pii: sp-00223-15
http://dx.doi.org/10.5665/sleep.5230
EARLY BLOOD LEAD LEVELS AND SLEEP DISTURBANCE IN PREADOLESCENCE
Early Blood Lead Levels and Sleep Disturbance in Preadolescence Jianghong Liu, PhD1; Xianchen Liu, MD, PhD2; Victoria Pak, PhD1; Yingjie Wang, MS1; Chonghuai Yan, PhD3; Jennifer Pinto-Martin, PhD1; David Dinges, PhD4 School of Nursing, University of Pennsylvania, Philadelphia, PA; 2Shandong University School of Public Health, Jinan, China; 3Xinhua Hospital, MOE-Shanghai Key Laboratory of Children’s Environmental Health, Shanghai Jiaotong University School of Medicine, China; 4Division of Sleep and Chronobiology, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
1
Study Objectives: Little is known about the effect of lead exposure on children’s sleep. This study examined the association between blood lead levels (BLL) and sleep problems in a longitudinal study of children. Setting: Four community-based elementary schools in Jintan City, China. Participants: 1,419 Chinese children. Measurement and Results: BLL were measured when children were aged 3–5 y, and sleep was assessed at ages 9–13 y. Sleep was assessed by both parents’ report, using the Children’s Sleep Habits Questionnaire (CSHQ), and children’s report, using an adolescent sleep questionnaire. A total of 665 children with complete data on BLL and sleep at both ages were included in the current study. Mean age of the sample at BLL assessment was 4.74 y (standard deviation [SD] = 0.89) and at sleep assessment was 11.05 y (SD = 0.88). Mean BLL was 6.26 µg/dL (SD = 2.54). There were significant positive correlations between BLL and 3 CSHQ subscales: Sleep onset delay (r = 0.113, P < 0.01), sleep duration (r = 0.139, P < 0.001), and night waking (r = 0.089, P < 0.05). Excessive daytime sleepiness (EDS) (26.1% versus 9.0%, P < 0.001) and use of sleeping pills (6.5% versus 1.8%, P = 0.03) were more prevalent in children BLL ≥ 10.0 µg/dL than in those children BLL < 10.0 µg/dL. After adjusting for demographics, BLL ≥ 10.0 µg/dL was significantly associated with increased risk for insomnia symptoms (odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.03–3.95) and EDS (OR = 2.90, 95% CI = 1.27–6.61). Conclusion: The findings indicate that elevated blood lead levels in early childhood are associated with increased risk for sleep problems and excessive daytime sleepiness in later childhood. Keywords: blood lead levels, daytime sleepiness, insomnia, lead exposure, sleep Citation: Liu J, Liu X, Pak V, Wang Y, Yan C, Pinto-Martin J, Dinges D. Early blood lead levels and sleep disturbance in preadolescence. SLEEP 2015;38(12):1869–1874.
INTRODUCTION Sleep problems are highly prevalent in children and adolescents1–3 and are associated with an increased risk of developmental disorders, including intellectual, neurocognitive, and behavioral problems.4–8 Multiple biological, psychosocial, and environmental factors are related to sleep problems in children.1 Because sleep disorders disrupt the timing (e.g., duration) and continuity (e.g., depth) of sleep, which are needed for healthy development, it is essential to identify the underlying factors involved in childhood sleep disturbance. One potentially important but understudied biological factor that could be related to sleep disturbance is lead toxicity.9 Animal models have suggested lead exposure may be associated with hyperactivity and insomnia.10 Occupational exposure to lead among workers has been reported to be associated with self-reported sleep disturbances.11,12 Kordas et al.9 reported that blood lead levels (BLL) greater than or equal to 10 μg/dL were associated with a later waking time but decreased sleep duration in 550 Mexican children ages 6–8 y old.9 However, their findings were derived from a cross-sectional study, and sleep was assessed by parental questionnaire. It is still unclear whether the long-term effects of lead exposure in early childhood relate
Submitted for publication April, 2015 Submitted in final revised form June, 2015 Accepted for publication June, 2015 Address correspondence to: Dr. Jianghong Liu, PhD, School of Nursing, University of Pennsylvania, 418 Curie Boulevard, Room 426, Philadelphia, PA 19104-6096; Tel: (215) 898-8293; Email: [email protected] and Dr. Xianchen Liu; Email: [email protected] SLEEP, Vol. 38, No. 12, 2015
to sleep disturbances in later childhood, and whether this is the case for both sleep reported by children and by their parents. Using a large community sample of a preschool cohort, the objective of this study was to test the hypothesis that early lead exposure in young children (age 3–5 y) is associated with sleep problems during later childhood (age 9–13 y). METHODS Subjects The data for these analyses are derived from an ongoing longitudinal project, the China Jintan Child Cohort Study, which included 1,656 preschool children in Jintan city, Jiangsu province, China. Participants were drawn from four preschools chosen to represent the entire city’s geographical, social, and economic profiles. In fall 2004, 3- to 5-y-old children attending the four preschools and their parents were invited to participate in this study. BLL was measured when children were aged 3–5 y and sleep was assessed when they were 9–13 y old. Signed consent forms for children’s participation were obtained from the parents. Institutional review board approval was obtained from the University of Pennsylvania and the ethical committee for research at Jintan Hospital in China. Detailed information on the Jintan Cohort Profile, including subjects, recruitment, and procedures has been reported elsewhere.13,14,15 A total of 665 children with complete data on BLL and sleep at both ages were included for analysis. Blood Lead Levels BLL was tested once for each child, at age 3, 4, or 5 y at the end of 2004. Blood collection was done by nurses using a
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wakenings, Parasomnias, Sleep disordered breathing, and Daytime sleepiness. The CSHQ has been widely used for the assessment of sleep behavior in children.17,18 Adolescent sleep patterns and problems during the past month were assessed by the AHQ. Sleep duration was represented by the number of hours of sleep during the weekdays and on weekends, separately. Insomnia was assessed by three items: difficulty initiating sleep (DIS) (“During the past month, how often would you say you have had difficulty falling asleep?”), difficulty maintaining sleep (DMS) (“…wake up frequently in the middle of night?”), and early morning awaking (EMA) (“…wake up very early and cannot get back to sleep?”). Two items addressed the use of hypnotics (“How often do you use prescribed/nonprescribed sleeping pills?”). Excessive daytime sleepiness (EDS) was assessed by asking “how often do you feel sleepy during the day?” All of the items were answered using a four-point scale with frequency responses: less than once per week, one to two times per week, three to five times per week, or almost every day. Higher scores represent worse sleep problems or daytime sleepiness. Insomnia symptoms were considered clinically significant if the problem occurred at least three times a week. The adolescent sleep questionnaire showed acceptable psychometric properties.5,18
Table 1—Sample characteristics at sleep assessment by blood lead level at 3–5 y (n = 665). BLL (µg/dL) < 10 ≥ 10 (n = 619) (n = 46) Sex, % Male Female Age, mean (SD)
90.1 95.9
9.9 4.1
11.0 (0.87)
11.40 (0.77)
School district School 1 School 2 School 3 School 4
97.0 92.8 93.8 84.1
3.0 7.2 6.2 15.9
Grade 4th 5th 6th
94.4 95.7 90.0
5.6 4.3 10.0
Father’s education Primary school Middle school High school College or above
88.9 91.6 92.1 95.0
11.1 8.4 7.9 5.0
Mother’s education Primary school Middle school High school College or above
74.2 93.6 92.4 94.9
20.8 6.4 7.6 5.1
Statistical Test P χ2 / t 8.51
0.037
2.93
0.004
15.94
0.001
6.68
0.036
2.29
0.515
8.21
0.042
BLL, blood lead level; SD, standard deviation.
