Sleep, which accounts for one-third part of the lifetime, is of the great essence in our daily routine [1
]. The National Sleep Foundation recommends that adults should get 7–8 h sleep every day, albeit sleep demands may vary in age and gender [2
]. As a modifiable lifestyle, healthy sleep is necessary for maintaining physical and psychological health. The daily sleep-wake cycle is controlled by circadian clock, different neurons, and hormones produced by the hypothalamus and environmental signals (dark/light) [3
]. In recent years, sleep disorders have become an epidemic throughout the world [5
], while many people, even medical staff, are not aware of their significance. Previous studies revealed that excessive sleep or sleep deprivation were associated with increased risk of adverse health events, including type II diabetes, hypertension, cancers, and all-cause mortality [9
Vitamin D as a unique, fat-soluble vitamin can either be ingested from diet or synthesized by ultraviolet-B (UVB) radiation [12
]. 25-hydroxyvitamin D (25(OH)D) is commonly considered as the best indicator of vitamin D status in the body [14
]. Due to the concentrations of serum 25(OH)D can be affected by many factors (such as lack of sunlight exposure, lifestyle, and skin color), and vitamin D deficiency (VDD) is prevalent; lesser known functions of vitamin D are being paid more attention such as the association between VDD and cardiovascular diseases [15
], infectious diseases [16
], and sleep disorders [17
]. Several studies reported that vitamin D receptors (VDR) were expressed in brain areas that regulate the sleep–wake cycle, such as the hypothalamus [18
]. This evidence indicated that higher vitamin D status was inversely associated with the risk of sleep disorders.
Furthermore, several observational studies showed the association between vitamin D deficiency and sleep disorders. A cross-sectional study reported that vitamin D deficiency correlated with poorer sleep quality [20
]. McCarty et al. observed that patients who exhibited vitamin D deficiency got lower scores on the Epworth Sleepiness Scale (ESSs) [21
], which is an effective instrument for measuring excessive daytime sleepiness [22
]. Additionally, several large sample epidemiology studies found that dietary intake of vitamin D was related to midpoint of sleep, sleep duration, and maintaining sleep [23
]. However, the results were inconsistent. Gunduz et al. [26
] found no significant difference in the Pittsburgh Sleep Quality Index (PSQI) total score between the VD-deficient group and the VD non-deficient group among women in the last trimester of pregnancy. The PSQI is a standardized self-questionnaire that measures sleep quality and disorders over a 1-month period [27
To address the divergence mentioned above, we conducted this systematic review and meta-analysis to explore the association between vitamin D deficiency and the risk of sleep disorders.
This meta-analysis discussed the relationship between vitamin D deficiency and sleep disorders including poor sleep quality, short sleep duration, and sleepiness. Overall, the results showed that serum 25(OH)D levels were inversely associated with an increased risk of sleep disorders.
Our finding indicates that low serum 25(OH)D may be a risk factor of unhealthy sleep (OR: 1.50, 95% CI: 1.31, 1.72). In subgroup analysis, sleep disorders were divided into three types in order to improve the generality of the results. There was significant inverse association between vitamin D status and the risk of short sleep duration. In addition, we used 10, 20, and 30 ng/mL cut-offs value in subgroup analysis because of the discrepancy in the standard of vitamin D deficiency [38
]. The results showed that the cut-off value of 20 ng/mL, in accordance with the criteria suggested by IOM, increased the risk of poor sleep quality by nearly 60% (pooled OR: 1.59, 95% CI: 1.31, 1.94). Our results further indicate that this criterion is more suitable for studying the correlation of vitamin D deficiency and the risk of certain chronic diseases and life quality.
The sensitivity analysis results showed that two studies may contribute to heterogeneity [26
]. There was a low degree of heterogeneity after excluding these two articles. Heterogeneity may be caused by pregnant women’s decision to act responsibly, which affects their dietary and sleep behavior during pregnancy. Results in the sensitivity analysis ranged from 1.41 (1.22, 1.63) to 1.63 (1.28, 2.07) showed that our results were robust. Based on the funnel plot, there is no publication bias. However, due to the small number of included studies, it is difficult to say that there is no asymmetry in the plot. Hence, we further evaluated the publication bias by Begg’s and Egger’s tests.
