- Email: [email protected]
Associations Between Early Low-Level Tobacco Smoke Exposure and Executive Function at Age 8 Years
ORIGINAL ARTICLES Associations Between Early Low-Level Tobacco Smoke Exposure and Executive Function at Age 8 Years Karin Oh1, Yingying Xu, PhD1, Brandon F. Terrizzi, MS, PhD1, Bruce Lanphear, MD, MPH2, Aimin Chen, MD, PhD3, Amy E. Kalkbrenner, MPH, PhD4, and Kimberly Yolton, PhD1,5 Objective To investigate whether exposure to tobacco smoke during early brain development is linked with later problems in behavior and executive function.
Study design We studied 239 children in a prospective birth cohort. We measured tobacco exposures by caregiver report and serum cotinine 3 times during pregnancy and 4 times during childhood. We used linear regression to examine the association between prenatal and childhood serum cotinine concentrations and behavior (the Behavior Assessment System for Children-2) and executive function (the Behavior Rating Inventory of Executive Function) at age 8 years while adjusting for important covariates. Results Neither prenatal nor child serum cotinine were associated with behavior problems measured by the Behavior Assessment System for Children-2. On the Behavior Rating Inventory of Executive Function, prenatal and childhood exposure was associated with poorer task initiation scores (B = 0.44; 95% CI, 0.03-0.85 and B = 0.69, 95% CI, 0.06-1.32 respectively). Additionally, in a subset of 208 children with nonsmoking mothers, prenatal exposure was associated with task initiation scores (B = 1.17; 95% CI, 0.47-1.87) and additional components of the metacognition index (eg, working memory, B = 1.20; 95% CI, 0.34-2.06), but not components of the behavioral regulation index. Conclusions Tobacco exposures during pregnancy (including low-level second-hand smoke) and childhood were associated with deficits in some domains of children’s executive function, especially task initiation and metacognition. These results highlight that decreasing early exposure to tobacco smoke, even second-hand exposure, may support ideal brain functioning. (J Pediatr 2019;-:1-7). See editorial, p
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espite the implementation of smoke-free policies and public health efforts to decrease tobacco use, the prevalence of cigarette smoking in the US remains high. Approximately 37.8 million adults smoke, and 7.2% of mothers smoke during pregnancy.1,2 Consequently, about 58 million fetal, child, and adult nonsmokers (including pregnant women) are exposed to second-hand tobacco smoke, representing a significant public health concern.3 The developing fetus and children may be particularly vulnerable to the harmful effects of tobacco smoke. In pregnant women who smoke, nicotine is detected in the amniotic fluid at levels 88% higher than maternal levels.4 Second-hand smoke exposure to the pregnant mother has been associated with low birth weight, preterm birth, asthma, and delayed language skills.5-17 In addition, later exposure to second-hand smoke during childhood has also been associated with some of the same consequences.18-21 Although parental reports suggest that 25% of US children are exposed to second-hand smoke in their homes, more objective biomarkers, like cotinine, indicate that 50% of US children are exposed to second-hand smoke.19,20 The documented associations between tobacco smoke exposure and child behavior and cognition are worrying.21,22 There is, however, limited research on the relationship of these exposures to a foundational ability partly underlying behaviors and cognition: executive functions. Executive functions refer to high-level processes responsible for goal-directed and From the Division of General and Community Pediatrics, problem-solving behaviors that facilitate goal setting, task switching, filtering Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, Cincinnati, OH; British distractions, and monitoring thoughts and behaviors.23 Core executive functions Columbia Children’s Hospital Research Institute and Faculty of Health Sciences, Simon Fraser University, include inhibition (eg, self-control), working memory, and cognitive flexibility. British Columbia, Canada; Division of Epidemiology, Department of Environmental Health, University of Generally, executive functions refer to a set of cognitive and behavioral skills that Cincinnati College of Medicine, Cincinnati, OH; Zilber are essential to success in school and life.24 Impairments in executive functions School of Public Health, University of WisconsinMilwaukee, Milwaukee, WI; and the Department of underlie clinical manifestations of some behavioral or cognitive deficits. Directly Pediatrics, Cincinnati Children’s Hospital Medical 1
2
3
4
5
Center, University of Cincinnati College of Medicine, Cincinnati, OH.
BASC-2 BRIEF BDI-II HOME
Behavior Assessment System for Children-2 Behavior Rating Inventory of Executive Function Beck Depression Inventory Health Outcomes and Measures of the Environment
Supported by the National Institutes of Health (P01ES11261, R01ES014575, and R01ES020349) and Health Resources and Services Administration T32 HP10027. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.11.032
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studying such impairments may help to resolve links with environmental exposures and shed light on the underlying pathology impacted. Piper and Corbett reported associations between maternal smoking in pregnancy and deficits in children’s executive function.24 They estimated tobacco exposure through maternal report, which is a less objective and inaccurate measure compared with biomarkers of exposure, like serum cotinine. In addition, because that study focused on children’s exposure via maternal smoking, their results do not elucidate whether exposure via second-hand smoke is associated with similar outcomes.25 Our objective was to investigate the associations between early life exposure to tobacco smoke and children’s behaviors and executive function. We improved on previous studies by using a more accurate and objective biomarker of children’s exposure relative to parents’ self-reported smoking, serum cotinine. Additionally, we examined children’s early exposures across distinct periods of early brain development to investigate the specific contribution of second-hand smoke exposure.