standard protocol to avoid lead contamination. Each specimen was analyzed twice for blood lead using a graphite furnace atomic absorption spectrophotometer,16 and Kaulson Laboratories provided blood lead reference materials for quality control. The limit of detection was 1.8 μg/dL; half of the limit of detection was imputed for three samples (0.2%) under the limit of detection. More details on this process are provided in the study by Liu et al.14 Sleep Assessment Sleep patterns were assessed by both parents’ report using the Chinese version of the Children’s Sleep Habits Questionnaire (CSHQ)17 and children’s self-reports using the Adolescent Health Questionnaire (AHQ).5,18 The CSHQ, developed by Owens et al.,17 consists of 33 sleep disturbance items and three items asking for information about bedtime, morning waking time, and daily total sleep duration. Parents were asked to recall the child’s sleep behaviors over a “typical” recent week. Items were rated on a three-point scale: usually if the sleep behavior occurred five to seven times per week, sometimes for two to four times per week, and rarely for zero to one time per week, with higher scores indicative of more frequent sleep problems. The 33 sleep disturbance items were conceptually grouped into eight subscales: Bedtime resistance, Sleep onset delay, Sleep duration (e.g., Sleeps too little, Sleeps the right amount, Sleeps same amount each day), Sleep anxiety, Night SLEEP, Vol. 38, No. 12, 2015
Statistical Analysis Characteristics of the study sample were summarized by descriptive statistics such as mean, standard deviation (SD), and percentages. Pearson product-moment correlation coefficients were used to estimate the bivariate correlations between BLL and CSHQ scale scores and self-reported sleep duration. General linear models were performed to examine the adjusted associations between BLL and individual CSHQ scale scores and sleep duration while controlling for child age, sex, parental education, and school district. Student t tests were performed to examine the differences in sleep problem scale scores between children with blood lead levle ≥ 10.0 µg/ dL and < 10.0 µg/dL, because it was defined as a toxic level of concern by the Centers for Disease Control and Prevention (CDC) during the time data were collected.19 Chi-square tests were used to examine the difference in self-reported sleep problems between children with BLL ≥ 10.0 µg/dL and < 10.0 µg/dL. Multiple logistic regression analyses were conducted to examine the association between BLL ≥ 10.0 µg/dL versus < 10.0 µg/dL and self-reported sleep problems while controlling for child age, child sex, parental education, and school district. A P value less than 0.05 was considered significant. Data were analyzed using SPSS, version 20 (IBM, Chicago, IL). RESULTS Sample Characteristics Of the 665 children included in the analysis, mean age at sleep assessment was 11.05 y (SD = 0.88), and 53% were male. Mean BLL of the sample at ages 3–5 y was 6.4 µg/dL (SD = 2.6), with 6.9% (n = 46) being ≥ 10.0 µg/dL. Child and family characteristics of the sample by BLL are summarized in
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Table 1. There were significant differences in sex, age, school district, grade, and maternal education between children with BLL ≥ 10.0 µg/dL and those < 10.0 µg/dL. Blood Lead Level and Parents’ Reported Sleep Problems Using CSHQ Scale Scores Bivariate correlation analysis shows that BLL at ages 3–5 y was significantly correlated with three CSHQ subscales at a mean age of 11 y: Sleep onset delay (r = 0.113, P < 0.01), Sleep duration (r = 0.139, P < 0.001), and Night waking (r = 0.089, P < 0.05). Adjusting for age, sex, parental education, and school district, the general linear model shows that BLL was significantly associated with increased scores for sleep onset delay (β = 0.033, 95% CI = 0.009– 0.056, P < 0.006). Other sleep variables were not significantly related to BLL (Table 2). BLL was divided into two categories to examine if a level of 10.0 µg/dL or greater is associated with increased CSHQ scores. As shown in Table 3, compared to children with BLL < 10.0 µg/dL, scores on the CSHQ for sleep onset delay and sleep duration were significantly higher in children with BLL ≥ 10 µg/dL. Other CSHQ scale scores and selfreported sleep duration did not significantly differ between children with BLL ≥ 10 µg/dL and < 10 µg/dL.
Table 2—Association between blood lead and CSHQ scale scores and self-reported sleep duration. r
β
a
BLL (µg/dL) 95% CI
Pb
CSHQ Bedtime resistance Sleep onset delay Sleep duration score c Sleep anxiety Night wakings Parasomnias Sleep disordered breathing Daytime sleepiness
0.040 0.014 0.113** 0.033 0.139*** 0.042 0.022 0.014 0.089 * 0.029 0.056 0.016 0.063 0.012 −0.013 −0.005
−0.069–0.097 0.009–0.056 −0.008–0.092 −0.046–0.074 −0.010–0.068 −0.062–0.094 −0.028–0.052 −0.111–0.100
0.734 0.006 0.097 0.646 0.151 0.691 0.565 0.923
Self-report Weekday sleep duration Weekend sleep duration
−0.024 −0.033
−0.016–0.088 −0.064–0.077
0.179 0.850
0.036 0.007
Adjusting for age, sex, parental education, and school district. bP value for β. cSleep duration (e.g., sleep too little, sleep the right amount, sleep same amount each day); the higher the score, the worse the sleep. CI, confidence interval; CSHQ, Children’s Sleep Habits Questionnaire. *P value of correlation is < 0.05. **P value of correlation is < 0.01. ***P value of correlation is < 0.001.
a
Table 3—Mean CSHQ scale scores and self-reported sleep duration by blood lead level.
