Association Between Insomnia Symptoms and Mortality
A Prospective Study of US Men
Background—Insomnia complaints are common in older adults and may be associated with mortality risk. However, evidence regarding this association is mixed. Thus, we prospectively examined whether men with insomnia symptoms had an increased risk of mortality during 6 years of follow-up.
Methods and Results—A prospective cohort study of 23 447 US men participating in the Health Professionals Follow-Up Study and free of cancer, reported on insomnia symptoms in 2004, were followed through 2010. Deaths were identified from state vital statistic records, the National Death Index, family reports, and the postal system. We documented 2025 deaths during 6 years of follow-up (2004–2010). The multivariable-adjusted hazard ratios of total mortality were 1.25 (95% confidence interval [CI], 1.04–1.50) for difficulty initiating sleep, 1.09 (95% CI, 0.97–1.24) for difficulty maintaining sleep, 1.04 (95% CI, 0.88–1.22) for early-morning awakenings, and 1.24 (95% CI, 1.05–1.46) for nonrestorative sleep, comparing men with those symptoms most of the time with men without those symptoms, after adjusting for age, lifestyle factors, and presence of common chronic conditions. Men with difficulty initiating sleep and nonrestorative sleep most of the time had a 55% (hazard ratio, 1.55; 95% CI, 1.19–2.04; P-trend=0.01) and 32% (hazard ratio, 1.32; 95% CI, 1.02–1.72; P-trend=0.002) increased risk of cardiovascular disease mortality, respectively, relative to men without those symptoms.
Conclusion—Some insomnia symptoms, especially difficulty initiating asleep and nonrestorative sleep, are associated with a modestly higher risk of mortality.
- cardiovascular disease
- sleep initiation and maintenance disorders
- sleep disorders
Insomnia, the most common sleep/wake disorder, is characterized by difficulty initiating sleep, difficulty maintaining sleep, early-morning awakenings, or nonrestorative sleep.1,2 Inadequate or unrefreshing nighttime sleep of insomniacs is accompanied by significant distress, daytime fatigue, and the likelihood of falling asleep during the day.1,3–8 Insomnia affects 10% to 30% of the general population in the United States7 depending on its definition. The total cost associated with insomnia is estimated at $92.5 to $107.5 billion annually in the United States.9
Clinical Perspective on p 746
Insomnia in older adults is of particular concern because it could increase risk of injury,10 impaired quality of life,6 cognitive impairment,11 depression,12 and metabolic syndrome.13 Insomnia is also associated with a moderately increased risk for cardiovascular diseases (CVD).14,15 In this context, insomnia has been thought to influence total mortality, and cardiovascular mortality specifically, but results to date have been inconsistent.16–19 Thus, we examined whether men with insomnia symptoms had an increased risk of all-cause and cause-specific mortality in the Health Professionals Follow-Up Study (HPFS), taking into account the effects of a variety of lifestyle factors and prevalent medical morbidities that are known to be associated with mortality risk. To further test our research hypothesis, we also conducted a meta-analysis including the current study with another 9 previously published studies8,20–27 regarding the association between insomnia symptoms and mortality.
Materials and Methods
The institutional review board at Brigham and Women’s Hospital and Harvard School of Public Health reviewed and approved this study, and receipt of each questionnaire implied participant’s consent.
The HPFS was established in 1986, when 51 529 US men health professionals (dentists, optometrists, osteopaths, podiatrists, pharmacists, and veterinarians) aged 40 to 75 years completed a mailed questionnaire about their medical history and lifestyle. Follow-up questionnaires were mailed to participants every 2 years to update information on potential risk factors and to ascertain newly diagnosed diseases.
In 2004, 34 884 men responded to the 2004 questionnaire, which included questions about insomnia. We excluded men with a cancer diagnosis (other than nonmelanoma skin cancer, n=7590) to reduce the potential for an effect of disease on insomnia symptoms and men with missing values for insomnia questions (n=3847), leaving 23 447 men for this analysis.
