Abstract
Shift work is common in many industries. The potential association between shift work and ischaemic heart disease (IHD) remains controversial.
To conduct a systematic review and meta-analysis of epidemiological evidence and summarize the potential relationship between shift work and IHD.
We searched all relevant case–control and cohort studies that were published from January 1970 to October 2017 on PubMed, Web of Science and Embase. The random-effects model and the generalized least-squares trend model were, respectively, used to evaluate the pooled relative risk and dose–response relationship between shift work and IHD. Two different authors extracted data and assessed the quality of each study independently.
Twenty-one articles with 31 independent results of 19 782 IHD cases in 320 002 participants were included. The pooled relative risk for the association between shift work and risk of IHD was 1.13 (95% CI 1.08–1.20, I2 = 53%, P < 0.001). Further evaluation of dose–response relationship indicated that each 1-year increase in shift work was associated with 0.9% (RR = 1.009; 95% CI 1.006–1.012) increase of the risk of IHD.
This meta-analysis updated the evidence that shift work was associated with the risk of IHD and supported a positive dose–response relationship between the risk of IHD and increasing duration of shift work.
What is already known about this subject:
Shift is a common employment practice; some studies have analyzed the potential association between shift work and ischemic heart disease.
Shift work may affect autonomic nervous system and cardiovascular system through disturbing circadian rhythm and sleep disorder.
What this study adds:
This study included recently published literature about shift work and ischemic heart disease. It has a large sample population through meta-analysis and most strict definition of ischemic heart disease.
After subgroup analysis by model, gender, area, shift type, endpoint, and adjusted covariates or not, shift work showed positive correlated with the risk of ischemic heart disease.
Each 1-year increase in shift work was associated with 0.9% (relative risk 1.009; 95% confidence interval 1.006–1.012) increase in the risk of ischemic heart disease.
What impact this may have on practice or policy:
Health examination of cardiovascular system including blood pressure and ultrasonic cardiogram is necessary for those engaged in shift work.
More attention should be paid on shift operator with ischemic heart disease or family history of ischemic heart disease.
Introduction
Ischaemic heart disease (IHD) is the leading cause of death in many parts of the world. The Global Burden of Disease Study showed that the number of deaths due to IHD was continuously rising from 7.6 million in 2005 to 8.9 million in 2015 [1]. In addition, the Disability-Adjusted Life Year (DALY) ranked IHD first among all other causes of disease worldwide [1].
Several risk factors, including age, gender, diabetes, hypertension, lifestyle and occupational factors, were reported to increase the morbidity and mortality of IHD [2–7]. Among occupational factors, shift work might play a role in the development and progression of IHD. Shift work, a work schedule involving irregular or unusual hours of work, like rotating shifts, evening and night work, is common in industrial production and company operations. In the early 1980s, Knutson et al. detected a significant association between risk of IHD and shift work after following-up 504 papermill workers for 15 years [7]. Alfredsson et al. also found that workers engaged in shift work were more frequently admitted to hospital due to myocardial infarction (MI) [8]. In contrast, other studies concluded protective effects of shift work on IHD with or without statistical significance. McNamee reported that the odds ratio (OR) and 90% confidence interval (CI) of shift work among IHD cases were 0.90 and 0.68–1.21, respectively [9]. In addition, Yong concluded that the hazard ratio of IHD mortality was 0.62 (95% CI 0.52–0.99) in 14 038 shift-workers when compared with 17 105 daytime workers, after adjusting for covariates [10]. The effect of shift work on IHD is still unclear.
We conducted a meta-analysis of published observational studies to summarize the epidemiological evidence on the association of shift work and the risk of IHD.
Methods
We systematically searched all observational epidemiological studies that explored the association between shift work and IHD on PubMed, Web of Science and Embase. To extract all pertinent literature published from January 1970 to October 2017, we used ‘ischaemic heart disease’ or ‘coronary heart disease’ or ‘coronary artery disease’ or ‘cardiovascular disease’ or ‘myocardial infarction’ and ‘shift work’ or ‘rotating shift work’ or ‘night shift work’ or ‘work at night’ or ‘irregular work schedule’ as search MeSH. Only English language publications were included. Eligible studies included in this meta-analysis had to meet all the following criteria; the study was designed as a case–control or cohort study; the purpose of the study was to evaluate the association between shift work and IHD; the exposure was shift work and IHD was the outcome; and the study provided relative risk (RR) or hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (95% CI) or sufficient information for calculation.