CSHQ Bedtime resistance Sleep onset delay Sleep duration scorea Sleep anxiety Night wakings Parasomnias Sleep disordered breathing Daytime sleepiness
BLL (µg/dL) < 10 ≥ 10 8.08 (2.54) 1.42 (0.69) 4.24 (1.52) 5.56 (1.80) 3.73 (1.15) 8.75 (2.60) 3.56 (1.31) 12.24 (3.00)
8.78 (3.00) 1.72 (0.83) 4.91 (1.65) 5.92 (2.25) 4.00 (1.74) 9.33 (3.20) 3.88 (1.82) 12.24 (3.16)
Statistical Test t P 1.797 2.769 2.852 1.297 1.366 1.455 1.574 0.033
0.073 0.006 0.004 0.194 0.172 0.146 0.116 0.975
Blood Lead Level and Self-Reported Sleep Problems Using AHQ The prevalence of self-reported sleep problems and use of sleeping pills by BLL is displayed in Table 4. Almost all sleep problems Self-report were more prevalent in children with BLL ≥ 10 Weekday sleep duration 9.14 (1.47) 9.36 (2.20) 0.935 0.350 µg/dL than in those with BLL < 10 µg/dL. Weekend sleep duration 9.47 (1.95) 9.02 (2.53) 1.459 0.145 More specifically, children with BLL ≥ 10 µg/dL versus children with BLL < 10 µg/dL Values presented as mean (standard deviation). aSleep duration (e.g. sleeps too little, sleeps exhibited higher prevalence of EDS (26.1% the right amount, sleeps same amount each day), the higher the score, the worse the sleep. BLL, blood lead level; CSHQ, Children’s Sleep Habits Questionnaire. versus 9.0%, χ2 = 13.54, P < 0.001), use of 2 sleeping pills (6.5% versus 1.8%, χ = 4.68, P = 0.03). Furthermore, all four items to assess insomnia showed higher prevalence in the group of chilDISCUSSION dren with BLL ≥ 10 µg/dL with “any insomnia” significantly increased. Other sleep problems were observed to have a trend Key Findings but did not significantly differ between children with BLL ≥ 10 Little is known about the effect of lead exposure on children’s µg/dL and < 10 µg/dL (P > 0.005) (Figure 1). sleep. This is the first longitudinal study exploring the relationMultivariate logistic regression was used to examine the inship between early lead exposure and later children’s sleep outdependent effect of elevated BLL (≥ 10 µg/dL) versus BLL < 10 comes in the general population. We found elevated BLL at ages µg/dL while adjusting for child age, sex, parental education, 3–5 y were associated with increased risk for sleep problems in early adolescence, particularly among children with BLL ≥ 10 and school district. As shown in Table 4, BLL ≥ 10 µg/dL was µg/dL compared to those with BLL < 10 µg/dL. Sleep onset delay significantly associated with increased odds for EDS problems was significantly linked to higher BLL, and there was a trend (OR = 2.39, 95% CI = 1.03–1.18) and any insomnia (OR = 2.01, toward more sleep disturbances in the BLL ≥ 10 µg/dL group, 95% CI = 1.03–3.95). with EDS and use of sleep medication significantly greater in Children with EDS problems had a shorter self-reported the high lead group than in children with BLL < 10 µg/dL. The (AHQ) weekday sleep duration (t = 3.604, P < 0.001), which odds of experiencing EDS and insomnia in later childhood were suggests shorter sleep duration is associated with EDS. SLEEP, Vol. 38, No. 12, 2015
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Table 4—Associations between blood lead level (≥ 10 µg/dL versus < 10 µg/dL) and self-reported sleep problems, adjusting for age, sex, parental education, and school district (n = 665). OR
95% CI
Insomnia Difficulty initiating sleep Difficulty maintaining sleep Early morning awaking Any insomnia
1.64 1.49 1.59 2.01
0.64–4.22 0.66–3.33 0.68–3.71 1.03–3.95
Excessive daytime sleepiness
2.90
1.27–6.61
Use of sleeping pills
3.29
0.61–17.82
At least 3 times/w for insomnia, excessive daytime sleepiness; At least once/w for use of sleeping pills. CI, confidence interval; OR, odds ratio.
≥ 10 µg/dL
< 10 µg/dL
Use of sleeping pills Excessive daytime sleepiness Any insomnia Early morning awaking Difficulty maintaining sleep Difficulty initiating sleep 0
10
20
30
40
50
Figure 1—Self-reported sleep problems (%) in adolescents by blood lead level at 3–5 y.
more than doubled among children with BLL ≥ 10 µg/dL versus those with BLL < 10 µg/dL. Results remained significant after adjusting for potential confounders. These findings highlight lead as an important pediatric risk factor for sleep disturbance. Lead Exposure and Sleep Disturbances Studies conducted in rhesus monkeys demonstrate that a BLL below 100 µg results in hyperactivity and insomnia.10 Few studies have investigated the relationship between BLL and sleep problems in children. Previously, Kordas et al.9 found that BLL ≥ 10 µg/dL was associated with later waking time and shorter sleep duration. Our study differs in that we included both self-reported measures of sleep behaviors and standardized parental report. We found that increased BLL SLEEP, Vol. 38, No. 12, 2015
was associated with increased problems of sleep onset, shorter sleep duration, and increased night awakenings based on parental report. Furthermore, children with BLL ≥ 10 µg/dL compared to those with BLL < 10 µg/dL took longer to fall asleep and exhibited shorter sleep duration. Children with a BLL ≥ 10 µg/dL compared to BLL < 10 µg/dL reported greater EDS, greater usage of sleeping pills, and more insomnia. Parents in our study reported more sleep onset and sleep maintenance problems (i.e., night awakenings) in children with elevated BLL, indicating more insomnia symptoms. In younger children, this disorder most often presents as bedtime refusal or resistance, delayed sleep onset, and/or prolonged nighttime waking that requires parental intervention.20 For an older age group, such as in our study sample, multiple factors besides lead exposure may contribute to the presentation of insomnia. Preadolescent sleep problems display greater complexity compared to sleep problems in childhood,1 perhaps because of additional stressors such as academic pressure and peer pressure. Insufficient sleep over time for children and adolescents results in chronic sleep deprivation, leading to a number of negative daytime consequences such as EDS, mood disturbances, behavior problems, cognitive impairment, and increased risk-taking behaviors21–24 in addition to poor physical health outcomes. Additional research is needed to investigate the various factors interacting with lead exposure to affect sleep disturbances, as well as assess the various adverse outcomes from lead exposure in early childhood, and integrate them into an analysis model. In addition, new methods of parental intervention for behavioral insomnia in an older age group should also take into account the multiple factors, such as reducing children’s media and technology usage25 or monitoring their caffeine and energy drink intake.26 Self-reported EDS, as shown in our logistic regression analysis (Table 4), was three times more prevalent in children with BLL ≥ 10 µg/dL than children with BLL ≤ 10 µg/dL. EDS in children has previously been reported to be associated with behavioral problems (learning, attention/hyperactivity, conduct) as well as poor performance in processing speed and working memory.24 It has also been associated with obesity, asthma, and parent-reported anxiety/depression.24 We found that the relationship between lead exposure and daytime sleepiness only held for children’s self-report and not for that of parents. Such poor concordance rates between parent and child reports of EDS are well documented.27–29 The discrepancy is expected; as children reach preadolescent age, daytime contact with parents diminishes. It has been noted that unless a teacher reports a child falling asleep in class, or the child complains of EDS, parents may be unaware of the level of daytime sleepiness children experience.27 This stresses the importance of asking children directly about their daytime sleepiness.27 Interestingly, we also found higher EDS scores in early adolescence were significantly related to shorter self-reported sleep duration, and a trend for this relationship was found for parent-reported sleep duration scores for their preadolescents. Child-reported insomnia and use of sleeping pills were two times and three times more prevalent, respectively, in children with BLL ≥ 10 µg/dL than in children with BLL < 10 µg/dL, which suggests that sleep disturbances appeared problematic enough for children to suffer from insomnia and even to use sleeping aids/pills in an attempt to ameliorate their symptoms. 1872
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Potential Mechanisms of Sleep Problems Attributed to Lead Exposure in Children We do not know the mechanism by which lead exposure could cause sleep problems. Lead is a well-known neurotoxin that damages, destroys, or impairs the function of the developing nervous system30 in multiple ways, including reduction in brain plasticity, disruption of the blood-brain barrier, negative alterations in cellular concentration of calcium, and induction of oxidative stress.31,32 Lead exposure can also result in disruption and dysregulation of neurochemicals (e.g., alterations of serotonin and/or catecholamine secretion),33 which contributes to negative psychological and physical outcomes with prolonged exposure, including sleep problems.34 Furthermore, dysregulation of catecholamines can increase the likelihood of depression and panic disorders,35 which are associated with poor sleep. Moreover, environmental lead exposure can cause oxidative stress,33 which has also been linked to sleep disorders such as sleep apnea.36 EDS has been characterized in patients exhibiting obstructive sleep apnea syndrome.37,38 Thus, oxidative stress resulting from lead exposure could be a mechanism that is linked to sleep problems such as EDS among children with BLL ≥ 10 µg/dL. In addition to possible biochemical mediators, other observed mediating factors may include neurobehavioral impairments, which have been found to be both a consequence of lead toxicity39,40 and correlated with sleep quality.41 It is possible that emotional behavior problems (e.g. internalizing or externalizing behavior problems) tie lead exposure to sleep problems, or alternatively, sleep disorders mediate lead exposure and behavioral problems. It may also be that the mechanism is not linear. Lead exposure could independently affect poor behavioral outcomes and sleep, which could also have a bidirectional relationship, exacerbating the negative outcomes of both. This study may provide an initial dialogue for future studies to unravel the relationships among lead exposure, sleep disturbances, and neurobehavioral outcomes.