Assessment of Insomnia Symptoms
In 2004, the participants in the HPFS were asked how often (rarely/never, sometimes, or most of the time) they (1) “have difficulty falling asleep” (referred to as “difficulty initiating sleep” throughout text), (2) “have trouble with waking up during the night” (referred to as “difficulty maintaining sleep”), (3) “are troubled by waking up too early and not being able to fall asleep again” (referred to as “early-morning awakenings”), and (4) “feel really rested when waking up in the morning” (we code nonrestorative sleep frequency as the opposite of feeling rested when waking up in the morning [referred to “nonrestorative sleep”]). Excessive daytime sleepiness was also assessed in 2004 with a question of whether they “get so sleepy during the day or the evening that [they] have to take a nap.”
In addition to individual insomnia symptoms described above, we defined insomnia disorder as the combination of a nocturnal insomnia symptom and a resulting consequence in 2 ways: having 1 or more of the 3 nocturnal insomnia symptoms (difficulty initiating sleep, difficulty maintaining sleep, and early-morning awakenings), accompanied by (1) nonrestorative sleep (“insomnia disorder A”) and (2) excessive daytime sleepiness (“insomnia disorder B”).
Ascertainment of Deaths
Deaths were identified from state vital statistics records, the National Death Index, reported by the families, and the postal system.28 The follow-up for death in the HPFS was at least 98% complete. Cause of death was identified from death certificates or review of medical records. In the current analysis, we evaluated all-cause mortality and also death from CVD (International Classification of Diseases, Eighth Revision codes 390 through 458), cancer (International Classification of Diseases, Eighth Revision codes 140 through 207), and other conditions.
Assessment of Other Covariates
Information on potential confounders, such as age, ethnicity, smoking status, weight, height, physical activity, marriage status, living status, medication use (eg, aspirin, antidepressant, tranquilizers, melatonin and antihypertensive drugs), and history of major chronic conditions (eg, elevated total cholesterol, elevated triglyceride, hypertension, diabetes mellitus, myocardial infarction, stroke, and lower urinary tract symptoms29) was collected via biennial questionnaires. Information on sleep duration and snoring frequency was collected in the 2000 questionnaire. Information on food and alcohol consumption was collected every 4 years via a validated semiquantitative food frequency questionnaire.30
Body mass index was calculated as weight (kg)/height (m).2 High blood pressure was considered as either professionally diagnosed hypertension or use of antihypertensive medications. A participant was considered as having depression symptoms if he reported being “sad, blue, or depressed” for 2 weeks or longer in the past 2 years or regular use of antidepressant medications. The phobic anxiety status was assessed by the Crown–Crisp phobia index.31 Information on lower urinary tract symptoms was collected based on the American Urologic Association Symptom Index.29 Diet quality was assessed by the alternate healthy eating index, which is associated with a lower risk of major chronic diseases and death in this cohort.32
We used Cox proportional hazard models to calculate the hazard ratios (HRs) of mortality and their 95% confidence intervals (CIs), across categories of each insomnia symptom. For tests of trend, we assigned a numeric value of 0 to 2 to the insomnia categories (0, rarely/never have insomnia complaint; 1, sometimes; 2, most of the time) and treated it as a continuous variable.
In addition to an age-adjusted model, we also ran two multivariable-adjusted models. In the first model, we simultaneously adjusted for the known risk factors of mortality, except for presence of chronic conditions and sleep-related variables, because they are possible biological intermediates in the relationship between insomnia symptoms and total mortality. The adjusted covariates in the multivariable model 1 included age, ethnicity, smoking status, alcohol drinking, body mass index, physical activity, alternate healthy eating index, marriage status, and living status. Model 2 further included regular use of aspirin, the Crown–Crisp phobic anxiety index, lower urinary tract symptoms, presence of chronic conditions, use of medications, sleep duration, and snoring frequency. Time-varying covariates were used to reflect the most recent information, except for ethnicity, sleep duration, and snoring frequency. If data were missing at a given time point, the last observation was carried forward for 1 cycle. We also did secondary analyses by using baseline covariates in the models.