Reviews, letters, animal trials and clinical research trials were excluded. If two or more papers reported the same population, the one with the longest follow-up period was selected.
Two authors (M.C. and H.H.) independently selected eligible publications and extracted the following data: the first author’s name, year of publication, location, study design, demographics of participants, types and definitions of shift work and IHD, adjusted confounders and related effects (HR, RR or OR with 95% CI). If the effects were divided into two or more parts in one publication, all of them were considered as independent studies. The Newcastle-Ottawa Quality Assessment Scale (NOS) [11] was used to assess the quality of enrolled literatures. The score scale consists of three parts and ranges from 0 to 9. Any literature with a score ≥7 was regarded as a high-quality study, and <7 but ≥5 was regarded as a low-quality study. Those with a score <5 were regarded as poor-quality studies and excluded. Disagreements were discussed and solved with the third author (W.C.).
Using International Labor Organization standards, we divided each type of shift work into rotating shift work, night work, irregular/other work and mixed work. Rotating shift work was defined as a method of organization of working time in which workers succeed one another at different daily and night hours regularly. Night work meant all work performed consistently during a period of not less than seven consecutive hours, including the period from midnight to 5 o’clock. Irregular work/other work was defined as non-standard daytime hours work except for rotating shift and night work. Mixed work was regarded as two or three work types mentioned above. To estimate the pooled effect of shift work and IHD, we initially conducted a fixed-effect model on all estimates reported in the literature. The heterogeneity among studies was assessed by the χ2 and I2 tests. If the result of the heterogeneity test was P < 0.05 for χ2 test or I2 > 50% for I2 test, it indicated that there was significant heterogeneity amongst the literature and the random-effect model was selected. Subgroup analysis was performed to explore the potential influence of variables on pooled effects, such as study design, origin country, gender, occupation, adjusting confounders, shift work and IHD types. Among various subgroup analyses, meta-regression was performed to explore the source of heterogeneity [12].
For the dose–response meta-analysis, studies were selected only if they listed three or more levels of shift work, provided exact number or person-years of case and control groups and reported the related effects (OR, RR and HR) with 95% CI for each category. Additionally, the midpoint of the lower and upper boundary in each category was regarded as the average time of shift work and 125% of the lower boundary for the highest category without upper boundary. Then, the generalized least-squares trend (GLST) model [13] was used to evaluate the trend of relative effects with increasing duration of shift work.
Sensitivity analysis was conducted to evaluate the potential effect of each study on the overall result [14]. The potential publication bias was assessed according to the funnel plot, Begg’s correlation test and Egger’s regression asymmetry test [15].
All statistical analyses were conducted with Stata version 14.0 (StataCorp, College Station, TX, USA). P < 0.05 was regarded as a significance level in all tests.
Result
Using the predefined search criteria, 21 studies were included in the analysis, with a total of 320 002 sample population and 19 782 cases. The detailed characteristics of the 21 publications are given in Table S1 (available as Supplementary data at Occupational Medicine Online). One publication [16] consisted of two separate cohorts (Nurses’ Health Study and Nurses’ Health Study II) and three different exposure categories were considered as six independent results. Two studies [17,18] calculated the related effects separately for gender and were regarded as four independent results. Another two papers [19,20] were considered as five independent results because they divided the related effects into two or three categories by types of shift work. Finally, the present study included 31 independent results (19 prospective studies, six retrospective studies and six case–control studies), published from 1970 to 2017. The detail of each article’s NOS score is given in Table S2 (available as Supplementary data at Occupational Medicine Online). Five studies with more than three levels of shift work duration were selected to evaluate dose–response relationships between increasing rotating duration and IHD. (Detailed information of five included studies can be found in Table S3 (available as Supplementary data at Occupational Medicine Online).) A random-effects analysis was performed to combine all related risks of included studies, giving a pooled RR of 1.13 (95% CI 1.08–1.20, I2 = 53%, P < 0.001). The pooled RR for prospective studies, retrospective studies and case–control studies were 1.11 (95% CI 1.05–1.17, I2 = 46%, P = 0.014), 1.17 (95% CI 0.97–1.40, I2 = 64%, P = 0.016) and 1.12 (95% CI 0.92–1.36, I2 = 51%, P = 0.072), respectively (Figure 1).