habits are strongly influenced by the direct and combined effects of multiple phenomena including cultural factors, psychosocial issues, familial factors, school-related aspects, and genetic factors.1,42,43 Yet despite this plethora of possible contributors, little is known about the effect of lead exposure on child sleep patterns. In this longitudinal cohort of Chinese children, we observed a novel finding of early childhood lead exposure relating to later preadolescent problems of sleep and sleepiness. This is an important advancement in identifying and understanding the contribution of lead exposure to childhood insomnia and daytime sleepiness. Poor sleep is considered to be a global public health problem, and identification of preventable and/ or modifiable contributors can not only help alleviate sleep disturbance but also indirectly improve sleep related health outcomes, including cognition, emotion, and behavior. Lead pollution is pervasive throughout China and other developing countries, and although rates of lead exposure are decreasing due to increased public awareness, its persistence presents a significant health risk to children. Lead exposure is preventable and treatable, but if left unchecked can result in irreversible neurological damage.40 Our initial evidence of the link between early environmental lead exposure and preadolescent sleep problems could facilitate continued discussion about the possible role of environmental toxicants in sleep disturbance44 and the potential biochemical factors underlying sleep disorders. Future studies can include objective measures of sleep45 to investigate further the role of environmental lead exposure at low levels in contributing to sleep problems.
Strengths and Limitations As a longitudinal cohort study, the strengths of the findings include the robust study design, allowing for assessment of baseline exposure to lead relative to pediatric sleep outcomes in both children and parents. It is limited by the absence of behavioral and physiological measures of sleep, which are more reliable, and not subject to recall bias. As typical of epidemiological studies, associations could be biased by uncontrolled confounders. Furthermore, the findings should be replicated in other ethnic groups as children’s sleep habits can be shaped by cultural influences. Other limitations include the fact that we do not have information on the types of sleeping pills reported by parents and children, and the question of sleep medication was subject to cultural interpretation and response bias in which respondents may not interpret the meaning of the question in exactly the same way. As a result of these limitations, we acknowledge the need to interpret our conclusions with caution.
DISCLOSURE STATEMENT This was not an industry supported study. Funding was provided by the National Institute of Environment Health Sciences (NIH/NIEHS, R01-ES018858; K02-ES019878; K01-ES015877), and P30-ES013508; the University of Pennsylvania Center of Excellence in Environmental Toxicology; the Wacker Foundation. Dr. Dinges time and effort supported by NIH grant R01 NR004281. He has also consulted for Mars, Inc. The other authors have indicated no financial conflicts of interest.
ACKNOWLEDGMENTS The authors thankfully acknowledge the Jintan Local Cohort Group for data collection. Thanks are extended to the participating children and their families from Jintan City. We are grateful for Dr. Xiaoming Shen and Dr. Herbert Needleman for providing instrumental support for the Jintan Cohort Study.
CONCLUSIONS Environmental lead exposure has been linked to poor cognition and behavior problems in children.40 Children’s sleep SLEEP, Vol. 38, No. 12, 2015
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7. Stein MA, Mendelsohn J, Obermeyer WH, Amromin J, Benca R. Sleep and behavior problems in school-aged children. Pediatrics 2001;107:E60. 8. Liu J, Li L, Wang Y, Yan C, Liu X. Impact of low blood lead concentrations on IQ and school performance in Chinese children. PloS One 2013;8:e65230. 9. Kordas K, Casavantes KM, Mendoza C, et al. The association between lead and micronutrient status, and children’s sleep, classroom behavior, and activity. Arch Environ Occup Health 2007;62:105–12. 10. Allen JR, McWey PJ, Suomi SJ. Pathobiological and behavioral effects of lead intoxication in the infant rhesus monkey. Environ Health Perspect 1974;7:239–46. 11. Valciukas JA, Lilis R, Singer R, Fischbein A, Anderson HA, Glickman L. Lead exposure and behavioral changes: comparisons of four occupational groups with different levels of lead absorption. Am J Ind Med 1980;1:421–6. 12. Bener A, Almehdi AM, Alwash R, Al-Neamy FR. A pilot survey of blood lead levels in various types of workers in the United Arab Emirates. Environ Int 2001;27:311–14. 13. Liu J, McCauley LA, Zhao Y, Zhang H, Pinto-Martin J. Cohort profile: the China Jintan Child Cohort Study. Int J Epidemiol 2010;39:668–74. 14. Liu J, Ai Y, McCauley L, et al. Blood lead levels and associated sociodemographic factors among preschool children in the South Eastern region of China. Paediatr Perinat Epidemiol 2012;26:61–9. 15. Liu J, Cao S, Chen Z, et al. Cohort profile update: the China Jintan Child Cohort Study. Int J Epidemiol 2015 Aug 31. [Epub ahead of print]. 16. Shen X, Zhou J, Yan C. Themethodology of BPb level measurement by Flamele GF-AAS. J Trace Element Res 1994;11:43–8. 17. Owens JA, Spirito A, McGuinn M. The Children’s Sleep Habits Questionnaire (CSHQ): psychometric properties of a survey instrument for school-aged children. Sleep 2000;23:1043–51. 18. Liu X, Zhao Z, Jia C, Buysse DJ. Sleep patterns and problems among chinese adolescents. Pediatrics 2008;121:1165–73. 19. Centers for Disease Control and Prevention. Building blocks for primary prevention: protecting children from lead-based paint hazards. Atlanta, GA: Centers for Disease Control and Prevention, 2005. Available at: http://www.cdc.gov/nceh/lead/Building Blocks June 2005.pdf. 20. Moore M, Meltzer LJ, Mindell JA. Bedtime problems and night wakings in children. Primary Care 2008;35:569–81, viii. 21. Dahl RE. The impact of inadequate sleep on children’s daytime cognitive function. Semin Pediatr Neurol 1996;3:44–50. 22. O’Brien EM, Mindell JA. Sleep and risk-taking behavior in adolescents. Behav Sleep Med 2005;3:113–33. 23. Fallone G, Owens JA, Deane J. Sleepiness in children and adolescents: clinical implications. Sleep Med Rev 2002;6:287–306. 24. Calhoun SL, Fernandez-Mendoza J, Vgontzas AN, et al. Learning, attention/hyperactivity, and conduct problems as sequelae of excessive daytime sleepiness in a general population study of young children. Sleep 2012;35:627–32. 25. Cain N, Gradisar M. Electronic media use and sleep in school-aged children and adolescents: a review. Sleep Med 2010;11:735–42. 26. Seifert SM, Schaechter JL, Hershorin ER, Lipshultz SE. Health effects of energy drinks on children, adolescents, and young adults. Pediatrics 2011;127:511–28. 27. Meltzer LJ, Biggs S, Reynolds A, Avis KT, Crabtree VM, Bevans KB. The Children’s Report of Sleep Patterns--Sleepiness Scale: a self-report measure for school-aged children. Sleep Med 2012;13:385–9.