We examined the joint effect on total mortality of difficulty initiating sleep with nonrestorative sleep and excessive daytime sleepiness separately. Because insomnia could result in depression symptoms,12 we also tested the joint effect between difficulty initiating sleep and depression. We tested the interaction by comparing the –2 log likelihood of the models with and without interaction term. To minimize potential residual confounding resulting from comorbidities of insomnia, we conducted sensitivity analyses excluding men with prevalent CVD and then further excluding frequent snoring (snoring every night or most night), diabetes mellitus, and Parkinson’s disease at baseline. We conducted another sensitivity analysis by excluding men who reported tranquilizer use (eg, Valium and Xanax) or melatonin, two groups of commonly used hypnotic medications, through the end of follow-up because benzodiazepines can cause several adverse effects33 and thus bias the observed insomnia–mortality relationship.
Finally, we conducted a meta-analysis to combine our study with previously published studies on insomnia symptoms and total and CVD mortality. Relevant studies were identified through searches of PubMed using the keywords of (insomnia OR sleep complaints OR difficulty falling asleep OR difficulty initiating sleep OR waking up at night OR waking up early OR early-morning awakening OR difficulty maintaining sleep OR nonrestorative sleep OR no restorative sleep) AND (dead OR death OR mortality OR survival) for all published studies in English by July 31, 2013. In addition, the reference lists from the relevant publications were used to identify additional studies. We focused on individual insomnia symptoms in the meta-analysis because there was no universal definition of insomnia across previous studies.16–27 In this meta-analysis, we did not include the studies (1) that reported the association between insomnia and mortality but did not provide results regarding individual insomnia symptoms, (2) that reported association but did not provide relative risk value, or (3) that did not include control individuals assessed in the same study. We identified 9 studies8,20–27 that met our criteria for the meta-analysis (Table I in the online-only Data Supplement). We used the Q statistic to examine heterogeneity among the studies. We used random-effects models to calculate the pooled HR because a significant heterogeneity (P<0.1) was observed. Publication bias was assessed using the Begg’s test.
We used the SAS statistical package (version 9; SAS Institute, Cary, NC) for the cohort analyses and Stata (version 9.0; StataCorp, College Station, TX) for the meta-analysis.
In this cohort, 4.1%, 25.2%, 7.7%, 6.2%, and 11.1% of men reported difficulty initiating sleep, difficulty maintaining sleep, early-morning awakenings, nonrestorative sleep, or excessive daytime sleepiness most of the time at baseline, respectively. The characteristics of the study population according to difficulty initiating sleep were presented in Table 1. The other 3 insomnia symptoms showed similar associations to these characteristics (data not shown). In general, insomnia symptoms were associated with lower physical activity, a higher body mass index, and a higher prevalence of depression symptoms, hypertension, elevated total cholesterol, elevated triglycerides, diabetes mellitus, myocardial infarction, and stroke.
Insomnia Symptoms and Total Mortality
We documented 2025 deaths during 6 years of follow-up (127 768 person years). Men with difficulty initiating sleep and nonrestorative sleep had an increased risk of total mortality compared with men without those symptoms in a dose-dependent manner (Table 2), which was independent of a variety of risk factors for mortality. In the fully adjusted models, the HRs (95% CIs) of total mortality were 1.25 (95% CI, 1.04–1.50) for men with difficulty initiating sleep most of the time and 1.24 (95% CI, 1.05–1.46) for men with nonrestorative sleep most of the time compared with those without those symptoms (P-trend<0.03 for both). We found no significant associations between difficulty maintaining sleep or early-morning awakenings and total mortality (Table 2). Similarly, excessive daytime sleepiness was also significantly associated with total mortality; the multivariable-adjusted HR comparing the two extreme categories of this symptom was 1.24 (95% CI, 1.09–1.42; P-trend=0.0006). The associations between the insomnia symptoms and mortality did not materially change after additional adjustment for use of tranquilizers or excessive daytime sleepiness (data not shown).
The multivariable-adjusted HR of total mortality was 1.13 (95% CI, 1.03–1.25) for insomnia disorder A, defined as having any of the 3 nocturnal insomnia symptoms accompanied by nonrestorative sleep, and 1.13 (95% CI, 1.03–1.24) for insomnia disorder B, defined as having any of the 3 nocturnal symptoms accompanied by excessive daytime sleepiness.
We also observed that men with both difficulty initiating sleep and nonrestorative sleep (Figure 1A) or both difficulty initiating sleep and excessive daytime sleepiness (Figure 1B) had the highest risk of total mortality compared with those without these symptoms. A similar pattern was observed for the combination of difficulty initiating sleep and depression symptoms (Figure 1C).