Methods We used data from the Health Outcomes and Measures of the Environment (HOME) Study, an ongoing prospective cohort study of environmental exposures.26 We enrolled pregnant women from the Cincinnati, Ohio, area from 2003 to 2006. Women from 9 prenatal clinics associated with 3 hospitals were identified and invited to the study after meeting the following criteria: (1) 16 3 weeks gestation; (2) >18 years of age; (3) HIV negative; and (4) not medicated for seizure or thyroid disorders. A total of 468 women enrolled in the study, 65 dropped out before delivery, and 3 were stillbirths. Of the 410 live births, 239 children (58%) had complete data through 8 years of age and were included in our analyses. The study protocol was approved by the Institutional Review Board at Cincinnati Children’s Hospital Medical Center. Prenatal and Postnatal Assessment We measured prenatal tobacco smoke exposure in 2 ways: maternal self-report and maternal serum cotinine. We measured childhood exposures using child serum cotinine. From pregnant women, we collected 3 serum samples: (at 16 and 26 weeks of gestation and at delivery) and from children, 4 serum samples (at ages 1, 2, 3, and 4 years) via venipuncture. All samples were stored at 20 C and shipped on dry ice to the Centers for Disease Control and Prevention Division of Laboratory Sciences. These were analyzed for cotinine using high-performance liquid chromatography-tandem mass spectrometry.27 To optimize statistical efficiency, for serum cotinine concentrations below the limit of detection (<0.015 ng/mL), we used the observed concentration rather than impute censored values.28 Prenatal exposure to lead was estimated using the mean of maternal whole blood samples obtained at 16 and 26 weeks of gestation and at 2
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delivery. We collected demographic information (child sex; maternal race, marital status, and education; and household income) during pregnancy and at delivery as covariates. Mothers also reported their use of tobacco products, exposure to second-hand smoke, and alcohol use while pregnant. Mothers completed both the Beck Depression Inventory (BDI-II) to measure maternal depression and the Wechsler Abbreviated Scale of Intelligence to measure maternal IQ.29,30 We also recorded the maternal age at delivery and quality of the home environment measured by the Home Observation for Measurement of the Environment Inventory when children were 1 year of age.31 Assessment at 8 Years of Age Caregivers completed the Behavior Assessment System for Children-2 (BASC-2) to measure children’s problem behaviors. The BASC-2 is a 160-item, valid, reliable measure of child behaviors in the home and community.32 We analyzed 3 composite scales from the BASC-2: externalizing problems (hyperactivity, aggression, conduct problems), internalizing problems (anxiety, depression, somatization), and the behavioral symptoms index (capturing overall levels of problem behaviors including atypicality, withdrawal, and attention problems). Caregivers also completed the Behavior Rating Inventory of Executive Function (BRIEF) to measure executive functions at 8 years of age. The BRIEF is a 86-item, valid, reliable measure of children’s executive function at home and school.33 The BRIEF produces subscale scores for several dimensions of executive function, as well as a composite score. The subscales are inhibit (inhibiting and resisting impulses), shift (easily moving between situations and activities), emotional control (modulating emotional responses), initiate (independently starting tasks and generating ideas), working memory (holding information in mind to complete tasks), plan/ organize (managing current and future demands), organization of materials (organizing work, play, and storage spaces), monitor (assessing his or her own work), behavioral regulation index (inhibit + shift + emotional control), metacognition index (initiate + working memory + plan/ organize + organization of materials + monitor), and global executive composite (summary score of all 8 scales). We converted raw scores from the BASC-2 to agestandardized T-scores, and raw scores from BRIEF to ageand sex-standardized T-scores, using publisher-supplied normative data. For both instruments, the T-scores have a mean of 50 10, and higher scores indicate more problems. Statistical Analyses We conducted univariate analyses to assess distributional assumptions, check missing data, and compute descriptive statistics. We calculated separate means for tobacco smoke exposure during pregnancy and childhood. We calculated pregnancy mean serum cotinine as the mean of maternal Oh et al
- 2019 serum cotinine concentrations at 16 and 26 weeks of gestation and delivery. Pearson correlations between log2 transformed maternal serum cotinine concentrations across these time points ranged from a r of 0.87 to 0.91. Pearson correlations between log2 transformed child cotinine measures at ages 1, 2, 3, and 4 years ranged from an r of 0.77 to 0.90. Given the stability of these values over time, we used the mean values of these concentrations in the following analyses. We excluded children from the analyses if they did not have serum cotinine measurements during childhood (n = 19). Serum cotinine concentrations had a log-normal distribution, thus we log-transformed the serum cotinine concentrations prior to analyses. A base of 2 was used for ease of interpretation; therefore, the beta estimates reported correspond to a doubling of serum cotinine concentration. We used separate multivariable regression models to examine the associations between both maternal and child mean serum cotinine with BASC-2 and BRIEF scores while adjusting for potential confounders (child sex, maternal race, marital status, education, household income, maternal alcohol use while pregnant, maternal depression, maternal IQ, maternal age at delivery, and Home Observation for Measurement of the Environment Inventory scores). We used a stepwise backward elimination method to obtain the most parsimonious models. During this process, we a priori included child sex and maternal race in all BASC-2 models, and maternal race in all BRIEF models. Other covariates were retained in the models if they were statistically significant (P < .05) or their removal resulted in >10% change in the beta estimate for maternal or child serum cotinine. We first obtained the most parsimonious model relating maternal mean cotinine and the Behavioral Symptoms Index, a composite score of the BASC-2, and then adjusted for the same set of covariates in the models examining the other BASC-2 scores. We chose the Behavioral Symptoms Index as the basis for modeling this association because it is the most comprehensive composite score of this assessment, incorporating six clinical subscales. The covariates included in the BASC-2 models were child sex, maternal race, marital status, and maternal BDI-II scores. We used a similar approach for the BRIEF. First, we obtained the most parsimonious model relating maternal mean cotinine and the global executive composite, a comprehensive composite score of the BRIEF that incorporates all subscales, and then adjusted for the same set of covariates (maternal race, education, marital status, and maternal BDI-II scores) in models examining the other BRIEF scores. Given the similarities in the covariates in models of BASC-2 and BRIEF scores, we additionally included maternal education in models of the BASC-2 and child sex in models of the BRIEF to improve the comparability of effect estimates between the two assessments, even though BRIEF scores are already standardized based on sex- and age-specific norms. The final set of covariates for both BASC and BRIEF models included child sex, maternal race, marital status, maternal education, and BDIII scores.
ORIGINAL ARTICLES Because primary smoking and second-hand smoke represent different chemical mixtures, we conducted a secondary analysis among children whose mothers were only exposed to second-hand smoke during pregnancy. We analyzed a subset of children (n = 208), excluding those whose mothers reported actively smoking during pregnancy, to assess the associations between pregnancy mean cotinine and BASC-2 and BRIEF outcomes, adjusting for the same set of covariates as the earlier models.