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28. Owens JA, Spirito A, McGuinn M, Nobile C. Sleep habits and sleep disturbance in elementary school-aged children. J Dev Behav Pediatr 2000;21:27–36. 29. Paavonen EJ, Aronen ET, Moilanen I, et al. Sleep problems of schoolaged children: a complementary view. Acta Paediatr 2000;89:223–8. 30. Liu J ,Lewis G. Environmental toxicity and poor cognitive outcomes in children and adults. J Environ Health 2014;76:130–8. 31. Brochin R, Leone S, Phillips D, Shepard N, Zisa D, Angerio A. The cellular effect of lead poisoning and its clinical picture. The Georgetown Undergraduate Journal of Health Sciences 2008;5(2). 32. Nava-Ruiz C, Mendez-Armenta M, Rios C. Lead neurotoxicity: effects on brain nitric oxide synthase. J Mol Histol 2012;43:553–63. 33. Lidsky TI, Schneider JS. Lead neurotoxicity in children: basic mechanisms and clinical correlates. Brain 2003;126(Pt 1):5–19. 34. Lechin F, Pardey-Maldonado B, van der Dijs B, Benaim M, Baez S, Orozco B, et al. Circulating neurotransmitters during the different wake-sleep stages in normal subjects. Psychoneuroendocrinology 2004;29:669–85. 35. Bouchard MF, Bellinger DC, Weuve J, et al. Blood lead levels and major depressive disorder, panic disorder, and generalized anxiety disorder in US young adults. Arch Gen Psychiatry 2009;66:1313–9. 36. Singh T, Patial K, Vijayan V, Ravi K. Oxidative stress and obstructive sleep apnoea syndrome. Indian J Chest Dis Allied Sci 2009;51:217–24. 37. Mediano O, Barceló A, de la Peña M, Gozal D, Agustí A, Barbé F. Daytime sleepiness and polysomnographic variables in sleep apnoea patients. Eur Respir J 2007;30:110–13. 38. Melendres CS, Lutz JM, Rubin ED, Marcus CL. Daytime sleepiness and hyperactivity in children with suspected sleep-disordered breathing. Pediatrics 2004;114:768–75. 39. Bellinger DC. Very low lead exposures and children’s neurodevelopment. Curr Opin Pediatr 2008;20:172–7. 40. Liu J, Liu X, Wang W, et al. Blood lead concentrations and children’s behavioral and emotional problems: a cohort study. JAMA Pediatr 2014;168:737–45. 41. Gregory AM, O’Connor TG. Sleep problems in childhood: a longitudinal study of developmental change and association with behavioral problems. J Am Acad Child Adolesc Psychiatry 2002;41:964–71. 42. Li S, Jin X, Wu S, Jiang F, Yan C, Shen X. The impact of media use on sleep patterns and sleep disorders among school-aged children in China. Sleep 2007;30:361–7. 43. Goel N, Dinges DF. Behavioral and genetic markers of sleepiness. J Clin Sleep Med 2011;7:S19–21. 44. Accinelli RA, Llanos O, Lopez LM, Matayoshi S, Oros YP, KheirandishGozal L, et al. Caregiver perception of sleep-disordered breathingassociated symptoms in children of rural Andean communities above 4000 masl with chronic exposure to biomass fuel. Sleep Med 2015;16:723–8. 45. Dorrian J, Rogers NL, Dinges D. Psychomotor vigilance performance: neurocognitive assay sensitive to sleep loss. In: Kushida CA, ed. Sleep Deprivation Clinical Issues, Pharmacology, and Sleep Loss Effects. New York, NY: Marcel Dekker, 2005:39–70.
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http://dx.doi.org/10.5665/sleep.5230
EARLY BLOOD LEAD LEVELS AND SLEEP DISTURBANCE IN PREADOLESCENCE
Early Blood Lead Levels and Sleep Disturbance in Preadolescence Jianghong Liu, PhD1; Xianchen Liu, MD, PhD2; Victoria Pak, PhD1; Yingjie Wang, MS1; Chonghuai Yan, PhD3; Jennifer Pinto-Martin, PhD1; David Dinges, PhD4 School of Nursing, University of Pennsylvania, Philadelphia, PA; 2Shandong University School of Public Health, Jinan, China; 3Xinhua Hospital, MOE-Shanghai Key Laboratory of Children’s Environmental Health, Shanghai Jiaotong University School of Medicine, China; 4Division of Sleep and Chronobiology, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
1
Study Objectives: Little is known about the effect of lead exposure on children’s sleep. This study examined the association between blood lead levels (BLL) and sleep problems in a longitudinal study of children. Setting: Four community-based elementary schools in Jintan City, China. Participants: 1,419 Chinese children. Measurement and Results: BLL were measured when children were aged 3–5 y, and sleep was assessed at ages 9–13 y. Sleep was assessed by both parents’ report, using the Children’s Sleep Habits Questionnaire (CSHQ), and children’s report, using an adolescent sleep questionnaire. A total of 665 children with complete data on BLL and sleep at both ages were included in the current study. Mean age of the sample at BLL assessment was 4.74 y (standard deviation [SD] = 0.89) and at sleep assessment was 11.05 y (SD = 0.88). Mean BLL was 6.26 µg/dL (SD = 2.54). There were significant positive correlations between BLL and 3 CSHQ subscales: Sleep onset delay (r = 0.113, P < 0.01), sleep duration (r = 0.139, P < 0.001), and night waking (r = 0.089, P < 0.05). Excessive daytime sleepiness (EDS) (26.1% versus 9.0%, P < 0.001) and use of sleeping pills (6.5% versus 1.8%, P = 0.03) were more prevalent in children BLL ≥ 10.0 µg/dL than in those children BLL < 10.0 µg/dL. After adjusting for demographics, BLL ≥ 10.0 µg/dL was significantly associated with increased risk for insomnia symptoms (odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.03–3.95) and EDS (OR = 2.90, 95% CI = 1.27–6.61). Conclusion: The findings indicate that elevated blood lead levels in early childhood are associated with increased risk for sleep problems and excessive daytime sleepiness in later childhood. Keywords: blood lead levels, daytime sleepiness, insomnia, lead exposure, sleep Citation: Liu J, Liu X, Pak V, Wang Y, Yan C, Pinto-Martin J, Dinges D. Early blood lead levels and sleep disturbance in preadolescence. SLEEP 2015;38(12):1869–1874.