Pooled random-effects RR and 95% CIs for the association of shift work and ischaemic heart disease by the study design.
Figure 2 shows the dose–response relationship between prolonged duration of shift work as continuous variable and the risk of IHD (RR 1.009; 95% CI 1.006–1.012). Furthermore, the goodness-of-fit test indicated that no statistically significant heterogeneity was found (P > 0.05). Results from the fixed-effects of dose–response model revealed that each 1-year extension of shift work was associated with a 0.9% enhanced risk of IHD when compared with daytime workers. We conducted subgroup analysis to explore the sources of heterogeneity and influence by area, gender, work, shift types, endpoint and NOS score (Table 1). Among all subgroup analyses, the difference in the pooled OR among myocardial infarct (MI) and IHD groups reached statistical significance (P for interaction < 0.05), while no other special subgroup responded to the heterogeneity with statistical significance.
Subgroup analyses of RR of ischaemic heart disease according to study characteristics
| Characteristics | No. of report | RR | (95% CI) | I2 (%) | P-value for heterogeneity | P-value for interaction |
|---|---|---|---|---|---|---|
| Gender | ||||||
| Male | 17 | 1.10 | 0.99 to 1.21 | 46 | 0.020 | 0.161 |
| Female | 11 | 1.11 | 1.05 to 1.17 | 47 | 0.040 | |
| Male and female | 3 | 1.34 | 1.20 to 1.49 | 0 | 0.373 | |
| Design | ||||||
| Prospective study | 19 | 1.11 | 1.05 to 1.17 | 46 | 0.014 | 0.543 |
| Retrospective study | 6 | 1.17 | 0.97 to 1.40 | 64 | 0.016 | |
| Case–control study | 6 | 1.12 | 0.92 to 1.36 | 51 | 0.072 | |
| Area | ||||||
| Europe | 21 | 1.13 | 1.05 to 1.23 | 38 | 0.040 | 0.586 |
| America | 7 | 1.10 | 1.04 to 1.16 | 59 | 0.023 | |
| Asia | 3 | 1.72 | 1.34 to 2.21 | 0 | 0.389 | |
| People | ||||||
| Worker | 22 | 1.15 | 1.05 to 1.26 | 50 | 0.004 | 0.291 |
| Nurse | 9 | 1.11 | 1.04 to 1.18 | 57 | 0.018 | |
| Shift type* | ||||||
| Rotating shift work | 20 | 1.10 | 1.04 to 1.17 | 54 | 0.002 | 0.157 |
| Night work | 4 | 1.44 | 1.10 to 1.89 | 0 | 0.575 | |
| Irregular/other work | 5 | 1.24 | 1.12 to 1.38 | 0 | 0.411 | |
| Mixed work | 8 | 1.19 | 1.05 to 1.35 | 25 | 0.228 | |
| Endpoint | ||||||
| MI | 9 | 1.27 | 1.17 to 1.39 | 0 | 0.643 | 0.030 |
| IHD | 22 | 1.10 | 1.04 to 1.16 | 54 | 0.001 | |
| Quality score | ||||||
| High-quality | 17 | 1.09 | 1.04 to 1.16 | 53 | 0.006 | 0.149 |
| Low-quality | 14 | 1.26 | 1.12 to 1.41 | 38 | 0.076 | |
| Adjust or non-adjust | ||||||
| Adjust | 24 | 1.11 | 1.05 to 1.18 | 52 | 0.002 | 0.142 |
| Non-adjust | 7 | 1.24 | 1.09 to 1.40 | 27 | 0.220 |
| Characteristics | No. of report | RR | (95% CI) | I2 (%) | P-value for heterogeneity | P-value for interaction |
|---|---|---|---|---|---|---|
| Gender | ||||||
| Male | 17 | 1.10 | 0.99 to 1.21 | 46 | 0.020 | 0.161 |
| Female | 11 | 1.11 | 1.05 to 1.17 | 47 | 0.040 | |