Insomnia and Cause-Specific Mortality
Men with difficulty initiating sleep and nonrestorative sleep most of the time had a 55% (HR, 1.55; 95% CI, 1.19–2.04; P-trend=0.01) and 32% (HR, 1.32; 95% CI, 1.02–1.72; P-trend=0.002) increased risk of CVD mortality, respectively, relative to men without those symptoms (Table 3). We did not observe significant associations between insomnia symptoms and mortality attributable to cancer or other causes, but these results were limited to rapidly fatal cancer because those with prevalent cancer were excluded at baseline.
After we excluded men with prevalent CVDs at baseline, the multivariable-adjusted HRs were 1.25 (95% CI, 0.99–1.56; P-trend=0.02) for total mortality and 1.45 (95% CI, 1.02–2.06; P-trend=0.04) for CVD mortality, comparing men with difficulty initiating sleep most of the time with those without this symptom. The multivariable-adjusted HRs among men with nonrestorative sleep most of the time were 1.26 (95% CI, 1.04–1.54; P-trend=0.02) for total mortality and 1.37 (95% CI, 0.98–1.91; P-trend=0.005) for CVD mortality. The significant associations between difficulty initiating sleep, nonrestorative sleep, and total mortality were basically unchanged even after we further excluded participants with frequent snoring, diabetes mellitus, and Parkinson’s disease or when we used covariates at baseline in the models (P-trend<0.05 for both). Because a previous study19 suggested that a short-sleep-duration insomnia (<6 hours) was associated with increased mortality risk, we also treated the covariate of sleep duration as a binary variable (<6 versus ≥6 hours) and obtained similar results (data not shown). After we excluded participants who used tranquilizers or melatonin through the follow-up, the adjusted HRs comparing the two extreme categories were 1.34 (95% CI, 1.09–1.66; P-trend=0.02) for difficulty initiating sleep and 1.21 (95% CI, 1.01–1.45; P-trend=0.01) for nonrestorative sleep.
We pooled the present study and 9 other published studies8,20–27 that evaluated the associations between individual insomnia symptoms and total mortality. The pooled HRs of total mortality were 1.14 (95% CI, 1.04–1.24) for difficulty initiating sleep, 1.08 (95% CI, 0.96–1.22) for difficulty maintaining sleep, 1.00 (95% CI, 0.94–1.06) for early-morning awakenings, and 1.17 (95% CI, 1.01–1.36) for nonrestorative sleep relative to individuals without those symptoms (Figure 2). The results did not change materially after excluding 2 studies21,23 with low quality scores (see Table I in the online-only Data Supplement) based on Newcastle–Ottawa Quality Assessment Scale (Figure 2). We also conducted a meta-analysis using data from the present study and 5 published studies22,25–27,34 that examined the associations between insomnia symptoms and CVD mortality. The pooled HRs of CVD mortality was 1.45 (95% CI, 1.09–1.93) for difficulty initiating sleep, 1.03 (95% CI, 0.89–1.17) for difficulty maintaining sleep, and 1.00 (95% CI, 0.89–1.13) for early-morning awakenings (Figure 3). However, the association between nonrestorative sleep and CVD mortality was not examined previously. Further excluding the present prospective study from the meta-analyses did not change the pooled results between insomnia and total/CVD mortality materially (see Figures I and II in the online-only Data Supplement).
In this large prospective cohort, we observed that men with difficulty initiating sleep and those with nonrestorative sleep had a modest but significantly increased and dose-dependent risk of total mortality compared with men without those symptoms. The increased risk was independent of a variety of risk factors for mortality, including lifestyle factors and presence of several medical morbidities.
