cardiovascular/cerebrovascular disease. ^, ^, Lifestyle modifications that encourage a healthy diet, physical activity, smoking cessation, and maintenance of a healthy BMI have been shown to decrease stroke incidence in women and improve outcomes after stroke in men and women. ^, Invariably, clinicians should evaluate how the individual’s functional, cognitive, and psychological deficits after stroke may negatively affect quality of life, especially if if the patient is a caregiver for another person.

Discussion

Women bear a disproportionate burden of stroke, with a higher lifetime risk of stroke and poorer outcomes after stroke. It is imperative to educate stroke survivors, care partners, and health care providers to acknowledge sex-specific differences after stroke and implement clinical best practices to address these disparities. Building clinical awareness of stroke symptoms, poststroke care, and stroke rehabilitation strategies for women may lead to improved outcomes and possibly a reduced incidence of stroke in women. Beyond secondary prevention, women-specific risk factors should be considered when developing preventive approaches targeted to women. ^,

Several subpopulations of women warrant special attention. The intersection of gender with race, ethnicity, age, and socioeconomic status creates an additional barrier to health care services and outcomes. In the United States, stroke is a leading cause of death for women, but may vary by race/ethnicity: Non-Hispanic Black women (third, 6.5%), Hispanic women (third, 6,5%), Non-Hispanic Asian women (third, 7.6%), Non-Hispanic Native Hawaiian or Pacific Islander women (third, 7.2%), Non-Hispanic white women (fifth, 6.0%), and Non-Hispanic American Indian or Alaska Native women (seventh, 4.5%)

Studies demonstrate that the index stroke rate may vary between genders by age:

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Ages 15 to 24, no difference
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Ages 25 to 34, more women had strokes than men (incidence rate ratio: men:women, 0.70 [95% confidence interval (CI)], 0.57–0.86)
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Ages 35 to 44, more women had strokes than men (incidence rate ratio: men:women, 0.87 [95% CI, 0.78–0.98])
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Ages 45 to 54, more men had strokes (incidence rate ratio, 1.25 [95% CI, 1.16–1.33]
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Ages 55 to 64, more men had strokes (incidence rate ratio, 1.41 [95% CI, 1.18–1.34])
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Ages 65 to 74; more men had strokes (incidence rate ratio, 11.18 [95% CI, 1.12–125])
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Ages 75 years old and up – no difference.

In a UK study, women of lower socioeconomic status were approximately 20% more likely to experience any stroke, mainly ischemic stroke. In a systematic review and meta-analysis, the lowest educational level, income, occupation, and composite socioeconomic status were associated with an increased risk of stroke mortality. ^, As these societal conditions are more likely to affect women, the numerous health care disparities compound to have an even greater negative impact on overall outcomes for women. Recognizing that sex refers to biological factors, while gender refers to social roles, behaviors, and expressions, future work within the medical community should clarify the factors that contribute to physiologic and societal differences between genders.

Unfortunately, women are under-represented in clinical research trials, and more well-designed clinical trials powered to detect sex-based differences are required to evaluate the underlying mechanisms responsible for these differences. As with many areas of health care, increased support is needed to increase the number of researchers who examine the health care needs specific to women. The study of nontraditional along with traditional risk factors may give additional insight into sex-specific comorbidities that lead to differences in outcomes. ^, Furthermore, additional resources specifically targeted toward increasing the number of women who lead stroke clinical trials may help to advance the clinical research trial design and enrollment of women after stroke.

Summary

Acute and postacute stroke care is complex, multifaceted, and should be highly personalized. Clinicians should be cognizant of gender-specific differences between risk factor management, clinical symptoms, and rehabilitation strategies to provide competent poststroke care and diminish health care disparities.

Clinics care points

Several risk factors for stroke are specific to women (eg, pregnancy, pre-eclampsia, OCPs, menopausal hormonal replacement therapy, and reproductive life span), while other risk factors impact both men and women, but have a stronger effect on women (eg, migraines with aura, AF, hypertension, and diabetes).

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Beyond the common symptoms of stroke, clinicians should be aware of alternate clinical symptoms in women (eg, fatigue, disorientation, confusion, memory problems, nausea, vomiting, and general weakness).
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Stroke rehabilitation strategies should be tailored for the individual; women have additional physiologic and psychosocial considerations that factor into developing a comprehensive approach to rehabilitation.

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