INTRODUCTION Sleep problems are highly prevalent in children and adolescents1–3 and are associated with an increased risk of developmental disorders, including intellectual, neurocognitive, and behavioral problems.4–8 Multiple biological, psychosocial, and environmental factors are related to sleep problems in children.1 Because sleep disorders disrupt the timing (e.g., duration) and continuity (e.g., depth) of sleep, which are needed for healthy development, it is essential to identify the underlying factors involved in childhood sleep disturbance. One potentially important but understudied biological factor that could be related to sleep disturbance is lead toxicity.9 Animal models have suggested lead exposure may be associated with hyperactivity and insomnia.10 Occupational exposure to lead among workers has been reported to be associated with self-reported sleep disturbances.11,12 Kordas et al.9 reported that blood lead levels (BLL) greater than or equal to 10 μg/dL were associated with a later waking time but decreased sleep duration in 550 Mexican children ages 6–8 y old.9 However, their findings were derived from a cross-sectional study, and sleep was assessed by parental questionnaire. It is still unclear whether the long-term effects of lead exposure in early childhood relate
Submitted for publication April, 2015 Submitted in final revised form June, 2015 Accepted for publication June, 2015 Address correspondence to: Dr. Jianghong Liu, PhD, School of Nursing, University of Pennsylvania, 418 Curie Boulevard, Room 426, Philadelphia, PA 19104-6096; Tel: (215) 898-8293; Email: [email protected] and Dr. Xianchen Liu; Email: [email protected] SLEEP, Vol. 38, No. 12, 2015
to sleep disturbances in later childhood, and whether this is the case for both sleep reported by children and by their parents. Using a large community sample of a preschool cohort, the objective of this study was to test the hypothesis that early lead exposure in young children (age 3–5 y) is associated with sleep problems during later childhood (age 9–13 y). METHODS Subjects The data for these analyses are derived from an ongoing longitudinal project, the China Jintan Child Cohort Study, which included 1,656 preschool children in Jintan city, Jiangsu province, China. Participants were drawn from four preschools chosen to represent the entire city’s geographical, social, and economic profiles. In fall 2004, 3- to 5-y-old children attending the four preschools and their parents were invited to participate in this study. BLL was measured when children were aged 3–5 y and sleep was assessed when they were 9–13 y old. Signed consent forms for children’s participation were obtained from the parents. Institutional review board approval was obtained from the University of Pennsylvania and the ethical committee for research at Jintan Hospital in China. Detailed information on the Jintan Cohort Profile, including subjects, recruitment, and procedures has been reported elsewhere.13,14,15 A total of 665 children with complete data on BLL and sleep at both ages were included for analysis. Blood Lead Levels BLL was tested once for each child, at age 3, 4, or 5 y at the end of 2004. Blood collection was done by nurses using a
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wakenings, Parasomnias, Sleep disordered breathing, and Daytime sleepiness. The CSHQ has been widely used for the assessment of sleep behavior in children.17,18 Adolescent sleep patterns and problems during the past month were assessed by the AHQ. Sleep duration was represented by the number of hours of sleep during the weekdays and on weekends, separately. Insomnia was assessed by three items: difficulty initiating sleep (DIS) (“During the past month, how often would you say you have had difficulty falling asleep?”), difficulty maintaining sleep (DMS) (“…wake up frequently in the middle of night?”), and early morning awaking (EMA) (“…wake up very early and cannot get back to sleep?”). Two items addressed the use of hypnotics (“How often do you use prescribed/nonprescribed sleeping pills?”). Excessive daytime sleepiness (EDS) was assessed by asking “how often do you feel sleepy during the day?” All of the items were answered using a four-point scale with frequency responses: less than once per week, one to two times per week, three to five times per week, or almost every day. Higher scores represent worse sleep problems or daytime sleepiness. Insomnia symptoms were considered clinically significant if the problem occurred at least three times a week. The adolescent sleep questionnaire showed acceptable psychometric properties.5,18
Table 1—Sample characteristics at sleep assessment by blood lead level at 3–5 y (n = 665). BLL (µg/dL) < 10 ≥ 10 (n = 619) (n = 46) Sex, % Male Female Age, mean (SD)
90.1 95.9
9.9 4.1
11.0 (0.87)
11.40 (0.77)
School district School 1 School 2 School 3 School 4
97.0 92.8 93.8 84.1
3.0 7.2 6.2 15.9
Grade 4th 5th 6th
94.4 95.7 90.0
5.6 4.3 10.0
Father’s education Primary school Middle school High school College or above
88.9 91.6 92.1 95.0
11.1 8.4 7.9 5.0
Mother’s education Primary school Middle school High school College or above
74.2 93.6 92.4 94.9
20.8 6.4 7.6 5.1
Statistical Test P χ2 / t 8.51
0.037
2.93
0.004
15.94
0.001
6.68
0.036
2.29
0.515
8.21
0.042
BLL, blood lead level; SD, standard deviation.
standard protocol to avoid lead contamination. Each specimen was analyzed twice for blood lead using a graphite furnace atomic absorption spectrophotometer,16 and Kaulson Laboratories provided blood lead reference materials for quality control. The limit of detection was 1.8 μg/dL; half of the limit of detection was imputed for three samples (0.2%) under the limit of detection. More details on this process are provided in the study by Liu et al.14 Sleep Assessment Sleep patterns were assessed by both parents’ report using the Chinese version of the Children’s Sleep Habits Questionnaire (CSHQ)17 and children’s self-reports using the Adolescent Health Questionnaire (AHQ).5,18 The CSHQ, developed by Owens et al.,17 consists of 33 sleep disturbance items and three items asking for information about bedtime, morning waking time, and daily total sleep duration. Parents were asked to recall the child’s sleep behaviors over a “typical” recent week. Items were rated on a three-point scale: usually if the sleep behavior occurred five to seven times per week, sometimes for two to four times per week, and rarely for zero to one time per week, with higher scores indicative of more frequent sleep problems. The 33 sleep disturbance items were conceptually grouped into eight subscales: Bedtime resistance, Sleep onset delay, Sleep duration (e.g., Sleeps too little, Sleeps the right amount, Sleeps same amount each day), Sleep anxiety, Night SLEEP, Vol. 38, No. 12, 2015
Statistical Analysis Characteristics of the study sample were summarized by descriptive statistics such as mean, standard deviation (SD), and percentages. Pearson product-moment correlation coefficients were used to estimate the bivariate correlations between BLL and CSHQ scale scores and self-reported sleep duration. General linear models were performed to examine the adjusted associations between BLL and individual CSHQ scale scores and sleep duration while controlling for child age, sex, parental education, and school district. Student t tests were performed to examine the differences in sleep problem scale scores between children with blood lead levle ≥ 10.0 µg/ dL and < 10.0 µg/dL, because it was defined as a toxic level of concern by the Centers for Disease Control and Prevention (CDC) during the time data were collected.19 Chi-square tests were used to examine the difference in self-reported sleep problems between children with BLL ≥ 10.0 µg/dL and < 10.0 µg/dL. Multiple logistic regression analyses were conducted to examine the association between BLL ≥ 10.0 µg/dL versus < 10.0 µg/dL and self-reported sleep problems while controlling for child age, child sex, parental education, and school district. A P value less than 0.05 was considered significant. Data were analyzed using SPSS, version 20 (IBM, Chicago, IL). RESULTS Sample Characteristics Of the 665 children included in the analysis, mean age at sleep assessment was 11.05 y (SD = 0.88), and 53% were male. Mean BLL of the sample at ages 3–5 y was 6.4 µg/dL (SD = 2.6), with 6.9% (n = 46) being ≥ 10.0 µg/dL. Child and family characteristics of the sample by BLL are summarized in
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Table 1. There were significant differences in sex, age, school district, grade, and maternal education between children with BLL ≥ 10.0 µg/dL and those < 10.0 µg/dL. Blood Lead Level and Parents’ Reported Sleep Problems Using CSHQ Scale Scores Bivariate correlation analysis shows that BLL at ages 3–5 y was significantly correlated with three CSHQ subscales at a mean age of 11 y: Sleep onset delay (r = 0.113, P < 0.01), Sleep duration (r = 0.139, P < 0.001), and Night waking (r = 0.089, P < 0.05). Adjusting for age, sex, parental education, and school district, the general linear model shows that BLL was significantly associated with increased scores for sleep onset delay (β = 0.033, 95% CI = 0.009– 0.056, P < 0.006). Other sleep variables were not significantly related to BLL (Table 2). BLL was divided into two categories to examine if a level of 10.0 µg/dL or greater is associated with increased CSHQ scores. As shown in Table 3, compared to children with BLL < 10.0 µg/dL, scores on the CSHQ for sleep onset delay and sleep duration were significantly higher in children with BLL ≥ 10 µg/dL. Other CSHQ scale scores and selfreported sleep duration did not significantly differ between children with BLL ≥ 10 µg/dL and < 10 µg/dL.