Results On most demographic characteristics, included children were not significantly different from excluded children (Table I). On average, mothers were 29.1 years of age at delivery, and 63.4% were married. Although only 28.2% of mothers reported any tobacco use or second-hand smoke exposure during pregnancy, 70.9% of mothers had detectable serum cotinine concentrations. Maternal mean cotinine during pregnancy ranged from 0.0005 to 291.7000 ng/mL, with a geometric mean of 0.0780 ng/mL. Similarly, whereas 24.1% of children were exposed to second-hand smoke by caregiver report, serum cotinine was above the limit of detection in 89.9% of children. Childhood mean cotinine ranged from 0.0002 to 20.2000 ng/mL, with a geometric mean of 0.126 ng/mL (Table II; available at www.jpeds.com). BASC-2 BASC-2 T-scores for the 3 composite scales (externalizing, internalizing, behavior symptoms index) all had a mean near 50 and a SD near 10, which is representative of the normal distribution for the measure and expected in this sample of typically developing children (Table III). With adjustment for covariates, we found no significant associations between maternal or child mean serum cotinine concentration and any of the BASC-2 scales (Table IV). BRIEF BRIEF T-scores had a mean near 50 and a SD near 10 (Table III), again representative of the normal distribution for the measure and expected in this sample. With adjustment for covariates (Table IV), we found that higher mean serum cotinine concentration during pregnancy was significantly associated with higher BRIEF subscale scores indicating poorer initiation (B = 0.44; 95% CI, 0.03-0.85; P = .038; Figure [available at www.jpeds.com]). Other subscales were elevated but did not meet thresholds for statistical significance, most notably the organization of materials (B = 0.43; 95% CI, 0.01 to 0.87; P = .059). Child mean serum cotinine concentration was also significantly associated with poorer initiation (B = 0.69; 95% CI, 0.061.32; P = .033; Figure), and a notable but nonsignificant association was found for poorer working memory (B = 0.76; 95% CI, 0.01 to 1.54; P = .055).
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Table I. Cohort characteristics of children included and not included in the current study Characteristics Child sex Male Female Maternal age at delivery (y) Maternal race Black Non-black Maternal marital status* Married Not married, living with partner Not married, living alone Maternal education High school or less Some college College graduate Graduate or professional Household income Maternal BDI-II* score Maternal IQ Home Observation for Measurment of the Environment score Reported prenatal tobacco smoke exposure Active smoker during pregnancy Passive exposure during pregnancy Any exposure during pregnancy No exposure Reported childhood tobacco smoke exposure Yes No Reported maternal alcohol use during pregnancy None <1 drink/month ³1 drink/month or binge
Included (n = 239)
Not included (n = 171)
106 (44.4) 133 (55.6) 29.1 5.9
84 (49.1) 87 (50.9) 29.7 5.5
80 (33.5) 159 (66.5)
45 (26.3) 121 (70.8)
151 (63.4) 28 (11.8)
115 (70.1) 28 (17.1)
59 (24.8)
21 (12.8)
59 (24.7) 65 (27.2) 70 (29.3) 44 (18.4)
36 (22.0) 35 (21.3) 48 (29.3) 45 (27.4)
$55k (18k, 85k) 9.9 6.4 105.7 15.0 39 5.2
$55k (28k, 85k) 9.8 7.5 106.8 13.5 40 4.000
31 (13.2)
18 (11.2)
56 (23.9)
36 (22.4)
66 (28.2)
43 (26.7)
168 (71.8)
118 (73.3)
57 (24.1) 180 (75.9)
N/A† N/A†
131 (55) 70 (29) 37 (16)
93 (57) 49 (30) 22 (13)
Values are number (%), (25th, 75th percentile), or mean SD. *Significantly different comparison between children included and those not included (P < .05). †Participants did not complete the age 8-year visit.
Secondary Analysis of Second-Hand Smoke Exposure during Pregnancy In our analysis among children of mothers who reported not smoking during pregnancy (n = 208), the mean serum cotinine concentration was associated with a wider range of outcomes. Once again, we found no significant associations between maternal serum cotinine concentration and any of the BASC-2 scales (Table V). However, higher maternal mean serum cotinine concentration was significantly associated with higher scores on both the metacognition index (B = 1.22; 95% CI, 0.44-2.00; P = .003) and the global executive composite (B = 1.05; 95% CI, 0.29-1.82; 4
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P = .007) as well as the individual scales of initiate (B = 1.17; 95% CI, 0.47-1.87; P = .001), working memory (B = 1.20; 95% CI, 0.34-2.06; P = .007), plan/organize (B = 1.20; 95% CI, 0.44-1.96; P = .002), and organization of materials (B = 0.98; 95% CI, 0.23-1.73; P = .011).
