Associations of Sleep Problems With Asthma/wheeze and Allergic Rhinitis Among Chinese Children Aged 0-6 Years: a Cross-sectional Study


 Background: Asthma/wheeze and allergic rhinitis are common among pre-school age children, which urgently need to identify more modifiable risk factors for prevention. The aim of this study was to examine the associations of sleep problems with asthma/wheeze and allergic rhinitis among Chinese children aged 0-6 years. Methods: This cross-sectional survey, a part of the National Survey on Physical Growth and Development of Children in nine cities of China (NSPGDC), was conducted in Guangzhou, China. Children aged 0-6 years were randomly selected from 29 communities and 32 kindergartens. Asthma/wheeze, allergic rhinitis and sleep problem were evaluated by a valid questionnaire which was completed by participants’ parent(s). Binary logistic regression models were employed to estimate the odds ratios (OR) and 95% confidence intervals (CI) for asthma/wheeze and allergic rhinitis according to short sleep duration, late bedtime and frequent nocturnal awaking. Results: We included 13376 children aged 0~6 years. Of these, 371 (2.8%) diagnosed as asthma/wheeze, and 610 (4.6%) diagnosed as allergic rhinitis. Frequent nocturnal awakening was associated with asthma/wheeze and allergic rhinitis, adjusted OR were 1.53 (95% CI: 1.20~1.94) and 1.39(1.14-1.71), respectively. Further subgroup analysis showed the association of frequent nocturnal awakening with asthma/wheeze and allergic rhinitis differed by age. No significant associations of short duration and late bedtime with asthma/wheeze and allergic rhinitis were identified. Conclusions: Our data suggested that frequent nocturnal awakening was associated with asthma/wheeze and allergic rhinitis, but this association differed by age. Further studies are warranted to confirm its’ causal association and to understand the underlying mechanisms.

The present study aimed to examine the associations of sleep problems with asthma and allergic rhinitis among Chinese children aged 0-6 years. We hypothesized that sleep problems, include frequent nocturnal awakening, short duration and late bedtime would be associated with ARDs even after adjustment for potential confounders.

Study design and participants
We conducted a cross-sectional survey of children aged 0-6 years in Guangzhou between July to October in 2015, which was a part of the National Survey on Physical Growth and Development of Children in nine cities of China (NSPGDC) [14]. The NSPGDC used the identical methodology to collect data from nine cities, thus data collected in each city could be analyzed to produce a general conclusion for the local population. The study design, organization, and implementation of the NSPGDC have been published previously [15]. Brie y, in each study city, a cluster random sampling method based on age groups (there were 22 age groups and 150-200 subjects for each sex-age subgroup) for both urban and rural areas was employed to produce a random sample [16].
Children under 3 years in a community was classi ed as a minimum cluster unit, and children aged 3 and above in kindergarten regarded as a unit. Exclusion criteria included temporary residents, acute illness within a month, chronic illness (such as cardiopathy, chronic nephrosis, tuberculosis, persistent hepatitis), obviously malnourished and physically handicapped.
In Guangzhou, we selected 12798 participants below the age of 3 years from 16 communities across three urban administrative districts (Yuexiu, Liwan and Haizhu) and 13 communities across four rural administrative districts (Conghua, Huadu, Panyu and Baiyun); 6707 participants aged 3 to 6 years were selected from 16 kindergartens in urban administrative districts, and 16 kindergartens in rural administrative districts. We excluded 6129 participants after reviewing the completeness of the questionnaire (with missing data >15%). Therefore, the remain 13376 participants were included in the nal analysis, with an effective response rate of 68.6% (13376/19505). Data was collected by local trained physicians with a structured questionnaire, which include participants' demographic characteristics, mother's health conditions during pregnancy, delivery model, feeding patterns in the rst 6 six months, sleep problems and ARDs of the participants. Body weight and height (supine length if under 3 years) were also measured by calibrated instruments and standard speci cations, and body mass index (BMI) was calculated by dividing the weight in kg by the square of length in m.

Ethics
The study was approved by the Ethical Committee for Biomedical Research in Guangzhou Women and Children's Medical Center (reference number : 2018052407). A written informed consent was obtained from all the participants' parents before starting of the survey.