Table 2—Association between blood lead and CSHQ scale scores and self-reported sleep duration. r
β
a
BLL (µg/dL) 95% CI
Pb
CSHQ Bedtime resistance Sleep onset delay Sleep duration score c Sleep anxiety Night wakings Parasomnias Sleep disordered breathing Daytime sleepiness
0.040 0.014 0.113** 0.033 0.139*** 0.042 0.022 0.014 0.089 * 0.029 0.056 0.016 0.063 0.012 −0.013 −0.005
−0.069–0.097 0.009–0.056 −0.008–0.092 −0.046–0.074 −0.010–0.068 −0.062–0.094 −0.028–0.052 −0.111–0.100
0.734 0.006 0.097 0.646 0.151 0.691 0.565 0.923
Self-report Weekday sleep duration Weekend sleep duration
−0.024 −0.033
−0.016–0.088 −0.064–0.077
0.179 0.850
0.036 0.007
Adjusting for age, sex, parental education, and school district. bP value for β. cSleep duration (e.g., sleep too little, sleep the right amount, sleep same amount each day); the higher the score, the worse the sleep. CI, confidence interval; CSHQ, Children’s Sleep Habits Questionnaire. *P value of correlation is < 0.05. **P value of correlation is < 0.01. ***P value of correlation is < 0.001.
a
Table 3—Mean CSHQ scale scores and self-reported sleep duration by blood lead level.
CSHQ Bedtime resistance Sleep onset delay Sleep duration scorea Sleep anxiety Night wakings Parasomnias Sleep disordered breathing Daytime sleepiness
BLL (µg/dL) < 10 ≥ 10 8.08 (2.54) 1.42 (0.69) 4.24 (1.52) 5.56 (1.80) 3.73 (1.15) 8.75 (2.60) 3.56 (1.31) 12.24 (3.00)
8.78 (3.00) 1.72 (0.83) 4.91 (1.65) 5.92 (2.25) 4.00 (1.74) 9.33 (3.20) 3.88 (1.82) 12.24 (3.16)
Statistical Test t P 1.797 2.769 2.852 1.297 1.366 1.455 1.574 0.033
0.073 0.006 0.004 0.194 0.172 0.146 0.116 0.975
Blood Lead Level and Self-Reported Sleep Problems Using AHQ The prevalence of self-reported sleep problems and use of sleeping pills by BLL is displayed in Table 4. Almost all sleep problems Self-report were more prevalent in children with BLL ≥ 10 Weekday sleep duration 9.14 (1.47) 9.36 (2.20) 0.935 0.350 µg/dL than in those with BLL < 10 µg/dL. Weekend sleep duration 9.47 (1.95) 9.02 (2.53) 1.459 0.145 More specifically, children with BLL ≥ 10 µg/dL versus children with BLL < 10 µg/dL Values presented as mean (standard deviation). aSleep duration (e.g. sleeps too little, sleeps exhibited higher prevalence of EDS (26.1% the right amount, sleeps same amount each day), the higher the score, the worse the sleep. BLL, blood lead level; CSHQ, Children’s Sleep Habits Questionnaire. versus 9.0%, χ2 = 13.54, P < 0.001), use of 2 sleeping pills (6.5% versus 1.8%, χ = 4.68, P = 0.03). Furthermore, all four items to assess insomnia showed higher prevalence in the group of chilDISCUSSION dren with BLL ≥ 10 µg/dL with “any insomnia” significantly increased. Other sleep problems were observed to have a trend Key Findings but did not significantly differ between children with BLL ≥ 10 Little is known about the effect of lead exposure on children’s µg/dL and < 10 µg/dL (P > 0.005) (Figure 1). sleep. This is the first longitudinal study exploring the relationMultivariate logistic regression was used to examine the inship between early lead exposure and later children’s sleep outdependent effect of elevated BLL (≥ 10 µg/dL) versus BLL < 10 comes in the general population. We found elevated BLL at ages µg/dL while adjusting for child age, sex, parental education, 3–5 y were associated with increased risk for sleep problems in early adolescence, particularly among children with BLL ≥ 10 and school district. As shown in Table 4, BLL ≥ 10 µg/dL was µg/dL compared to those with BLL < 10 µg/dL. Sleep onset delay significantly associated with increased odds for EDS problems was significantly linked to higher BLL, and there was a trend (OR = 2.39, 95% CI = 1.03–1.18) and any insomnia (OR = 2.01, toward more sleep disturbances in the BLL ≥ 10 µg/dL group, 95% CI = 1.03–3.95). with EDS and use of sleep medication significantly greater in Children with EDS problems had a shorter self-reported the high lead group than in children with BLL < 10 µg/dL. The (AHQ) weekday sleep duration (t = 3.604, P < 0.001), which odds of experiencing EDS and insomnia in later childhood were suggests shorter sleep duration is associated with EDS. SLEEP, Vol. 38, No. 12, 2015
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Table 4—Associations between blood lead level (≥ 10 µg/dL versus < 10 µg/dL) and self-reported sleep problems, adjusting for age, sex, parental education, and school district (n = 665). OR
95% CI
Insomnia Difficulty initiating sleep Difficulty maintaining sleep Early morning awaking Any insomnia
1.64 1.49 1.59 2.01
0.64–4.22 0.66–3.33 0.68–3.71 1.03–3.95
Excessive daytime sleepiness
2.90
1.27–6.61
Use of sleeping pills
3.29
0.61–17.82
At least 3 times/w for insomnia, excessive daytime sleepiness; At least once/w for use of sleeping pills. CI, confidence interval; OR, odds ratio.
≥ 10 µg/dL
< 10 µg/dL
Use of sleeping pills Excessive daytime sleepiness Any insomnia Early morning awaking Difficulty maintaining sleep Difficulty initiating sleep 0
10
20
30
40
50
Figure 1—Self-reported sleep problems (%) in adolescents by blood lead level at 3–5 y.