Discussion In this study, we found that children’s early exposure to tobacco smoke was associated with poorer executive function at age 8 years, even after adjustment for important covariates. The areas of executive function associated with these exposures included initiation, working memory, and organization. We observed similar associations when examining exposures during different windows of early brain development (ie, during pregnancy and early childhood) and after excluding women who reported actively smoking during pregnancy. However, excluding mothers who reported active smoking revealed the greatest number of associations between early exposure to tobacco smoke and children’s later executive functions. Our findings highlight associations between children’s early exposure to tobacco smoke and later deficits in executive function tasks using the BRIEF. Specifically, early exposure to tobacco smoke was associated with scores in the area of initiation (ie, the ability to independently begin tasks and generate ideas), the organization of materials (ie, the ability to organize work, play, and storage spaces), and working memory (ie, the ability to retain critical information and complete specific tasks). These results are consistent with results reported by Piper and Corbett, who previously used the BRIEF to assess executive function in relation to pregnant mothers’ active smoking.24 Piper and Corbett also identified significantly higher scores on the BRIEF initiate scale when comparing children with high vs no exposure to prenatal tobacco smoke. They also identified additional elevated scores on the plan/
Table III. BASC-2 and BRIEF scores at 8 years of age (n = 239) Variables BASC-2 Externalizing problems Internalizing problems Behavioral symptoms index BRIEF Inhibit Shift Emotional control Initiate Working memory Plan/organization Organization of materials Monitor Behavioral regulation index Metacognition index Global executive composite
Minimum
Maximum
Mean
SD
32 31 31
90 81 80
49.5 48.3 49.7
9.4 8.8 9.0
36 36 35 35 35 33 32 28 33 31 31
83 91 78 79 86 85 73 81 79 83 84
49.1 47.3 47.4 48.6 51.0 48.4 48.8 46.3 47.6 48.4 48.1
10.0 9.9 9.9 9.6 11.7 10.9 10.2 10.7 9.9 10.9 10.6
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Table IV. Adjusted* change in BASC-2 and BRIEF scores for each doubling of serum cotinine concentration Maternal mean serum cotinine B
Variables BASC-2 Externalizing problems Internalizing problems Behavioral symptoms index BRIEF Inhibit Shift Emotional control Initiate Working memory Plan/organize Organization of materials Monitor Behavioral regulation index Metacognition index Global executive composite
95% CI
Child mean serum cotinine P value
B
95% CI
P value
0.05 0.23 0.01
0.35 to 0.44 0.61 to 0.15 0.37 to 0.39
.814 .241 .964
0.23 0.06 0.46
0.36 to 0.83 0.51 to 0.63 0.11 to 1.04
.443 .839 .117
0.19 0.11 0.09 0.44 0.35 0.36 0.43 0.09 0.07 0.34 0.26
0.24 to 0.62 0.32 to 0.54 0.52 to 0.35 0.03 to 0.85 0.15 to 0.86 0.09 to 0.82 0.01 to 0.87 0.55 to 0.38 0.35 to 0.49 0.12 to 0.81 0.19 to 0.71
.383 .622 .700 .038 .163 .115 .059 .715 .749 .146 .256
0.12 0.24 0.02 0.69 0.76 0.28 0.53 0.03 0.09 0.54 0.40
0.54 to 0.79 0.42 to 0.9 0.69 to 0.64 0.06 to 1.32 0.01 to 1.54 0.42 to 0.98 0.15 to 1.21 0.69 to 0.74 0.55 to 0.74 0.18 to 1.25 0.29 to 1.08
.715 .475 .950 .033 .055 .427 .131 .943 .777 .143 .256
Boldface values indicate statistically significant associations. *All models adjusted for child sex, maternal race, education, marital status, and maternal depression (measured with the BDI-II).
organize, and monitor subscales, whereas our results for prenatal exposures identified impairments only on the initiate subscale. These discrepancies could result from a number of factors, including random error, our quantitative measurement of serum cotinine (which is more accurate than the self-reported measures of exposure used by Piper and Corbett), or differences in prenatal exposure between the study samples (where they included direct maternal smoking and we included all sources of tobacco smoke exposure during pregnancy, dominated by second-hand smoke).24 In addition, we adjusted for maternal race and maternal depression in our analyses; these covariates were not considered by
Table V. Secondary analysis: adjusted* change in BASC-2 and BRIEF scores for each doubling of serum cotinine concentration among children with mothers who were not self-reported active smokers during pregnancy (n = 208) Maternal mean serum cotinines BASC-2 Externalizing problems Internalizing problems Behavioral symptoms index BRIEF Inhibit Shift Emotional control Initiate Working memory Plan/organize Organization of materials Monitor Behavioral regulation index Metacognition index Global executive composite
B
95% CI
P value
0.45 0.07 0.53
0.21 to 1.12 0.58 to 0.72 0.11 to 1.18
.181 .839 .108
0.74 0.48 0.37 1.17 1.20 1.20 0.98 0.70 0.61 1.22 1.05
0.07 to 1.48 0.26 to 1.22 0.38 to 1.12 0.47 to 1.87 0.34 to 2.06 0.44 to 1.96 0.23 to 1.73 0.08 to 1.47 0.12 to 1.34 0.44 to 2.00 0.29 to 1.82
.053 .205 .339 .001 .007 .002 .011 .078 .105 .003 .007
Boldface values indicate statistically significant associations. *All models adjusted for child sex, maternal race, education, marital status, and maternal depression (measured with the BDI-II).