| Male and female | 3 | 1.34 | 1.20 to 1.49 | 0 | 0.373 | |
| Design | ||||||
| Prospective study | 19 | 1.11 | 1.05 to 1.17 | 46 | 0.014 | 0.543 |
| Retrospective study | 6 | 1.17 | 0.97 to 1.40 | 64 | 0.016 | |
| Case–control study | 6 | 1.12 | 0.92 to 1.36 | 51 | 0.072 | |
| Area | ||||||
| Europe | 21 | 1.13 | 1.05 to 1.23 | 38 | 0.040 | 0.586 |
| America | 7 | 1.10 | 1.04 to 1.16 | 59 | 0.023 | |
| Asia | 3 | 1.72 | 1.34 to 2.21 | 0 | 0.389 | |
| People | ||||||
| Worker | 22 | 1.15 | 1.05 to 1.26 | 50 | 0.004 | 0.291 |
| Nurse | 9 | 1.11 | 1.04 to 1.18 | 57 | 0.018 | |
| Shift type* | ||||||
| Rotating shift work | 20 | 1.10 | 1.04 to 1.17 | 54 | 0.002 | 0.157 |
| Night work | 4 | 1.44 | 1.10 to 1.89 | 0 | 0.575 | |
| Irregular/other work | 5 | 1.24 | 1.12 to 1.38 | 0 | 0.411 | |
| Mixed work | 8 | 1.19 | 1.05 to 1.35 | 25 | 0.228 | |
| Endpoint | ||||||
| MI | 9 | 1.27 | 1.17 to 1.39 | 0 | 0.643 | 0.030 |
| IHD | 22 | 1.10 | 1.04 to 1.16 | 54 | 0.001 | |
| Quality score | ||||||
| High-quality | 17 | 1.09 | 1.04 to 1.16 | 53 | 0.006 | 0.149 |
| Low-quality | 14 | 1.26 | 1.12 to 1.41 | 38 | 0.076 | |
| Adjust or non-adjust | ||||||
| Adjust | 24 | 1.11 | 1.05 to 1.18 | 52 | 0.002 | 0.142 |
| Non-adjust | 7 | 1.24 | 1.09 to 1.40 | 27 | 0.220 |
*Three studies provided detail on related risks on ischaemic heart disease with different types of shift work.
Subgroup analyses of RR of ischaemic heart disease according to study characteristics
| Characteristics | No. of report | RR | (95% CI) | I2 (%) | P-value for heterogeneity | P-value for interaction |
|---|---|---|---|---|---|---|
| Gender | ||||||
| Male | 17 | 1.10 | 0.99 to 1.21 | 46 | 0.020 | 0.161 |
| Female | 11 | 1.11 | 1.05 to 1.17 | 47 | 0.040 | |
| Male and female | 3 | 1.34 | 1.20 to 1.49 | 0 | 0.373 | |
| Design | ||||||
| Prospective study | 19 | 1.11 | 1.05 to 1.17 | 46 | 0.014 | 0.543 |
| Retrospective study | 6 | 1.17 | 0.97 to 1.40 | 64 | 0.016 | |
| Case–control study | 6 | 1.12 | 0.92 to 1.36 | 51 | 0.072 | |
| Area | ||||||
| Europe | 21 | 1.13 | 1.05 to 1.23 | 38 | 0.040 | 0.586 |
| America | 7 | 1.10 | 1.04 to 1.16 | 59 | 0.023 | |
| Asia | 3 | 1.72 | 1.34 to 2.21 | 0 | 0.389 | |
| People | ||||||
| Worker | 22 | 1.15 | 1.05 to 1.26 | 50 | 0.004 | 0.291 |
| Nurse | 9 | 1.11 | 1.04 to 1.18 | 57 | 0.018 | |
| Shift type* | ||||||
| Rotating shift work | 20 | 1.10 | 1.04 to 1.17 | 54 | 0.002 | 0.157 |
| Night work | 4 | 1.44 | 1.10 to 1.89 | 0 | 0.575 | |
| Irregular/other work | 5 | 1.24 | 1.12 to 1.38 | 0 | 0.411 | |
| Mixed work | 8 | 1.19 | 1.05 to 1.35 | 25 | 0.228 | |
| Endpoint | ||||||
| MI | 9 | 1.27 | 1.17 to 1.39 | 0 | 0.643 | 0.030 |
| IHD | 22 | 1.10 | 1.04 to 1.16 | 54 | 0.001 | |
| Quality score | ||||||
| High-quality | 17 | 1.09 | 1.04 to 1.16 | 53 | 0.006 | 0.149 |
| Low-quality | 14 | 1.26 | 1.12 to 1.41 | 38 | 0.076 | |