more than doubled among children with BLL ≥ 10 µg/dL versus those with BLL < 10 µg/dL. Results remained significant after adjusting for potential confounders. These findings highlight lead as an important pediatric risk factor for sleep disturbance. Lead Exposure and Sleep Disturbances Studies conducted in rhesus monkeys demonstrate that a BLL below 100 µg results in hyperactivity and insomnia.10 Few studies have investigated the relationship between BLL and sleep problems in children. Previously, Kordas et al.9 found that BLL ≥ 10 µg/dL was associated with later waking time and shorter sleep duration. Our study differs in that we included both self-reported measures of sleep behaviors and standardized parental report. We found that increased BLL SLEEP, Vol. 38, No. 12, 2015
was associated with increased problems of sleep onset, shorter sleep duration, and increased night awakenings based on parental report. Furthermore, children with BLL ≥ 10 µg/dL compared to those with BLL < 10 µg/dL took longer to fall asleep and exhibited shorter sleep duration. Children with a BLL ≥ 10 µg/dL compared to BLL < 10 µg/dL reported greater EDS, greater usage of sleeping pills, and more insomnia. Parents in our study reported more sleep onset and sleep maintenance problems (i.e., night awakenings) in children with elevated BLL, indicating more insomnia symptoms. In younger children, this disorder most often presents as bedtime refusal or resistance, delayed sleep onset, and/or prolonged nighttime waking that requires parental intervention.20 For an older age group, such as in our study sample, multiple factors besides lead exposure may contribute to the presentation of insomnia. Preadolescent sleep problems display greater complexity compared to sleep problems in childhood,1 perhaps because of additional stressors such as academic pressure and peer pressure. Insufficient sleep over time for children and adolescents results in chronic sleep deprivation, leading to a number of negative daytime consequences such as EDS, mood disturbances, behavior problems, cognitive impairment, and increased risk-taking behaviors21–24 in addition to poor physical health outcomes. Additional research is needed to investigate the various factors interacting with lead exposure to affect sleep disturbances, as well as assess the various adverse outcomes from lead exposure in early childhood, and integrate them into an analysis model. In addition, new methods of parental intervention for behavioral insomnia in an older age group should also take into account the multiple factors, such as reducing children’s media and technology usage25 or monitoring their caffeine and energy drink intake.26 Self-reported EDS, as shown in our logistic regression analysis (Table 4), was three times more prevalent in children with BLL ≥ 10 µg/dL than children with BLL ≤ 10 µg/dL. EDS in children has previously been reported to be associated with behavioral problems (learning, attention/hyperactivity, conduct) as well as poor performance in processing speed and working memory.24 It has also been associated with obesity, asthma, and parent-reported anxiety/depression.24 We found that the relationship between lead exposure and daytime sleepiness only held for children’s self-report and not for that of parents. Such poor concordance rates between parent and child reports of EDS are well documented.27–29 The discrepancy is expected; as children reach preadolescent age, daytime contact with parents diminishes. It has been noted that unless a teacher reports a child falling asleep in class, or the child complains of EDS, parents may be unaware of the level of daytime sleepiness children experience.27 This stresses the importance of asking children directly about their daytime sleepiness.27 Interestingly, we also found higher EDS scores in early adolescence were significantly related to shorter self-reported sleep duration, and a trend for this relationship was found for parent-reported sleep duration scores for their preadolescents. Child-reported insomnia and use of sleeping pills were two times and three times more prevalent, respectively, in children with BLL ≥ 10 µg/dL than in children with BLL < 10 µg/dL, which suggests that sleep disturbances appeared problematic enough for children to suffer from insomnia and even to use sleeping aids/pills in an attempt to ameliorate their symptoms. 1872
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Potential Mechanisms of Sleep Problems Attributed to Lead Exposure in Children We do not know the mechanism by which lead exposure could cause sleep problems. Lead is a well-known neurotoxin that damages, destroys, or impairs the function of the developing nervous system30 in multiple ways, including reduction in brain plasticity, disruption of the blood-brain barrier, negative alterations in cellular concentration of calcium, and induction of oxidative stress.31,32 Lead exposure can also result in disruption and dysregulation of neurochemicals (e.g., alterations of serotonin and/or catecholamine secretion),33 which contributes to negative psychological and physical outcomes with prolonged exposure, including sleep problems.34 Furthermore, dysregulation of catecholamines can increase the likelihood of depression and panic disorders,35 which are associated with poor sleep. Moreover, environmental lead exposure can cause oxidative stress,33 which has also been linked to sleep disorders such as sleep apnea.36 EDS has been characterized in patients exhibiting obstructive sleep apnea syndrome.37,38 Thus, oxidative stress resulting from lead exposure could be a mechanism that is linked to sleep problems such as EDS among children with BLL ≥ 10 µg/dL. In addition to possible biochemical mediators, other observed mediating factors may include neurobehavioral impairments, which have been found to be both a consequence of lead toxicity39,40 and correlated with sleep quality.41 It is possible that emotional behavior problems (e.g. internalizing or externalizing behavior problems) tie lead exposure to sleep problems, or alternatively, sleep disorders mediate lead exposure and behavioral problems. It may also be that the mechanism is not linear. Lead exposure could independently affect poor behavioral outcomes and sleep, which could also have a bidirectional relationship, exacerbating the negative outcomes of both. This study may provide an initial dialogue for future studies to unravel the relationships among lead exposure, sleep disturbances, and neurobehavioral outcomes.
habits are strongly influenced by the direct and combined effects of multiple phenomena including cultural factors, psychosocial issues, familial factors, school-related aspects, and genetic factors.1,42,43 Yet despite this plethora of possible contributors, little is known about the effect of lead exposure on child sleep patterns. In this longitudinal cohort of Chinese children, we observed a novel finding of early childhood lead exposure relating to later preadolescent problems of sleep and sleepiness. This is an important advancement in identifying and understanding the contribution of lead exposure to childhood insomnia and daytime sleepiness. Poor sleep is considered to be a global public health problem, and identification of preventable and/ or modifiable contributors can not only help alleviate sleep disturbance but also indirectly improve sleep related health outcomes, including cognition, emotion, and behavior. Lead pollution is pervasive throughout China and other developing countries, and although rates of lead exposure are decreasing due to increased public awareness, its persistence presents a significant health risk to children. Lead exposure is preventable and treatable, but if left unchecked can result in irreversible neurological damage.40 Our initial evidence of the link between early environmental lead exposure and preadolescent sleep problems could facilitate continued discussion about the possible role of environmental toxicants in sleep disturbance44 and the potential biochemical factors underlying sleep disorders. Future studies can include objective measures of sleep45 to investigate further the role of environmental lead exposure at low levels in contributing to sleep problems.
Strengths and Limitations As a longitudinal cohort study, the strengths of the findings include the robust study design, allowing for assessment of baseline exposure to lead relative to pediatric sleep outcomes in both children and parents. It is limited by the absence of behavioral and physiological measures of sleep, which are more reliable, and not subject to recall bias. As typical of epidemiological studies, associations could be biased by uncontrolled confounders. Furthermore, the findings should be replicated in other ethnic groups as children’s sleep habits can be shaped by cultural influences. Other limitations include the fact that we do not have information on the types of sleeping pills reported by parents and children, and the question of sleep medication was subject to cultural interpretation and response bias in which respondents may not interpret the meaning of the question in exactly the same way. As a result of these limitations, we acknowledge the need to interpret our conclusions with caution.
DISCLOSURE STATEMENT This was not an industry supported study. Funding was provided by the National Institute of Environment Health Sciences (NIH/NIEHS, R01-ES018858; K02-ES019878; K01-ES015877), and P30-ES013508; the University of Pennsylvania Center of Excellence in Environmental Toxicology; the Wacker Foundation. Dr. Dinges time and effort supported by NIH grant R01 NR004281. He has also consulted for Mars, Inc. The other authors have indicated no financial conflicts of interest.
ACKNOWLEDGMENTS The authors thankfully acknowledge the Jintan Local Cohort Group for data collection. Thanks are extended to the participating children and their families from Jintan City. We are grateful for Dr. Xiaoming Shen and Dr. Herbert Needleman for providing instrumental support for the Jintan Cohort Study.
CONCLUSIONS Environmental lead exposure has been linked to poor cognition and behavior problems in children.40 Children’s sleep SLEEP, Vol. 38, No. 12, 2015
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