Piper and Corbett.24 Overall, our findings and those of Piper and Corbett reveal similar associations between early life exposure to tobacco smoke and later deficits in executive functions. Our findings also provide some evidence that mother’s exposure to second-hand smoke during pregnancy may impair children’s later executive functions. In our secondary analysis, we excluded children whose mothers reported that they were active smokers during pregnancy. In addition to replicating the pattern of findings in our primary analysis, we observed significant associations with several additional dimensions of executive function (working memory, plan/ organize, the organization of materials, and significant associations with the composite metacognition and global executive composite indexes), and the overall effect sizes were larger. It is possible that this pattern emerged because including active smokers in the primary analysis did not account for unidentified confounding that masked the associations we observed after excluding active smokers. Assuming a causal effect of exposure to tobacco smoke on executive functions, it is possible that the greatest magnitude of impairments to executive functions occur with increases in the lowest levels of exposure. Indeed, this phenomenon has been reported previously for impairments to cognitive functions and associations with exposure to both second-hand smoke and lead during childhood.18,34 However, our sample may not be ideal for exploring this possibility given that our overall cotinine concentrations tended to be low. Nevertheless, our study was well-suited to study prenatal exposure to second-hand smoke because of the relatively small number of mothers who actively smoked and the inclusion of multiple measures of cotinine in pregnancy, capturing multiple sources of tobacco exposures. Overall, the associations we observed between tobacco smoke exposure and executive function were modest. Our largest detected association for pregnancy second-hand
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smoke exposure was a 1.22 score increase per each doubling of serum cotinine. This would reflect a change of 4.28 points for a change reflecting the interquartile range of this population, from 0.011 ng/mL (25th percentile of cotinine) to 0.123 ng/mL (75th percentile of cotinine), which is close to one-half a SD for the BRIEF. Bellinger notes that even slight effects of exposure may have a substantial impact at the population level by progressively shifting the population distribution of neurobehavioral traits.5 At the population level, this can increase the risk of neurodevelopmental disorders, such as learning disabilities. Because 90% of children in our sample had detectable exposure to second-hand smoke, this finding suggests that the majority of children regularly come into contact with second-hand smoke. Thus, our findings provide support for the implementation of policies to eliminate maternal smoking during pregnancy and to minimize children’s exposure to second-hand smoke during childhood. There are several limitations in our study. First, in this cohort study we can only report associations and cannot conclude a causal relationship between our measured variables. Second, our moderately sized sample (n = 239) may have limited our ability to detect associations between early exposure to tobacco smoke, child behaviors, and other domains of executive function. For example, a previous study documenting an association between early exposure to tobacco smoke and child behaviors used a sample of 1265 children, >5 times our sample.21 Third, although we adjusted for a variety of potential confounders, additional unmeasured covariates or confounders like substance use, psychosocial factors, or life experiences occurring between the ages of 4 and 8 years may explain some of our observed associations. It is also possible that other measures of either behavior or executive function that do not depend on parental report would show larger or smaller associations with exposure to tobacco smoke. Finally, we found that childhood tobacco exposures had a similar association with executive function as prenatal exposures. Still, it is possible that childhood exposures were partially confounded by prenatal exposures. This may occur because women who smoke during pregnancy may continue to smoke after delivery, leading to our observed collinearity between pregnancy and child mean serum cotinine concentrations (r = 0.79), so that we were not able to simultaneously adjust childhood associations for prenatal exposure to tobacco smoke. The results of this study suggest that early exposure to tobacco smoke, both during pregnancy and childhood, is associated with later deficits in children’s executive function. The specific executive function skills that were affected—task initiation, working memory, the planning/organization of tasks, and the organization of materials—are components of metacognition: a higher-level cognitive ability essential for monitoring and controlling thoughts.23 In contrast, we found no significant associations with behavioral regulation aspects of executive function. Thus, our findings are consistent with the possibility that tobacco smoke exhibits greater 6
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deleterious effects on metacognitive executive functions than on behavioral regulation. These findings highlight the need to increase public awareness to protect pregnant women and developing fetuses from tobacco smoke. This need is emphasized by the high prevalence of detectable tobacco smoke exposure in this sample, even at low levels, and significant associations between exposure levels and later executive functions. Future studies examining similar associations across cultural and geographic boundaries are needed to determine the generalizability of these findings. In addition, similar investigations in larger samples will help to assess the robustness of the more marginal associations we observed, and to corroborate our conclusion that early exposure to tobacco smoke is negatively associated with children’s executive functions. n We thank the staff and participants of the HOME Study and the Tobacco Laboratory at the Centers for Disease Control and Prevention for their contributions to this research. Submitted for publication Jul 22, 2019; last revision received Oct 31, 2019; accepted Nov 20, 2019. Reprint requests: Brandon F. Terrizzi, MS, PhD, 3333 Burnet Ave, Cincinnati, OH 45229. E-mail: [email protected]
Data Statement Data sharing statement available at www.jpeds.com.
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- 2019 12. US Department of Health and Human Services. The health consequences of involuntary exposure to tobacco smoke: a report of the surgeon general. Atlanta: Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2006. 13. Shariat M, Gharaee J, Dalili H, Mohammadzadeh Y, Ansari S, Farahani Z. Association between small for gestational age and low birth weight with attention deficit and impaired executive functions in 3-6 years old children. J Matern Fetal Neonatal Med 2019;32:1474-7. 14. Simons E, To T, Moineddin R, Stieb D, Dell SD. Maternal second-hand smoke exposure in pregnancy is associated with childhood asthma development. J Allergy Clin Immunol Pract 2014;2:201-7.e203. 15. Steyn K, de Wet T, Saloojee Y, Nel H, Yach D. The influence of maternal cigarette smoking, snuff use and passive smoking on pregnancy outcomes: the Birth To Ten Study. Paediatr Perinat Epidemiol 2006;20:90-9. 16. Kabir Z, Connolly GN, Alpert HR. Secondhand smoke exposure and neurobehavioral disorders among children in the United States. Pediatrics 2011;128:263-70. 17. Yolton K, Dietrich K, Auinger P, Lanphear BP, Hornung R. Exposure to environmental tobacco smoke and cognitive abilities among US children and adolescents. Environ Health Perspect 2005;113:98. 18. Soliman S, Pollack HA, Warner KE. Decrease in the prevalence of environmental tobacco smoke exposure in the home during the 1990s in families with children. Am J Public Health 2004;94:314-20. 19. Pirkle JL, Bernert JT, Caudill SP, Sosnoff CS, Pechacek TF. Trends in the exposure of nonsmokers in the US population to secondhand smoke: 1988–2002. Environ Health Perspect 2006;114:853. 20. Fergusson DM, Horwood LJ, Lynskey MT. Maternal smoking before and after pregnancy: effects on behavioral outcomes in middle childhood. Pediatrics 1993;92:815-22. 21. Park S, Cho SC, Hong YC, Kim JW, Shin MS, Yoo HJ, et al. Environmental tobacco smoke exposure and children’s intelligence at 8–11 years of age. Environ Health Perspect 2014;122:1123-8.