| Adjust or non-adjust | ||||||
| Adjust | 24 | 1.11 | 1.05 to 1.18 | 52 | 0.002 | 0.142 |
| Non-adjust | 7 | 1.24 | 1.09 to 1.40 | 27 | 0.220 |
| Characteristics | No. of report | RR | (95% CI) | I2 (%) | P-value for heterogeneity | P-value for interaction |
|---|---|---|---|---|---|---|
| Gender | ||||||
| Male | 17 | 1.10 | 0.99 to 1.21 | 46 | 0.020 | 0.161 |
| Female | 11 | 1.11 | 1.05 to 1.17 | 47 | 0.040 | |
| Male and female | 3 | 1.34 | 1.20 to 1.49 | 0 | 0.373 | |
| Design | ||||||
| Prospective study | 19 | 1.11 | 1.05 to 1.17 | 46 | 0.014 | 0.543 |
| Retrospective study | 6 | 1.17 | 0.97 to 1.40 | 64 | 0.016 | |
| Case–control study | 6 | 1.12 | 0.92 to 1.36 | 51 | 0.072 | |
| Area | ||||||
| Europe | 21 | 1.13 | 1.05 to 1.23 | 38 | 0.040 | 0.586 |
| America | 7 | 1.10 | 1.04 to 1.16 | 59 | 0.023 | |
| Asia | 3 | 1.72 | 1.34 to 2.21 | 0 | 0.389 | |
| People | ||||||
| Worker | 22 | 1.15 | 1.05 to 1.26 | 50 | 0.004 | 0.291 |
| Nurse | 9 | 1.11 | 1.04 to 1.18 | 57 | 0.018 | |
| Shift type* | ||||||
| Rotating shift work | 20 | 1.10 | 1.04 to 1.17 | 54 | 0.002 | 0.157 |
| Night work | 4 | 1.44 | 1.10 to 1.89 | 0 | 0.575 | |
| Irregular/other work | 5 | 1.24 | 1.12 to 1.38 | 0 | 0.411 | |
| Mixed work | 8 | 1.19 | 1.05 to 1.35 | 25 | 0.228 | |
| Endpoint | ||||||
| MI | 9 | 1.27 | 1.17 to 1.39 | 0 | 0.643 | 0.030 |
| IHD | 22 | 1.10 | 1.04 to 1.16 | 54 | 0.001 | |
| Quality score | ||||||
| High-quality | 17 | 1.09 | 1.04 to 1.16 | 53 | 0.006 | 0.149 |
| Low-quality | 14 | 1.26 | 1.12 to 1.41 | 38 | 0.076 | |
| Adjust or non-adjust | ||||||
| Adjust | 24 | 1.11 | 1.05 to 1.18 | 52 | 0.002 | 0.142 |
| Non-adjust | 7 | 1.24 | 1.09 to 1.40 | 27 | 0.220 |
*Three studies provided detail on related risks on ischaemic heart disease with different types of shift work.
Relative risk for ischaemic heart disease by years of shift work based on the results of the dose–response meta-analyses. Solid line represents the estimated relative risk, while the dotted lines represent the 95% CIs.
In addition to subgroup analyses, further sensitivity analysis was performed to test the robustness of our study findings. No significant difference was observed between the random-effects model and fixed-effects model. The pooled RR were 1.13 (95% CI 1.08–1.20) for random-effects model and 1.10 (95% CI 1.07–1.13) for fixed-effects model. The pooled RR was 1.11 (95% CI, 1.05–1.18) after excluding studies without adjusting covariates. Similar findings were detected after excluding the study by Vetter et al. [16], which had the largest sample size with the pooled RR at 1.17 (95% CI, 1.07–1.28). All sensitivity analysis indicated that shift work significantly increased the risk of IHD. The funnel plots are provided in Figure 3. In addition, no significant publication bias was detected from the result of Egger’s test (P > 0.05) or Begg’s test (P > 0.05).