Measurement
Asthma/wheeze and allergic rhinitis was diagnosed by the parental questionnaire based on the International Study of Asthma and Allergy in Children Questionnaire (ISAACQ) ("Has your baby had wheezing or whistling in the chest during the past 12 months?", "Has your baby had a problem with sneezing, or a runny, or a blocked nose when he/she did not have a cold or the u during the past 12 months?" and "Has this nose problem been accompanied by itchy-watery eyes during the past 12 months?" ) [22].
We measured short sleep duration, late bedtime and frequent night waking in the present study. Sleep duration was calculated based on 2 questions ("How many hours did your baby sleep during the night in the past 2 weeks?" and "How many hours did your baby sleep during the daytime in the past 2 weeks?") derived from the Pittsburgh sleep quality index [18]. According to the National Sleep Foundation's recommendation, infants (0-11 months) who sleep less than 12 hours, toddlers (1-2 years) who sleep less than 11 hours for and preschoolers (3-6years) who sleep less than 10 hours were de ned as short sleep duration [19]. Bedtime was classi ed into 2 groups: at or before 11:00 PM, and after 11:00 PM. Participants whose bedtime later than 11:00 PM was considered as a late bedtime [20,21]. The nocturnal awakening frequency was also classi ed into 3 groups: none or seldom, once per night, and twice or more per night. According to the previous study by the National Sleep Foundation [22], children who wakened twice or more per night among infants (0-11 months) and toddlers (1-2 years), and once per night among preschoolers (3-6 years) were de ned as frequent nocturnal wakening.
Previous studies suggested a broad range of demographic characteristic and environmental factors that are associated with Asthma/wheeze and allergic rhinitis [9,10,23,24]. Therefore, we adjusted for these potential confounders in our analysis as much as we could, which included resident area, age group, gender, family annual income, ethnicity, mother's education and occupation, delivery model, gestational age, birth weight, maternal smoking, passive smoking and maternal alcohol consumption during pregnancy, feeding patterns in the rst 6 months, passive smoking and BMI of children.

Statistical analysis
Mean and standard deviation were reported for continuous variables. Frequencies and percentage were reported for categorical variables. T tests and Chi-square tests were used for comparing continuous and categorical variables, respectively. Binary logistic regression models were employed to estimate the odds ratios (OR) and 95% con dence intervals (CI) for asthma/wheeze and allergic rhinitis according to short sleep duration, late bedtime and frequent nocturnal awaking, respectively. In each logistic regression model, four models were tted.
In model 1, we estimated the crude ORs. In model 2, we adjusted for demographic characteristics, included region (urban/rural), sex (male/female), age group ( 12 months/1-2 years/3-6years ), family annual income (below 50000 RMB/50000-100000 RMB/100000-300000 RMB/above 300000 RMB) [25], mother's educational level (college or above/senior high school/junior high school or below) and occupation (farmers/workers/service/others). In model 3, we additionally adjusted for factors related to pregnancy, including delivery models (vaginal delivery/cesarean delivery), preterm birth (≤37 weeks/ >37-42 weeks), birth weight (<2500 g/2500-3900g/ ≥4000 g), maternal smoking (yes/no) and maternal alcohol consumption (yes/no). In mode 4, we additionally adjusted for feeding patterns in the rst 6 months of the participants (breastfeeding/arti cial feeding/mixed feeding), passive smoking (yes/no) and BMI (continuous data) of children. We further conducted subgroup analysis to examine whether age in uence the associations of asthma/wheeze and allergic rhinitis allergic rhinitis with frequent nocturnal awaking where signi cant associations were found. Missing data of continuous covariables was inputted based on means and categorical covariables was inputted by the median.
Signi cance level was set at P<0.05 and all tests were 2-sided. Statistical analyses were conducted using SPSS Statistics, version 25.0 (IBM Corp).

Participants' characteristics
We included 13376 children in the current analysis. Of them, 6718 (50.2%) were boys and 6010 (44.9%) were from the urban areas. The age of the participants ranged from 0 to 6 years (mean ±SD: 1.92±1.98 years), 4895 (36.6%) were aged between 0 to 12 months and 4781 (36.4%) were aged between 3 to 6 years. The other characteristics of the participants were summarized in Table 1. Overall, 371 (2.8%) of the participants were diagnosed as asthma/wheeze. Compared with the participants without asthma/wheeze, participants with asthma/wheeze were more likely to be living in urban areas, boys and premature. There were 610 (4.6%) participants diagnosed as allergic rhinitis. Compared with participants without allergic rhinitis, those with allergic rhinitis were likely to be living in urban areas, boys, premature and cesarean delivery (see Table 1).