ORIGINAL ARTICLES 22. Gerard A, Gioia PKI, Guy SC, Kenworthy L. Behavior Rating Inventory of Executive Function Professional Manual. Lutz (FL): PAR; 1996. 23. Diamond A. Executive functions. Annu Rev Psychol 2013;64:135-68. 24. Piper BJ, Corbett SM. Executive function profile in the offspring of women that smoked during pregnancy. Nicotine Tob Res 2011;14: 191-9. 25. Benowitz NL. Cotinine as a biomarker of environmental tobacco smoke exposure. Epidemiol Rev 1996;18:188-204. 26. Braun JM, Kalloo G, Chen A, Dietrich KN, Liddy-Hicks S, Morgan S, et al. Cohort profile: the Health Outcomes and Measures of the Environment (HOME) study. Int J Epidemiol 2017;46:24. 27. Bernert JT, McGuffey JE, Morrison MA, Pirkle JL. Comparison of serum and salivary cotinine measurements by a sensitive high-performance liquid chromatography-tandem mass spectrometry method as an indicator of exposure to tobacco smoke among smokers and nonsmokers. J Anal Toxicol 2000;24:333-9. 28. Cole SR, Chu H, Nie L, Schisterman EF. Estimating the odds ratio when exposure has a limit of detection. Int J Epidemiol 2009;38:1674-80. 29. Beck AT, Steer RA, Brown GK. Beck depression inventory-II. San Antonio (TX): The Psychological Corporation; 1996. 30. Wechsler W. Wechsler abbreviated scale of intelligence. San Antonio (TX): The Psychological Corporation; 1999. 31. Caldwell BM, Bradley RR. Home observation for the measured environment. Little Rock: University of Arkansas at Little Rock; 1984. 32. System for children (BASC-2) handout. Circle Pines, MN: AGS Publishing; 2004. 33. Gioia GA. Behavior Rating Inventory of Executive Function: professional manual. Lutz (FL): Psychological Assessment Resources, Incorporated; 2000. 34. Lanphear BP, Hornung R, Khoury J, Yolton K, Baghurst P, Bellinger DC, et al. Low-level environmental lead exposure and children’s intellectual function: an international pooled analysis. Environ Health Perspect 2005;113:894-9.
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Figure. Bivariate association between mean prenatal maternal and child serum cotinine concentrations (ng/mL) and T-scores on the BRIEF’s Initiate subscale.
Table II. Serum cotinine concentrations (ng/mL) in maternal and child samples Variables Maternal cotinine (prenatal) 16 weeks 26 weeks Delivery Prenatal mean Child cotinine (postnatal) 1 year 2 years 3 years 4 years Postnatal mean
No.
Minimum
Maximum
Geometric mean (95% CI)
%>LOD*
%>3†
234 229 211 239
0 0 0 0.0005
349.0 252.0 282.0 291.7
0.075 (0.052-0.106) 0.06 (0.041-0.088) 0.05 (0.035-0.073) 0.078 (0.055-0.109)
70.9 65.5 61.1 70.2
9.8 10.9 10.0 11.3
186 147 157 128 238
0 0 0.002 0.003 0.002
35.3 10.5 21.6 14.9 20.2
0.114 (0.085-0.153) 0.094 (0.068-0.13) 0.071 (0.052-0.097) 0.06 (0.043-0.084) 0.126 (0.098-0.162)
89.2 89.8 77.1 75.8 89.9
7.5 6.8 7.0 3.1 7.1
*Limit of detection (LOD) = 0.015 ng/mL. †A value of 3 ng/mL is commonly used as an indicator of active smoking.
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Study design We studied 239 children in a prospective birth cohort. We measured tobacco exposures by caregiver report and serum cotinine 3 times during pregnancy and 4 times during childhood. We used linear regression to examine the association between prenatal and childhood serum cotinine concentrations and behavior (the Behavior Assessment System for Children-2) and executive function (the Behavior Rating Inventory of Executive Function) at age 8 years while adjusting for important covariates. Results Neither prenatal nor child serum cotinine were associated with behavior problems measured by the Behavior Assessment System for Children-2. On the Behavior Rating Inventory of Executive Function, prenatal and childhood exposure was associated with poorer task initiation scores (B = 0.44; 95% CI, 0.03-0.85 and B = 0.69, 95% CI, 0.06-1.32 respectively). Additionally, in a subset of 208 children with nonsmoking mothers, prenatal exposure was associated with task initiation scores (B = 1.17; 95% CI, 0.47-1.87) and additional components of the metacognition index (eg, working memory, B = 1.20; 95% CI, 0.34-2.06), but not components of the behavioral regulation index. Conclusions Tobacco exposures during pregnancy (including low-level second-hand smoke) and childhood were associated with deficits in some domains of children’s executive function, especially task initiation and metacognition. These results highlight that decreasing early exposure to tobacco smoke, even second-hand exposure, may support ideal brain functioning. (J Pediatr 2019;-:1-7). See editorial, p
D
espite the implementation of smoke-free policies and public health efforts to decrease tobacco use, the prevalence of cigarette smoking in the US remains high. Approximately 37.8 million adults smoke, and 7.2% of mothers smoke during pregnancy.1,2 Consequently, about 58 million fetal, child, and adult nonsmokers (including pregnant women) are exposed to second-hand tobacco smoke, representing a significant public health concern.3 The developing fetus and children may be particularly vulnerable to the harmful effects of tobacco smoke. In pregnant women who smoke, nicotine is detected in the amniotic fluid at levels 88% higher than maternal levels.4 Second-hand smoke exposure to the pregnant mother has been associated with low birth weight, preterm birth, asthma, and delayed language skills.5-17 In addition, later exposure to second-hand smoke during childhood has also been associated with some of the same consequences.18-21 Although parental reports suggest that 25% of US children are exposed to second-hand smoke in their homes, more objective biomarkers, like cotinine, indicate that 50% of US children are exposed to second-hand smoke.19,20 The documented associations between tobacco smoke exposure and child behavior and cognition are worrying.21,22 There is, however, limited research on the relationship of these exposures to a foundational ability partly underlying behaviors and cognition: executive functions. Executive functions refer to high-level processes responsible for goal-directed and From the Division of General and Community Pediatrics, problem-solving behaviors that facilitate goal setting, task switching, filtering Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, Cincinnati, OH; British distractions, and monitoring thoughts and behaviors.23 Core executive functions Columbia Children’s Hospital Research Institute and Faculty of Health Sciences, Simon Fraser University, include inhibition (eg, self-control), working memory, and cognitive flexibility. British Columbia, Canada; Division of Epidemiology, Department of Environmental Health, University of Generally, executive functions refer to a set of cognitive and behavioral skills that Cincinnati College of Medicine, Cincinnati, OH; Zilber are essential to success in school and life.24 Impairments in executive functions School of Public Health, University of WisconsinMilwaukee, Milwaukee, WI; and the Department of underlie clinical manifestations of some behavioral or cognitive deficits. Directly Pediatrics, Cincinnati Children’s Hospital Medical 1
2
3
4
5
Center, University of Cincinnati College of Medicine, Cincinnati, OH.
