Risk of incident gastroesophageal reflux disease (GERD) in patients with sleep disorders: a population-based cohort study

Sleep disorders pose a serious threat to human, which may cause variety diseases. Recent reviews on the epidemiology examine that gastroesophageal reflux disease (GERD) has different levels of causality about asthma, chronic dry cough, sleep apnea, non-cardiac chest pain, chest tightness, and chronic bronchitis. The relationship between sleep disorders and GERD has been explained in various ways, but only limited reports on the complication rates in Taiwan. The objective of this follow-up study is to evaluate the risk of incident GERD in Taiwanese people with sleep disorders from January 1, 2000 to December 31, 2012. We used the Taiwan’s National Health Insurance Research Database to conduct a nationwide population-based cohort study to assess the risk of incident GERD in people with sleep disorders. A total of 66,133 sleep disorders patients and 264,532 non-sleep disorders controls were included. Sleep disorders was a risk factor of incident GERD (adjusted hazard ratio being 1.722, 95% CI 1.69–1.76, p < 0.001) after controlling potential confounders including age, sex, comorbidities, and hiatal hernia. In conclusion, sleep disorders might be a risk factor for development of GERD based on the 12-year follow-up.


Background
The field of sleep disorders encompasses a broad range of phenomena; such us sleep apnea, insomnia, excessive sleepiness, and many other sleep disorders [1]. In previous study, obstructive sleep apnea has been evidenced to be associated with reflux disease [2]. Sleep disorders result from comorbid conditions that impact sleep, such as chronic pain disorders, gastroesophageal reflux disease (GERD), or some lung-related diseases. There are some symptoms about insomnia including insufficient sleep, tossing and turning, feeling tired during the day, and waking up in the middle of night. Some evidence-based studies showed that several factors about reducing sleep quality, such us having a very stressful life [3,4], unemployed, shift workers [1], or sleeping in an inadequate bedrooms, are associated with an increasing risk for sleep disorders in the general population [4]. Sleep disorders not only increases an individual's obesity and insulin resistance and risk for a variety of physical and mental disorders [5][6][7][8], but also decreases one's quality Yu-Hsien Cheng and Tao-Hsin Tung have contributed equally in this study. of life, cognitive, emotional, and social functioning and academic performance [9]. Insufficient sleep will pose a serious threat to brain and lead beta-amyloid (one kind of proteins is associated with Alzheimer's disease) accumulation, more and more, and then loss memory [10,11].
The subject symptoms of GERD are mainly heartburn, direct acid injuries such as esophageal erosion, respiratory diseases such as asthma, and any other complications including sleep disorders. Recently, there are studies reporting the association of sleep disorders with GERD. GERD is defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms or complications is one of common prevalent chronic disorders in many countries [12]. It is associated with a huge economic burden in the western countries and significantly decreased quality of life [13]. Recent reviews on the epidemiology examines that GERD have different levels of causality about asthma, chronic dry cough, sleep apnea, non-cardiac chest pain, chest tightness, and chronic bronchitis [14,15]. Risk factors in GERD include obesity, pregnancy, smoking, hiatal hernia and specific drugs, including antihistamines, calcium channel blockers, antidepressants, and sedatives that medicine help sleep [16]. Some studies even show that chronic life stress and psychological disturbances, such as depression, anxiety, and somatization, increase their symptoms [17,18].
The relationship between sleep disorders and GERD has been explained in various ways, and to date, there have been only limited reports on the complication rates in Taiwan. We conducted a nationwide population-based study on the incidence of GERD to elucidate the relationship between sleep disorders (especially in sleep disturbance and nonorganic sleep disorder) and GERD in the Taiwanese population.

Data source
The Taiwan National Health Insurance (NHI) Program was enacted in 1995. The NHI program is a mandatory health insurance program offering comprehensive medical care for more than 23 million residents, and enrolling participants exceeded 99% of the population of Taiwan. The National Health Insurance Research Database (NHIRD) contains comprehensive information on clinical visits, including prescription details, and the diagnoses recorded are coded according to the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) [19][20][21]. Based on the Personal Information Protection Act, the NHIRD cryptographically assigned an anonymous code to each enrollee for protecting the confidentiality; therefore, informed consent was waived. Therefore, several previous studies have revealed a high accuracy and validity of the diagnoses in the NHIRD, and it is, therefore, suitable to use the NHIRD to examine the longitudinal association between GERD and sleep disorders.
In this study, we used the data set 'Longitudinal Health Insurance Database 2000' (LHID), comprising data on 1 million people (approximately 5% of Taiwan's population), which were systematically and randomly sampled from the LHID 2005. The NHIRD has been used extensively in many previous epidemiologic studies in Taiwan [22].

Study population
The flowchart about how to select study population and some excluding criteria is illustrated in Fig. 1. We excluded the people who had been diagnosed with GERD before 2000 for purpose of avoiding overestimation of the risk of incident GERD. The sleep disorders defined by ICD-9-CM codes in this study included sleep disturbance (78,050) and nonorganic sleep disorder (30,740). In the previous NHIRD studies about sleep disorders, these codes have been used [19][20][21]. The exposed group was composed of subjects with sleep disorders newly diagnosed by a psychiatrist since 2000 onwards; conversely, those who were not diagnosed with sleep disorders were considered as the control subjects some of which were made up control group. The index date is the date when the sleep disorders were first diagnosed, while the index date for the control group was January 1st, 2000.