Association between sleep problems and asthma/wheeze
Of the 13376 children included, 1220 (9.1%) had a short sleep duration. Among the children who diagnosed as asthma/wheeze, 26 (7.0%) had a short sleep duration; while among the children without asthma/wheeze, 1194 (9.2%) had a short sleep duration. No signi cant association between short sleep duration and asthma/wheeze was found ( Table 2). There were 655 (4.9%) participants go to sleep after 11 PM, namely had late bedtime. Among the children who diagnosed as asthma/wheeze or not, 13 (3.5%) and 643 (4.9%) had late bedtime, respectively. There was also no signi cant association between late bedtime and asthma/wheeze (  The unadjusted and adjusted ORs for asthma/wheeze for sleep problems were showed in Table 3. From model 1 to model 4, the ORs were not change substantially. In the fully adjusted models, signi cant association was only found between frequent nocturnal awakenings and asthma/wheeze, the OR was 1.53 (95% CI: 1.20~1.94). Further subgroup analysis showed that signi cant association between frequent nocturnal awakenings and asthma/wheeze was found among children aged 1-6 years but not among children aged 0-12months (Table 4).   Table 3). However, signi cant association was only found between frequent nocturnal awakenings and allergic rhinitis after adjusted for potential confounders (Table 3). In the fully adjusted model (Model 4), the adjusted OR for allergic rhinitis for frequent nocturnal awakenings was 1.39(95%CI: 1.14-1.71). However, similar association between frequent nocturnal awakenings and allergic rhinitis was only found among children aged 3-6 years, the adjusted OR was 1.52 (95%CI: 1.11-1.92) ( Table 5). b Model 2: Adjusted for demographic characteristics: region, gender, age, family income, mother's educational level and occupation, delivery mode, preterm birth, birth weight, maternal alcohol consumption and smoking during the pregnancy, feeding patterns in the rst 6 months, BMI and passive smoking of children.

Discussion
In this study, we used a large-scale survey data, which was part of the NSPGDC, to investigate the association of sleep problems with asthma/wheeze and allergic rhinitis among children aged 0-6 years in Guangzhou. The results revealed the prevalence of asthma/wheeze and allergic rhinitis among children aged 0-6 years was 2.8%, and 4.6% respectively. The ndings also suggested that frequent nocturnal awakenings but not short sleep duration and late bedtime, was signi cant associated with asthma/wheeze and allergic rhinitis. However, these associations differed by children' age.