Normal sleep continuity is considered to be important for the maintenance of cardiovascular, metabolic, and immune function, physiological homeostasis, and psychological balance.35,36 Suboptimal sleep disturbs both circadian rhythms and other physiological systems.35,36 Sleep disturbance has been shown to adversely influence metabolism and endocrine function similar to the effects of premature aging,37 including reducing endogenous testosterone levels,38 altering the hypothalamic pituitary adrenal axis,39 and elevating markers of chronic inflammation.35 Insomnia has also been associated with incident depression,12 a risk factor for cardiovascular morbidity and mortality.40 Thus, insomnia may increase mortality risk through effects on several biological pathways. This notion has been supported by a study conducted by Dew et al,16 who assessed sleep status of 184 healthy older adults via polysomnography. They found that insomnia symptoms, such as difficulty falling asleep and poor sleep efficiency, were associated with an almost doubled risk of all-cause mortality (n=66) during 12 years of follow-up.16 The current study with a much larger sample size and the meta-analysis further confirmed that observation. In the present study, we controlled for multiple confounders using updated information on lifestyle risk factors and common chronic diseases over the course of follow-up. In addition, we conducted a sensitivity analysis by excluding the participants with CVD and depression and found that the association between insomnia symptoms and mortality was basically unchanged. Although the possibility of residual confounding cannot be completely excluded, our study, together with the previous studies,14,41 suggests that chronic disorders cannot totally explain the observed association between insomnia symptoms and total mortality. Thus, it is likely that sleep disturbances characterized by insomnia symptoms represent novel risk factors for mortality.
Several epidemiological studies have found significant associations between insomnia and CVD intermediate markers and risk factors, such as carotid intima-media thickness42; cardiorespiratory fitnes,43 and Framingham risk score.44 Difficulty initiating sleep was associated with 20-year incidence of myocardial infarction or coronary death among women in the Framingham Study.34 Trouble initiating sleep, but not difficulty maintaining sleep or early-morning awakenings, was reported to be associated with a higher risk of CVD mortality in a cohort of middle-aged Swedish men,22 the Piedmont Health Survey15,45 and the Malmo Preventive study.25 Difficulty initiating sleep also appeared to have the strongest and the most robust association with acute myocardial infarction.14 Biologically, it is plausible that prolonged sleep latency or reduced sleep maintenance have different effects on sleep-stage distribution and associated neurohormonal activities.16,46 Furthermore, delayed sleep could also lead to alterations in circadian rhythms,47 which are important for CVD pathogenesis. Most previous epidemiological studies focused on 3 nocturnal insomnia symptoms: (1) difficulty initiating sleep, (2) difficulty maintaining sleep, and (3) early-morning awakenings.20,21,23,26,27 Nonrestorative sleep, another important component of insomnia, is included in criteria of insomnia recommended by the National Institutes of Health,1 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,48 and International Classification of Sleep Disorders, Second Edition,49 but few studies have addressed its potential effects on mortality8,24 because there is controversy as to whether individuals with this complaint share similar pathophysiologic mechanisms with the other nocturnal symptoms. The finding of the present cohort study and meta-analysis indicates an increased higher risk of total mortality among people with nonrestorative sleep. Excessive daytime sleepiness has also been increasingly recognized as a major health hazard and has been linked to an increased risk of all-cause mortality.8,23 In the Cardiovascular Health Study, women with excessive daytime sleepiness and frequent nighttime awakenings were more likely to develop congestive heart failure.23 In the present study, men with the combination of difficulty initiating sleep and excessive daytime sleepiness most of the time were the most prone to total mortality. Because we did not find a significant interaction on risk of mortality, it was more likely that both symptoms were independently associated with mortality.
The strengths of our study include a relatively large sample size, with a sufficient number of cases to explore the CVD and cancer-specific mortality and detailed and repeated assessments of lifestyle risk factors and common chronic diseases over the course of follow-up. Another important strength is the high follow-up rate. In each 2- or 4-year cycle of the HPFS, follow-up rates have averaged 94%. The follow-up for death in the HPFS is at least 98% completed.