BASC-2 BRIEF BDI-II HOME
Behavior Assessment System for Children-2 Behavior Rating Inventory of Executive Function Beck Depression Inventory Health Outcomes and Measures of the Environment
Supported by the National Institutes of Health (P01ES11261, R01ES014575, and R01ES020349) and Health Resources and Services Administration T32 HP10027. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.11.032
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studying such impairments may help to resolve links with environmental exposures and shed light on the underlying pathology impacted. Piper and Corbett reported associations between maternal smoking in pregnancy and deficits in children’s executive function.24 They estimated tobacco exposure through maternal report, which is a less objective and inaccurate measure compared with biomarkers of exposure, like serum cotinine. In addition, because that study focused on children’s exposure via maternal smoking, their results do not elucidate whether exposure via second-hand smoke is associated with similar outcomes.25 Our objective was to investigate the associations between early life exposure to tobacco smoke and children’s behaviors and executive function. We improved on previous studies by using a more accurate and objective biomarker of children’s exposure relative to parents’ self-reported smoking, serum cotinine. Additionally, we examined children’s early exposures across distinct periods of early brain development to investigate the specific contribution of second-hand smoke exposure.
Methods We used data from the Health Outcomes and Measures of the Environment (HOME) Study, an ongoing prospective cohort study of environmental exposures.26 We enrolled pregnant women from the Cincinnati, Ohio, area from 2003 to 2006. Women from 9 prenatal clinics associated with 3 hospitals were identified and invited to the study after meeting the following criteria: (1) 16 3 weeks gestation; (2) >18 years of age; (3) HIV negative; and (4) not medicated for seizure or thyroid disorders. A total of 468 women enrolled in the study, 65 dropped out before delivery, and 3 were stillbirths. Of the 410 live births, 239 children (58%) had complete data through 8 years of age and were included in our analyses. The study protocol was approved by the Institutional Review Board at Cincinnati Children’s Hospital Medical Center. Prenatal and Postnatal Assessment We measured prenatal tobacco smoke exposure in 2 ways: maternal self-report and maternal serum cotinine. We measured childhood exposures using child serum cotinine. From pregnant women, we collected 3 serum samples: (at 16 and 26 weeks of gestation and at delivery) and from children, 4 serum samples (at ages 1, 2, 3, and 4 years) via venipuncture. All samples were stored at 20 C and shipped on dry ice to the Centers for Disease Control and Prevention Division of Laboratory Sciences. These were analyzed for cotinine using high-performance liquid chromatography-tandem mass spectrometry.27 To optimize statistical efficiency, for serum cotinine concentrations below the limit of detection (<0.015 ng/mL), we used the observed concentration rather than impute censored values.28 Prenatal exposure to lead was estimated using the mean of maternal whole blood samples obtained at 16 and 26 weeks of gestation and at 2
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delivery. We collected demographic information (child sex; maternal race, marital status, and education; and household income) during pregnancy and at delivery as covariates. Mothers also reported their use of tobacco products, exposure to second-hand smoke, and alcohol use while pregnant. Mothers completed both the Beck Depression Inventory (BDI-II) to measure maternal depression and the Wechsler Abbreviated Scale of Intelligence to measure maternal IQ.29,30 We also recorded the maternal age at delivery and quality of the home environment measured by the Home Observation for Measurement of the Environment Inventory when children were 1 year of age.31 Assessment at 8 Years of Age Caregivers completed the Behavior Assessment System for Children-2 (BASC-2) to measure children’s problem behaviors. The BASC-2 is a 160-item, valid, reliable measure of child behaviors in the home and community.32 We analyzed 3 composite scales from the BASC-2: externalizing problems (hyperactivity, aggression, conduct problems), internalizing problems (anxiety, depression, somatization), and the behavioral symptoms index (capturing overall levels of problem behaviors including atypicality, withdrawal, and attention problems). Caregivers also completed the Behavior Rating Inventory of Executive Function (BRIEF) to measure executive functions at 8 years of age. The BRIEF is a 86-item, valid, reliable measure of children’s executive function at home and school.33 The BRIEF produces subscale scores for several dimensions of executive function, as well as a composite score. The subscales are inhibit (inhibiting and resisting impulses), shift (easily moving between situations and activities), emotional control (modulating emotional responses), initiate (independently starting tasks and generating ideas), working memory (holding information in mind to complete tasks), plan/ organize (managing current and future demands), organization of materials (organizing work, play, and storage spaces), monitor (assessing his or her own work), behavioral regulation index (inhibit + shift + emotional control), metacognition index (initiate + working memory + plan/ organize + organization of materials + monitor), and global executive composite (summary score of all 8 scales). We converted raw scores from the BASC-2 to agestandardized T-scores, and raw scores from BRIEF to ageand sex-standardized T-scores, using publisher-supplied normative data. For both instruments, the T-scores have a mean of 50 10, and higher scores indicate more problems. Statistical Analyses We conducted univariate analyses to assess distributional assumptions, check missing data, and compute descriptive statistics. We calculated separate means for tobacco smoke exposure during pregnancy and childhood. We calculated pregnancy mean serum cotinine as the mean of maternal Oh et al
