The intuition of an association between sleep duration and mortality goes back to the 1970s. Since then, many prospective studies have suggested that short and long sleepers have an increased risk of all-cause and cause-specific mortality compared to subjects who sleep 7–8 hours per night. In the recent publication by Kabat and colleagues, data from the Women's Health Initiative (WHI) were used to examine sleep duration, insomnia, and use of sleep medications in relation to total and cause-specific mortality (cardiovascular, cancer, other) [1]. A total of 158,203 subjects in the combined clinical trial and observational study components of the WHI were included, among which a total of 30,400 deaths occurred, including 8857 cardiovascular disease (CVD) deaths, 9284 cancer deaths, and 11,928 other deaths over a median of 17.8 years. Sleep duration, sleep quality, assessed by the WHI Insomnia Rating Score, and use of sleep aids (alcohol or medication) were recorded at baseline and information on duration and quality of sleep was collected at multiple time points for most cohort members. Women with the lowest and highest number of hours of sleep per night (≤ 5 h or ≥ 9 h) had higher body mass index (BMI) and systolic blood pressure, higher levels of depression, use of sleep aids, fair-to-poor health, and a history of diabetes, CVD, or cancer. Moreover, they had lower levels of physical activity and were less likely to be white, to be college graduates, or to report ever use of hormone therapy. Women with insomnia had higher BMI, more pack-years of smoking, higher systolic blood pressure, higher proportions of use of sleep aids, higher proportions of diabetes, CVD, and/or cancer, and higher levels of depression. Short and long sleep durations measured at the baseline visit were associated with increased risk of total mortality, CVD mortality, and other mortality, but not with cancer mortality. Insomnia reported at baseline showed a weak inverse association with total and CVD mortality. Use of sleep aids was associated with increased risk of total mortality, CVD mortality, and other mortality. In time-dependent analysis, insomnia only showed a borderline positive association with cancer mortality. The association of short sleep duration with total mortality and CVD mortality was unchanged, while that with other mortality was strengthened and the association of long sleep duration with all four outcomes was strengthened. Use of sleep aids was positively associated with mortality.

Comment

In this large, prospective cohort of postmenopausal women, short and long sleep durations were significantly positively associated with total mortality, CVD mortality, and other mortality, although the authors discussed that the association of long sleep duration may be due to residual confounding. Altered sleep duration was associated with a number of conditions, all independent risk factors for increased morbidity and mortality, indicating that the etiology of inadequate sleep in postmenopausal women is very complex and probably multidirectional. Among the analyzed parameters, unfortunately, information was unavailable for two important determinants of poor sleep in postmenopausal women: vasomotor symptoms and obstructive sleep apnea (OSA) [2-4]. In the last decade, longitudinal studies have shown a link between vasomotor symptoms and poor sleep, specifically increased sleep fragmentation, increased wakefulness after sleep onset, poor sleep efficiency and longer sleep duration [2, 5]. Moreover, vasomotor symptoms persist well beyond the final menstrual period in a significant percentage of postmenopausal women [6] and seem to be a marker for CVD in postmenopausal women [7], as they are linked to significantly higher systolic and diastolic blood pressures, higher circulating total cholesterol levels, and a higher BMI than in non-symptomatic women [7]. OSA increases with the menopause, especially in those women who undergo surgical menopause, and alters sleep by causing apnea episodes, sleep onset insomnia or maintenance insomnia symptoms [4] and is also a major risk factor for CVD in women through association with hypertension and ischemic heart diseases [8]. OSA could be an independent risk factor for left ventricular hypertrophy in women and is associated with incident heart failure and death among females [8]. Both vasomotor symptoms and OSA seem to be linked to an increase in oxidative stress, tissue inflammation and endothelial dysfunction, which are the mechanistic bases for many diseases. Interestingly, a recent study has found severe vasomotor symptoms to be more often associated to high risk of OSA in midlife women [9]. Sleep disruption, at least in some women, may be a byproduct of pathological processes that begin undermining the health of women from midlife. On the other hand, in the WHI study [1], the positive associations of short and long sleep durations with total mortality were not attenuated when women with pre-existing disease, those in poor general health, or those who developed chronic diseases during follow-up were excluded; short and long sleep continued to be associated with increased CVD mortality and other mortality [1]. More longitudinal studies with objective measures in postmenopausal women who suffer from altered sleep are necessary. Nonetheless, because of the association with increased mortality [1], all factors disrupting sleep in postmenopausal women should be adequately addressed with appropriate instruments and therapeutic strategies.

Dr Patrizia Monteleone

References

1. Kabat GC, Xue X, Kamensky V, et al. The association of sleep duration and quality with all-cause and cause-specific mortality in the Women's Health Initiative. Sleep Med 2018;50:48-54
   http://www.ncbi.nlm.nih.gov/pubmed/29982090
2. Freeman EW, Sammel MD, Gross SA, et al. Poor sleep in relation to natural menopause: a population-based 14-year follow-up of midlife women. Menopause 2015; 22:719-26
   http://www.ncbi.nlm.nih.gov/pubmed/25549066
3. Huang T, Lin BM, Redline S, Curhan GC, Hu FB, Tworoger SS. Type of menopause, age at menopause, and risk of developing obstructive sleep apnea in postmenopausal women. Am J Epidemiol 2018;187:1370-9
   http://www.ncbi.nlm.nih.gov/pubmed/29365014
4. Jehan S, Auguste E, Zizi F, et al. Obstructive sleep apnea: women’s perspective. J Sleep Med Disord 2016;3:1064
   http://www.ncbi.nlm.nih.gov/pubmed/28239685
5. Kravitz HM, Avery E, Sowers M, et al. Relationships between menopausal and mood symptoms and EEG sleep measures in a multi-ethnic sample of middle-aged women: the SWAN sleep study. Sleep 2011;34:1221-32
   http://www.ncbi.nlm.nih.gov/pubmed/21886360
6. Avis NE, Crawford SL, Greendale G, et al.; Study of Women's Health Across the Nation. Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med 2015;175:531-9
   http://www.ncbi.nlm.nih.gov/pubmed/25686030
7. Muka T, Oliver-Williams C, Colpani V, et al. Association of vasomotor and other menopausal symptoms with risk of cardiovascular disease: a systematic review and meta-analysis. PLoS One 2016;11:e0157417
   http://www.ncbi.nlm.nih.gov/pubmed/27315068
8. Sánchez-de-la-Torre M, Campos-Rodriguez F, Barbé F. Obstructive sleep apnoea and cardiovascular disease. Lancet Respir Med 2013;1:61-72
   http://www.ncbi.nlm.nih.gov/pubmed/24321805
9. Gao CC, Kapoor E, Lipford MC, Miller VM, Schroeder DR, Mara KC, Faubion SS. Association of vasomotor symptoms and sleep apnea risk in midlife women. Menopause 2018;25:391-8
   http://www.ncbi.nlm.nih.gov/pubmed/29088020

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