Funnel plot of shift work and risk of ischaemic heart disease. The solid line represents the summary effect estimates, and the dotted lines are pseudo-95% CIs.
Discussion
This meta-analysis including 21 epidemiological papers with 31 results revealed a positive association (RR 1.13; 95% CI 1.08–1.20) between shift work and IHD. The pooled estimates ranged from 1.09 to 1.44 with statistical significance in most subgroup analyses. These results suggest that shift work has a harmful effect on human cardiovascular function. Furthermore, our results indicate that a positive dose–response relationship between duration of shift work and risk of IHD (pooled RR 1.009; 95% CI 1.006–1.012) through analysis of five eligible studies.
The strength of this study is that it includes a large number of participants, with a total of 320 002 sample population and 19 782 cases. In addition, a positive association between shift work and risk of IHD with statistical significance could be found in most subgroup analysis and sensitivity analysis. The dose–response relationship with exposure to shift work was also estimated to improve the robustness of this result. However, there are two potential limitations in this meta-analysis. First, the definition of shift work was inconsistent in some papers. Misclassification bias might have occurred when we reclassified the type of shift work according to International Labor Organization standards. Second, adjustment for confounders across different studies was different. Some articles ignored one or more potential cardiovascular risk factors like age, smoking status, body mass index, social status and disease history in their analysis. This may strengthen or weaken the harmful effect of shift work on IHD. More rigorous design and related studies about shift work and IHD are needed to strengthen the evidence in the future.
Our findings were consistent with three related reviews and meta-analyses on the epidemiological association of shift work and IHD published in 2012 [21], 2011 [22] and 2017 [23]. The meta-analysis by Vyas et al. [21] reviewed the effect of shift work on vascular events and found that shift work correlated with vascular events. Ha et al. [22] assessed attribution of occupational factors to the mortality of IHD and concluded a crude RR of 1.12 (95% CI 0.94–1.33) from seven studies. Torquati et al. [23] reported similar findings in the relationship between shift work and the risk of cardiovascular disease. There are three differences between their studies and ours. First, the definition of IHD in our study strictly corresponded to the International Classification of Diseases. Studies about shift work and stroke or cerebrovascular disease were not included in our study. In addition, more published literature and participants were included in our study. Furthermore, we evaluated the effects of shift work duration and found that each 1-year extension of shift work was associated with a 0.9% increase in risk of IHD. The results from dose–response relationship between shift work duration and risk of IHD provide more information for their causality.
Some possible biological mechanisms may explain why shift work could increase the risk of IHD. First, disturbed circadian rhythm is a major consequence of shift work. Circadian rhythms are controlled by intracellular molecular clocks that allow the organism to prepare itself for an anticipated stimulus. Long-term exposure to shift work would result in desynchronization of endogenous and exogenous components and disturbances of the cardiovascular system [24]. Previous studies also suggested that circadian rhythm could disturb the ability of the heart through altering the expression of CLOCK genes in the heart and blood vessels [25]. Secondly, shift work can increase stress via disturbance of normal metabolic and hormonal functions [26]. To compensate, more glucocorticoids and catecholamines are secreted which subsequently cause suppression of the gonadal, growth hormone and thyroid axes [27]. These metabolic disturbances may lead to a series of physical changes and the clinical expression including central obesity, hypertension, dyslipidaemia and endothelial dysfunction [26]. The latter are reported to increase the risk of IHD [26]. Thirdly, according to many epidemiological research studies, unhealthy lifestyles such as smoking, poor diet and lack of physical exercise are more common among shift workers. All of these potential factors can lead to weight gain or loss in rare cases [28]. Finally, obesity and metabolic syndrome would subsequently increase the risk of IHD.
In conclusion, this meta-analysis suggests that shift work is associated with the risk of IHD and a positive dose–response relationship was observed between the risk of IHD and increasing duration of shift work. Given the growing prevalence of shift work worldwide and heavy disease burden of IHD, further research is required to consider how to protect workers from IHD.
Funding
This study was supported by the Fundamental Research Funds for the Central Universities, Huazhong University of Science and Technology (2016JCTD116).
Competing Interests
All authors declared no support from any organization for the submitted work; no financial relationships with any organization that might have an interest in the submitted work in the previous three years and no other relationships or activities that could appear to have influenced the submitted work.