In addition to bone homeostasis, vitamin D plays a role in multiple physiological mechanisms, including sleep, immunity, and others [40
]. Although the underlying mechanisms to explain the association between vitamin D deficiency (VDD) and sleep disorders are not yet known, several possible mechanisms have been suggested. Recent experimental studies have identified that vitamin D receptors (VDR) are common in nearly all tissues of the body, including the central nervous system [41
]. VDR are widely distributed in human brain, such as the hypothalamus, prefrontal cortex, midbrain central gray, substantia nigra, and raphe nuclei, all of which are known to execute important roles in sleep regulation [42
]. VDD [44
] is a prevalent condition that is associated with a deforming demineralization of bones, as well as more recent problems such as chronic nonspecific pain [45
], which may cause poor sleep [51
]. Chronic, nonspecific clinical pain seems to be a marker of VDD: The prevalence of VDD was high in patients who complained about intractable pain of an uncertain cause. Okura, et al. reported that individuals with chronic pain gained an increased risk of poor sleep quality and short sleep duration [52
]. Increased pain sensation related to sleep deprivation is reported to be associated with an increase in IL-6 [53
]; an inflammatory marker can be elevated in patients with obstructive sleep apnea (OSA) [54
] and low 25(OH)D [55
]. One study about veterans with chronic pain found that their pain levels, sleep quality, and various aspects of Quality of Life (QoL) can be significant improved after standardized vitamin D supplementation [56
]. Furthermore, Vitamin D deficiency increases the risk of autoimmune disease and respiratory infectious diseases. Emerging lines of evidence suggest that vitamin D can play an immunomodulatory role by altering immune regulation, decreasing the release of inflammatory substances, including those that regulate sleep, such as prostaglandin D2, tumor necrosis factor alpha (TNF-a), and cytokine [57
]. Barcelo et al. founded that patients with obstructive sleep apnea syndrome (OSAS) had higher levels of lipocalin-type PGD synthase than patients without OSAS [60
]. In summary, recent articles suggest that VDD regulates the development of symptoms of wakefulness that are commonly related to sleep disorders [21
]. There remains much to be studied about the complex relationship between long-term low levels of vitamin D, normal sleep, and sleep disorders.
Moreover, some epidemiologic evidence has verified the impact of vitamin D supplements on sleep disorders. An intervention study reported that vitamin D supplementation (D3) in veterans (50,000 IU/week) increased their sleep duration [56
]. Another double-blind clinical trial showed use of vitamin D supplementation (50,000 IU/fortnight for 8 weeks) facilitated sleep duration and quality in people with sleep disorder [61
]. Consequently, combined with our findings, it may be useful to ameliorate poor sleep by increasing vitamin D levels in the body. However, as there were only two reported RCT studies and the existing high heterogeneity, we cannot include them in this meta-analysis.
The present meta-analysis has several strengths. First, to our knowledge, this is the first meta-analysis to assess the association between VDD and sleep disorders. Second, we use poor sleep quality, short sleep duration, and sleepiness as three different outcomes to conduct subgroup analysis. The results were almost as same as the overall sleep disorders. Furthermore, the subgroup and sensitivity analysis validated the reliability and robustness of our results.
Several potential limitations of this meta-analysis should be recognized. First, the number of studies eligible for our meta-analysis was small, and different study designs also prevented data extraction. Second, heterogeneity that existed in the studies should not be ignored when we interpret the results. The heterogeneity may be due to the difference in the assessment of sleep and grouping criteria of vitamin D. Last, most of the studies were cross-sectional, so they cannot establish a causal association. Therefore, further high-quality cohort studies and well-designed randomized controlled trials (RCTs) are needed to verify this relationship and to determine the effect of vitamin D supplementation in unhealthy sleep therapy.