The Relationship between Smoking and Stroke Risk in Women: Breaking the Habit

“Cigarette smoking is the single most preventable cause of mortality in society today, attributable for 140,000 strokes in the USA annually.”

Can you imagine a legal drug and a delivery system that offers no tangible benefit to the user, induces significant disease in the user and nearby nonusers, reduces the life expectancy of the average user by over 14 years, is addictive and marketed towards the young, whose affects are crippling the healthcare system owing to a 20% population addiction rate, as well as a healthcare system that forces nonusers to subsidize the care of the users? Well think no further, we have cigarette smoking.

As a vascular neurologist I am frequently called to the emergency room to evaluate stroke patients for potential acute therapies and to inform family members that their loved one has just experienced a medical condition that will probably result in irreversible brain injury and permanent disability. My initial evaluation not only delves into determining the safety of potential acute therapies, but also focuses on determining the etiologic cause of the stroke. As I hear the patient's history, including the presence of standard risk factors, such as hypertension, diabetes and smoking, I often find myself thinking that this patient's stroke was probably preventable. Of the various risk factors, I find smoking particularly bothersome, since cessation of this self-mediated habit definitively results in a significant decrease in the likelihood of experiencing a stroke. I find myself lamenting, “if I had only seen this patient prior to their stroke, this could have been prevented”. Since I cannot see all prestroke smokers, this burden passes onto you, the healthcare providers and readers of this article. Finally, as a motivator, it is important to remember that it is always better to prevent a stroke than deal with the aftermath; this is true for the patient, the patient's family, and the patient's primary healthcare advocate. As such, working to control and remove all vascular risk factors, including all forms of smoking, becomes paramount.

The societal cost of smoking

Up to a quarter of all strokes are directly attributable to cigarette smoking. This percentage can rise up to 50% for young adults admitted for a cryptogenic ischemic stroke [1]. If one assumes a 20% risk of stroke is associated with smoking, considered in conjunction with the 700,000 strokes that occur in the USA annually, then if all Americans stopped smoking there would be 140,000 fewer strokes. The cost–benefits would be enormous, potentially saving a fifth of the US$69 billion spent annually on stroke care in the USA [2]. Should all smoking cease in the US, an estimated 14.5 years of life would be saved for each female who currently smokes [3].

“…it is important to remember that it is always better to prevent a stroke than deal with the aftermath; this is true for the patient, the patient's family, and the patient's primary healthcare advocate.”

Given the global economic crisis, and subsequent healthcare crisis in the USA and other nations worldwide, it is hard to fathom that smoking remains on the ‘back-burner’ during these discussions. The economic burden required for the care of smokers regarding their smoking-induced illnesses is enormous. I would suggest an additional large scale tax of $4–5 per pack over the current rates. These monies could be placed into an account that would be drawn upon by the healthcare system when the smoker inevitably requires care. The fact that such a system is not in place implies that the nonsmoking majority are subsidizing the healthcare of the smoking minority.

So who smokes? While both the general public and the global healthcare system are aware of the risks associated with smoking, the prevalence of tobacco use over the last quarter century remains largely unchanged. At present, approximately one in five US adults are classified as regular smokers, with other industrialized countries worldwide having similar or greater prevalence rates. Currently, the prevalence of smoking among US male adults is still greater than that of US females – 23 versus 19%, respectively [101]. Among women of reproductive age, those aged 18–24 years were most likely to have attempted to quit (68.4%), but least likely to have successfully quit smoking (26.3%), bringing to light an important target population for additional smoking cessation programs [102]. The prevalence among African–Americans and Caucasians females is similar at approximately 21%. Hispanic and Asian females are approximately half as likely to smoke [101].

An impetus to begin smoking is clearly present during the teenage years. While only 6% of middle school students were smokers in 2006, data collected 1 year later showed a prevalence of 20% among high school students [103]. This 20% prevalence among high school students is consistent with the overall USA adult smoking prevalence rate. Similar age-related prevalence data has been reported worldwide. Hence, these statistics clearly argue for the need for more aggressive smoking prevention programs in our schools, notably in the middle school years (grades 6–9) or earlier. In general, the prevalence of smoking in females (and males) peaks between the ages of 18 and 44 years and decreases dramatically after the age of 65 years; this is directly related to smoking-related illnesses [101].

Association between smoking & stroke

The evidence linking smoking to stroke risk is extremely convincing. I would refer interested readers to a recent review article describing the results of numerous ethnically diverse studies evaluating the association between cigarette smoking and stroke risk [4]. To summarize, studies performed across varying ethnicities and populations demonstrate a highly consistent association between smoking and ischemic stroke risk, with current smokers having at a two- to fourfold increased risk of ischemic stroke compared with lifelong nonsmokers or individuals who had quit smoking >10 years prior. In one study, this risk increased to sixfold when this population was compared with nonsmokers who had never been exposed to environmental tobacco smoke (i.e., second-hand smoke) [5]. In a separate study, this sixfold increase in risk persisted when cigarette smoking women with smoking spouses were compared with smoking women with nonsmoking spouses, further demonstrating the effect of second-hand smoke on stroke risk [6]. Convincingly, a large USA-based cohort study consisting of over 27,000 individuals demonstrated a 1.5-fold (95% CI: 1.07–02.09) increased risk of first ischemic stroke in women exposed to 20 h or more per week of environmental tobacco smoke at home compared with those exposed to <1 h per week [7].