Our study has several potential limitations. First, assessment of insomnia symptoms was based on self-report, and objective measures of sleep quality were not available in our cohort. Such perceived symptoms may reflect a negative self-view or early onset of depression, and the latter is associated with mortality.40 Although we adjusted for depressed mood and use of antidepressants in the main analyses, we still could not totally rule out the confounding effects attributable to depression. Likewise, we used frequent snoring as a surrogate measure of obstructive sleep apnea. Frequent snoring has been shown to correlate closely with obstructive sleep apnea in men and has been used as a surrogate of obstructive sleep apnea in previous epidemiological studies,50 although misclassification is inevitably introduced. To minimize the residual confounding effects attributable to imperfect measures of obstructive sleep apnea, we excluded men with frequent snoring and other common chronic disorders in the sensitivity analysis and generated similar results. Second, we did not ask a specific question in the HPFS regarding use of hypnotic drugs, except for benzodiazepine and melatonin, until 2008. Previous studies suggested that hypnotics were associated with several adverse health outcomes, including dementia and mortality.33 However, the observed association between insomnia symptoms and mortality did not materially change after excluding men using benzodiazepine or melatonin. Further excluding those who reported hypnotic drugs in 2008 also did not change our results (data not shown). It is worth noting that, if the observed associations were attributable to hypnotic medication use rather than insomnia per se, we would expect to observe similar associations for all individual insomnia symptoms. However, in our cohort study and the meta-analysis, the significant associations were consistently observed only in some but not all insomnia symptoms. In this context, although we cannot rule out the possibility of residual confounding attributable to hypnotic drug use, the effects are likely to be modest. Another limitation was that this cohort included mostly white men; thus, these findings might not be generalizable to women or nonwhite men populations. However, in the meta-analysis including populations with diverse social and economic backgrounds, we observed similar patterns between different insomnia symptoms and mortality. It is also worth noting that only 9 published studies were included in the meta-analyses, which precludes use to conduct subgroup analysis to explore potential sources of the observed heterogeneity across studies, suggesting that additional works in this area should be a priority.
In conclusion, this large prospective cohort study indicates that difficulty initiating sleep and nonrestorative sleep are associated with a modestly higher risk of total and CVD-specific mortality, and these associations persisted even after we excluded participants with CVDs and depression. These observations were supported by our concurrent meta-analysis including results of the present study and 9 previously published studies. Future research in this field is warranted, especially the long-term epidemiological studies about the association between individual insomnia symptoms and mortality, and experimental and clinical studies probing mechanisms underlying the insomnia–mortality associations. Although future studies are still needed before a firm conclusion can be reached, our study provides consistent evidence that insomnia symptoms may be an important modifiable risk factor affecting longevity.
Sources of Funding
The study was supported by National Institute of Neurological Disorders and Stroke grant R01 NS062879-01A2, National Cancer Institute grant P01 CA87969, and National Institutes of Health Transdisciplinary Research in Energetics and Cancer Center grant 1U54CA155626. None of the sponsors participated in the design of study or in the collection, analysis, or interpretation of the data.
Dr. Winkelman receives research grants from UCB (Neupro Clinical Trial), GlaxoSmithKline (MRS imaging with restless legs syndrome subjects), and Impax (Clinical Trial for Restless Legs Syndrome) and reports a consulting relationship with Xenoport. Dr. Redline receives multiple National Institutes of Health research grants examining sleep disorders, their epidemiology, and treatment and is a Board of Director for the American Academy of Sleep Medicine, a nonprofit professional society for sleep medicine. The other authors report no conflicts.
Insomnia, the most common sleep/wake disorder, is characterized by difficulty initiating sleep, difficulty maintaining sleep, early-morning awakenings, or nonrestorative sleep. Insomnia affects 10% to 30% of the general population in the United States depending on its definition. Insomnia has been thought to influence total mortality and cardiovascular mortality specifically, but results to date have been inconsistent. Thus, we prospectively examined the association between insomnia symptoms and all-cause and cause-specific mortality in 23 447 men participating the Health Professionals Follow-Up Study (HPFS), a well-characterized US ongoing cohort. We found that difficulty initiating asleep and nonrestorative sleep, but not difficulty maintaining sleep or early-morning wakeup, were associated with a modestly higher risk of total mortality and cardiovascular mortality. The increased risk was independent of a variety of risk factors for mortality, including lifestyle factors and presence of several medical morbidities. These observations were supported by our concurrent meta-analysis, including results of the present study and 9 previously published studies on this topic. Although future studies are still needed before a firm conclusion can be reached, our study provides additional evidence that insomnia symptoms may be an important modifiable risk factor affecting longevity.
Guest Editor for this article was Jonathan M. Samet, MD, MS.
The online-only Data Supplement is available at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.113.004500/-/DC1.
- Received June 18, 2013.
- Accepted October 3, 2013.
- © 2013 American Heart Association, Inc.
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