Outcomes and potential confounders
The claim data of the NHIRD are completeness and accuracy, including medication history and ICD-9 diagnosis, which have been validated NHIRD. Using ICD-9-CM codes (53011 and 53081), we identified subjects diagnosed with GERD. In the previous NHIRD studies about GERD, these codes have been used [23,24]. The period of GERD subjects follow-up was the time from the index date to the date of the first diagnosis in the inpatient or outpatient records. The censored time of subjects without GERD was from the index date to the end of 2012 or the date to withdrawing the NHI program. We confirmed the endpoints by requiring records of the diagnosis at least two occasions in 180 days so as to enhance the accuracy of outcomes.

Statistical analysis
To migrate selection bias, frequently matching was conducted in which one sleep disorder patient in the cohort was matched four counterparts in the comparison cohort, which means that the control group consisted of randomly selected patients who never been diagnosed with sleep disorders and fourfold size frequency matched with sleep disorders group by index year, age, gender, and Charlson Comorbidity Index 1 3 (CCI). To compare continuous and categorical data, we used the Student's t test and Chi-squared test, respectively. The Cox regression model was used to investigate the hazard ratio (HR), between the two groups after adjustment for demographic data (age, sex), Charlson Comorbidity Index (CCI: the risk adjustment for the samples' disease severity was conducted using this classifying method of prognostic comorbidity employed by the previous definitions), and hiatal hernia. A two-sided p value of < 0.05 was considered statistically significant. All statistical analyses were conducted using the SAS software version 9.2.

Results
The basic demographic data of the study population are illustrated in Table 1   with GERD. Based on the 1:4 matches between sleep disorders and control group, the mean age was the same (48.09 ± 16.97) for people in two groups. Overall, the risk of developing GERD in sleep disorder cohort (incidence rate: 1.21) was 1.29-fold higher than that of the control group (incidence rate: 0.94). The bar graphs and tables for GERD incidence in sleep disorders vs. non-sleep disorders are illustrated in Fig. 2. The GERD incidence in the sleep disorders group was significantly higher than that in non-sleep disorder controls (p value < 0.01). Figure 3 shows the sex-specific bar graphs and tables for GERD incidence in sleep disorders vs. non-sleep disorders. The incidence of GERD in the sleep disorder group was significantly higher than that in non-sleep disorders controls both in men and women subgroups (p value < 0.01).
The effect of independently associated risk factors upon incident GERD was examined using the multiple Cox regression models. As is depicted in

Clinical implications
This study is the first population-based study conducted to explore the association between sleep disorders and GERD. In the United States and Europe, since around 2000, GERD has been increasingly reported as a complication in patients with obstructive sleep apnea syndrome (OSAS), which is one kind of sleep disorders. In addition, at least 50% of patients with sleep disturbance seen in primary care practices have comorbidity conditions [25]. Specifically, Taylor et al. found a higher prevalence of gastrointestinal (GI) problems in those with chronic insomnia compared with those without insomnia (33.6% vs. 9.2%; Odds ratio: 3.33, 95% CI 1.83-6.05) [26].
In the past studies, GERD was a risk factor for sleep disorders, and many articles have hypothesized that this association appears to be bidirectional [27][28][29]. In the existing literature, there is little evidence which shows the causality between sleep disorders and GERD. Patients with sleep disorders may cause worse sleep quality and indirectly influencing not only mental but also digestive system. Identically, in these two diseases, there are some common risk factors [30]. When the incidence of a disease increases, the other one will naturally increase. Pattern of gastritis in H. pylori infected  patients could be associated with GERD [31]. Apparently, gastritis is likely to deteriorate GERD, if it is not well controlled. In addition, stress and lifestyle are cardinal risk factors in gastritis, so when the sleep disorders is improved, it may reduce the incidence of gastritis and then reduce GERD indirectly [32]. In clinical trials, the side effects of sedatives which are taken in patients with sleep disorders also increase the incidence of GERD, which could be the reason why increase in the incidence of GERD while having medication treatment [33].

Methodological considerations
Although based on the long-term follow-up study design, that is, being prospective in design as well as in a welldefined patient population, we not only determined the cumulative incidence of GERD, but also further explored the prognostic factors related to incident GERD. However, the major limitation in this study is that it is difficult to collect patients' information of obesity, H. pylori eradication, lifestyles, diets, and drugs (calcium antagonists, bronchodilators, nitrates). It is important to consider other potential limitations in the future. Second, the data source of this study was the NHIRD which lacked relevant variables such as stress indicators, living habits even side effect of medicine. A misclassification bias might have been present. Nevertheless, it seems reasonable to assume that any misclassification bias was not related to incident GERD, which thus could be viewed as nondifferential misclassification. Third, there might have been some cases of milder GERD that were delayed in diagnosis or were not detected during the follow-up. Fourth, the level of evidence derived from cohort studies is generally lower than that from randomized trials because of potential biases related to unknown confounders that could not be adjusted. Finally, the effect of treatment on sleep disorders could not be thoroughly studied. Information from clinical treatments beyond insurance coverage, treatment compliance, and treatment duration was not available in the NHIRD.

Conclusion
In conclusion, this 12-year follow-up study indicated that sleep disorders might be a risk factor for the development of GERD based on the 12-year follow-up. Our study clarified the potential relationship between sleep disorders and GERD in the Taiwanese population. However, maybe, sleep disorders and GERD are a vicious circle that deserves more research in the future.
Acknowledgements The authors would like to thank the Sunflower Statistical Consulting Company, Kaohsiung, Taiwan for statistical advice.
Author contributions YHC, PEC, CWC, CYT, and THT conducted the study and drafted the manuscript. YHC and PEC participated in the design of the study and performed statistical analyses. CYT and THT conceived the study, and participated in its design and coordination. All of the authors read and approved the final manuscript.
Funding There was no additional financial support from public or private sources.
Availability of data and material All data underlying the findings are within the paper.