The plausible mechanisms by which primary and environmental tobacco smoke exposure can increase ischemic stroke risk are numerous, with most centering on the fact that that tobacco smoke contains over 4000 different chemical constituents, including heavy metals and other known toxins. Such chemicals promote the development of free radicals that induce vascular endothelial dysfunction and inflammation, ultimately leading to the development and acceleration of the atherosclerotic process. Smoking also induces a global circulatory procoagulant state thought to be related to altered hemostatic and inflammatory marker concentrations. Among its other detrimental effects, smoking increases fibrinogen concentration, decreases fibrinolytic activity, increases platelet aggregability and induces polycythemia [8]. In combination with these undesirable effects, smoking also decreases cerebral blood flow via a vasoconstrictive mechanism, further increasing the risk of clot formation and stroke risk through a slowed flow or stasis phenomenon [9].

Ischemic stroke is not the only form of stroke associated with smoking; the risks of intracerebral hemorrhage and subarachnoid hemorrhage are also elevated, with a recent study demonstrating increased risk of total hemorrhagic stroke, intracerebral hemorrhage and subarachnoid hemorrhage in females smoking 15 cigarettes per day (relative risk [RR]: 3.29 [95% CI: 1.72–6.29]; RR: 2.67 [95% CI: 1.04–06.90]; and RR: 4.02 [95% CI: 1.63–69.89], respectively [10]).

Smoking discontinuance demonstrates a considerable reduction in stroke risk across gender, race and age. This fact has been demonstrated in numerous studies both in the USA and worldwide. In a Nurse's Health Study manuscript by Kawachi et al., the RR of total stroke among US nurses who smoked compared with those who had never smoked was 2.58 (95% CI: 2.08–3.19) [11]. The RR among former smokers was 1.34 (95% CI: 1.04–1.73). For total and ischemic stroke, the excess risks among former smokers dissipated 2–4 years after cessation. This pattern of decline was observed regardless of quantity smoked, age at initiation of smoking or in the presence of other stroke risk factors. Mechanistically, the return to baseline stroke risk is thought to be related to normalization of the procoagulant state seen in smokers. However, not all studies demonstrate a full return to nonsmoker risk status, which may in part be related to several factors, including the duration of smoking, concomitant risk factors and the quantity of atherosclerotic disease developed while smoking [12]. Nevertheless, smoking cessation produces a major reduction in stroke risk across all races, both genders and all age groups.

“Smoking discontinuance demonstrates a considerable reduction in stroke risk across gender, race and age.”

Finally, a strong dose–response relationship exists between smoking and stroke risk that can be succinctly described as: ‘the more you smoke the more you stroke’. For greater than 20 years the dose–response relationship between tobacco consumption and stroke risk has been well established [4]. However, this relationship is less well known among the general medical community; as such, this information is often not passed onto the smoking population. This relationship is notable as it provides smokers with a significant opportunity to garner definitive and measurable health benefits if they can reduce the daily number of cigarettes smoked, although complete discontinuance is the ultimate goal.

High-risk scenarios among female smokers

Standard stroke risk factors, such as hypertension, diabetes and smoking, among others, have been shown to act in synergy with one another to increase stroke risk; that is, combinations of these risk factors elevate risk in a greater-than additive fashion. Further studies have implicated increased synergistic risk among female smokers in the context of several nontraditional risk factors, such HRT [13] and estrogen-based contraceptive use [14], during the postpartum period [15] and among migrainuers with aura [16]. As such, combinations of these risk factors, both alone and in the context of standard risk factors, are of particular concern among smokers. While it is beyond the scope of this article to discuss these various stroke risk factors individually, some general comments regarding the most dangerous combinations are warranted.

While the precise risk association between contraceptive use and stroke remains uncertain, an important caveat should be addressed: women with migraines taking oral contraception (OC) must not smoke. Considerable evidence indicates a markedly elevated ischemic stroke risk in this setting. A relatively recent review article [17] eloquently summarizes the relationships between estrogens, migraine and stroke according to age.

Findings in women aged <50 years show that 30% of women in this age category are affected by migraine. Migraines are strongly influenced by estrogens, as evidenced by their onset at puberty, the existence of menstrual migraine and their tendency to improve during pregnancy. Migraine is a risk factor for ischemic stroke, with a relative risk of approximately 3. The risk is higher in migraine with aura and is further increased by tobacco smoking and OC use. The absolute risk of ischemic stroke is very low, and therefore there is no overall contraindication to OC use in migraineurs but rather a firm recommendation that users not smoke and use either low-estrogen-content pills or progestogen-only pills.

Findings in women after menopause show that migraine improves in 50–60% of cases but tends to worsen with HRT. Migraine is not proven as a risk factor for ischemic stroke in this population. Stroke is very frequent in this population, affecting one in every five women, and the risk is significantly increased by use of HRT. There are no specific data thus far on the association between migraine and HRT with regard to the risk of stroke. Thus, migraine in itself is not a contraindication to the use of HRT and decisions should be made on a case-by-case basis.

“While the precise risk association between contraceptive use and stroke remains uncertain, an important caveat should be addressed: women with migraines taking oral contraception (OC) must not smoke.”

Working to avoid these high-risk combinations among female smokers becomes paramount; further emphasizing the importance of individually optimizing each patient's risk factor profile.

Conclusion

While a clear correlation between smoking and health risk has long been established, the prevalence of smoking in our society remains at unacceptable levels. Cigarette smoking is the single most preventable cause of mortality in society today, attributable for 140,000 strokes in the USA annually. Smoking prevention and education efforts need to start early in life. While never smoking is optimal, there is clear evidence that smoking cessation and reduction has beneficial effects on health. Healthcare providers need to take an active role to help all patients to quit smoking. Increasing funding for smoking prevention and cessation programs makes fiscal sense and will help achieve our goals towards establishing a healthier worldwide population.