Comparison with other studies
In the present study, we found that the prevalence of asthma/wheeze and allergic rhinitis were lower than previous studies conducted both in China and western countries. For example, a study conducted in six representative cities in China, found that the prevalence of asthma and allergic rhinitis were 8.0% and 16.6%, respectively [26]. A population-based birth cohort study conducted in Sweden reported that the prevalence of wheeze episodes before 2 years of age was 25% [27]. A nationwide study conducted in Portugal reported that the prevalence of current rhinitis was 43.4% among child aged 3-5 years [28]. The discrepancies might be related to different characteristics of study participants, apart from the different measurements for asthma/wheeze and allergic rhinitis. However, our ndings were similar to a study conducted in Shanghai, which reported that the prevalence of wheeze and allergic rhinitis were 3.7% and 2.5%, respectively [9].
Our ndings suggest that frequent nocturnal awakening was associated with asthma/wheeze (OR=1.53, 1.20-1.94) and allergic rhinitis (OR=1.39, 1.14-1.71), which were similar to previous studies that investigated the association of sleep problems with allergic diseases among children under 6 years [9,10]. Wang et al conducted a study to examine the associations of sleep disorders with the risk of wheeze and allergic rhinitis among 566 Chinese toddlers and found that having more than 2 times of nocturnal awaking per night was associated with a higher risk of wheeze (OR=6.16, 1.28~29.74) [9]. Kozyrskyj et al analyzed the conditions of 2398 children from on a community-based birth cohort in Australia and found that persistent nocturnal awakening before 3 years of age was associated with an increased risk of nonatopic asthma at age 6 (OR=1.87, 1.08~3.25), after adjusting for other risk factors of asthma, including co-sleeping, wheeze and family stress [10]. In this study, we also found that the associations of frequent nocturnal awakening with asthma/wheeze and allergic rhinitis were differed by age, which was not reported in previous studies [9,10]. This age differences may be due to age difference prevalence rate of asthma/wheeze and allergic rhinitis, which had low diagnosis rate among children aged 0-3 years. To reduce the harmful of asthma/wheeze and allergic rhinitis to the child, parent need detect the early symptoms of the disease as early as possible [29], although age difference on association of frequent nocturnal awakening with asthma/wheeze and allergic rhinitis need to be veri ed in different population.
Possible explanations of the association of frequent nocturnal awaking with asthma/wheeze and allergic rhinitis The association between frequent nocturnal awaking and asthma/wheeze and allergic rhinitis could be explained by several plausible biological mechanisms. Firstly, frequent nocturnal awakening may increase the levels of pro-in ammatory cytokines and decrease the immunologic tolerance to allergen [9,10], shifting the balance between Th1 and Th2 cytokines towards an allergy related (Th2) pattern [30], which are known factors contributing to allergic diseases such as asthma/wheeze and allergic rhinitis. Secondly, frequent nocturnal awakening could disrupt the regulation of the hypothalamic-pituitary-adrenal (HPA) axis [31,32] and the circadian rhythms of melatonin [33,34]. Children with impaired HPA-axis regulation showed a blunted cortisol awakening response and lower cortisol levels [31,32], which lacks suppression of airway in ammation that could increase the risk of asthma and rhinitis [35,36]. Additionally, melatonin may also play a very important role in anti-in ammatory and immunomodulatory functions [35,37], thus a decline in the level of melatonin could reduce the suppression of in ammation and airway hyperresponsiveness, which in turn could trigger asthma and allergic rhinitis [38,39].

Strengths and limitations
The major strength of this study is the sample size. For this large-scale cross-sectional study, we recruited 13376 representative participants from rural and urban Guangzhou by using a well-designed protocol, which makes our results more generalized. The other major strength of this study is that we have adjusted for several important confounders, such as region and maternal smoking and children's passive smoking, which was not adjusted in previous studies, making our results more robust. Additionally, this is the rst investigation on the association of sleep problems with asthma/wheeze and allergic rhinitis among Chinese child aged 0-6 years, which also lled in the age gap in this area of research.
There were several limitations in our study. First, asthma/wheeze and allergic rhinitis were not determined by objective measures, but rather parent reported ISAACQ, which although was highly recognized for its reliability and validity and was used in previous studies [30,17]. Second, sleep problems were assessed through questionnaires based on the parents' reports, instead of objective measurement, thus recall bias may exist. On balance, previous studies have demonstrated that information regarding sleep garnered from parents is likely to be reliable [40]. Third, although we have adjusted for various potential confounders, we did not adjust for family allergy history of the parents or mother's stress during pregnancy, which are risk factors for allergenic diseases [10]. Fourth, this study is a cross-sectional study, which deduces a weak association in the exploration of the causal relationship of sleep problems and asthma/wheeze and allergic rhinitis. Future prospective research studies are needed to validate these ndings, since asthma/wheeze and allergic rhinitis are signi cant clinical and public concerns.
Sleep problems including shortened sleep duration, late bedtime and frequent nocturnal awaking are common among children aged 0-6 years, which have a broad impact on children's development and physical health. In the present study, we used data from the NSPGDC to investigate the association of sleep problems with asthma/wheeze and allergic rhinitis among Chinese children 0-6 years and found that frequent nocturnal awakening was associated with asthma/wheeze and allergic rhinitis. Although this is a crosssectional study and the association of frequent nocturnal awakening with asthma/wheeze and allergic rhinitis differed by age, the results suggests that pediatricians should consider evaluating sleep problems when evaluating the risk factors for asthma/wheeze and allergic rhinitis, and that parents should help their children develop good sleeping habits to reduce the risk of asthma/wheeze and allergic rhinitis.

Conclusions
Findings from this large-scale cross-sectional study suggested that frequent nocturnal awakening was associated with asthma/wheeze and allergic rhinitis, but this association differed by age. Further studies are warranted to con rm whether nocturnal awaking has an impact on asthma/wheeze and allergic rhinitis and to understand the underlying mechanisms.

Abbreviations
ARDs: Allergic respiratory diseases