- 2019 serum cotinine concentrations at 16 and 26 weeks of gestation and delivery. Pearson correlations between log2 transformed maternal serum cotinine concentrations across these time points ranged from a r of 0.87 to 0.91. Pearson correlations between log2 transformed child cotinine measures at ages 1, 2, 3, and 4 years ranged from an r of 0.77 to 0.90. Given the stability of these values over time, we used the mean values of these concentrations in the following analyses. We excluded children from the analyses if they did not have serum cotinine measurements during childhood (n = 19). Serum cotinine concentrations had a log-normal distribution, thus we log-transformed the serum cotinine concentrations prior to analyses. A base of 2 was used for ease of interpretation; therefore, the beta estimates reported correspond to a doubling of serum cotinine concentration. We used separate multivariable regression models to examine the associations between both maternal and child mean serum cotinine with BASC-2 and BRIEF scores while adjusting for potential confounders (child sex, maternal race, marital status, education, household income, maternal alcohol use while pregnant, maternal depression, maternal IQ, maternal age at delivery, and Home Observation for Measurement of the Environment Inventory scores). We used a stepwise backward elimination method to obtain the most parsimonious models. During this process, we a priori included child sex and maternal race in all BASC-2 models, and maternal race in all BRIEF models. Other covariates were retained in the models if they were statistically significant (P < .05) or their removal resulted in >10% change in the beta estimate for maternal or child serum cotinine. We first obtained the most parsimonious model relating maternal mean cotinine and the Behavioral Symptoms Index, a composite score of the BASC-2, and then adjusted for the same set of covariates in the models examining the other BASC-2 scores. We chose the Behavioral Symptoms Index as the basis for modeling this association because it is the most comprehensive composite score of this assessment, incorporating six clinical subscales. The covariates included in the BASC-2 models were child sex, maternal race, marital status, and maternal BDI-II scores. We used a similar approach for the BRIEF. First, we obtained the most parsimonious model relating maternal mean cotinine and the global executive composite, a comprehensive composite score of the BRIEF that incorporates all subscales, and then adjusted for the same set of covariates (maternal race, education, marital status, and maternal BDI-II scores) in models examining the other BRIEF scores. Given the similarities in the covariates in models of BASC-2 and BRIEF scores, we additionally included maternal education in models of the BASC-2 and child sex in models of the BRIEF to improve the comparability of effect estimates between the two assessments, even though BRIEF scores are already standardized based on sex- and age-specific norms. The final set of covariates for both BASC and BRIEF models included child sex, maternal race, marital status, maternal education, and BDIII scores.
ORIGINAL ARTICLES Because primary smoking and second-hand smoke represent different chemical mixtures, we conducted a secondary analysis among children whose mothers were only exposed to second-hand smoke during pregnancy. We analyzed a subset of children (n = 208), excluding those whose mothers reported actively smoking during pregnancy, to assess the associations between pregnancy mean cotinine and BASC-2 and BRIEF outcomes, adjusting for the same set of covariates as the earlier models.
Results On most demographic characteristics, included children were not significantly different from excluded children (Table I). On average, mothers were 29.1 years of age at delivery, and 63.4% were married. Although only 28.2% of mothers reported any tobacco use or second-hand smoke exposure during pregnancy, 70.9% of mothers had detectable serum cotinine concentrations. Maternal mean cotinine during pregnancy ranged from 0.0005 to 291.7000 ng/mL, with a geometric mean of 0.0780 ng/mL. Similarly, whereas 24.1% of children were exposed to second-hand smoke by caregiver report, serum cotinine was above the limit of detection in 89.9% of children. Childhood mean cotinine ranged from 0.0002 to 20.2000 ng/mL, with a geometric mean of 0.126 ng/mL (Table II; available at www.jpeds.com). BASC-2 BASC-2 T-scores for the 3 composite scales (externalizing, internalizing, behavior symptoms index) all had a mean near 50 and a SD near 10, which is representative of the normal distribution for the measure and expected in this sample of typically developing children (Table III). With adjustment for covariates, we found no significant associations between maternal or child mean serum cotinine concentration and any of the BASC-2 scales (Table IV). BRIEF BRIEF T-scores had a mean near 50 and a SD near 10 (Table III), again representative of the normal distribution for the measure and expected in this sample. With adjustment for covariates (Table IV), we found that higher mean serum cotinine concentration during pregnancy was significantly associated with higher BRIEF subscale scores indicating poorer initiation (B = 0.44; 95% CI, 0.03-0.85; P = .038; Figure [available at www.jpeds.com]). Other subscales were elevated but did not meet thresholds for statistical significance, most notably the organization of materials (B = 0.43; 95% CI, 0.01 to 0.87; P = .059). Child mean serum cotinine concentration was also significantly associated with poorer initiation (B = 0.69; 95% CI, 0.061.32; P = .033; Figure), and a notable but nonsignificant association was found for poorer working memory (B = 0.76; 95% CI, 0.01 to 1.54; P = .055).
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Table I. Cohort characteristics of children included and not included in the current study Characteristics Child sex Male Female Maternal age at delivery (y) Maternal race Black Non-black Maternal marital status* Married Not married, living with partner Not married, living alone Maternal education High school or less Some college College graduate Graduate or professional Household income Maternal BDI-II* score Maternal IQ Home Observation for Measurment of the Environment score Reported prenatal tobacco smoke exposure Active smoker during pregnancy Passive exposure during pregnancy Any exposure during pregnancy No exposure Reported childhood tobacco smoke exposure Yes No Reported maternal alcohol use during pregnancy None <1 drink/month ³1 drink/month or binge
Included (n = 239)
Not included (n = 171)
106 (44.4) 133 (55.6) 29.1 5.9
84 (49.1) 87 (50.9) 29.7 5.5
80 (33.5) 159 (66.5)
45 (26.3) 121 (70.8)
151 (63.4) 28 (11.8)
115 (70.1) 28 (17.1)
59 (24.8)
21 (12.8)
59 (24.7) 65 (27.2) 70 (29.3) 44 (18.4)
36 (22.0) 35 (21.3) 48 (29.3) 45 (27.4)
$55k (18k, 85k) 9.9 6.4 105.7 15.0 39 5.2
$55k (28k, 85k) 9.8 7.5 106.8 13.5 40 4.000
31 (13.2)
18 (11.2)
56 (23.9)
36 (22.4)
66 (28.2)
43 (26.7)
168 (71.8)
118 (73.3)
57 (24.1) 180 (75.9)
N/A† N/A†
131 (55) 70 (29) 37 (16)
93 (57) 49 (30) 22 (13)
Values are number (%), (25th, 75th percentile), or mean SD. *Significantly different comparison between children included and those not included (P < .05). †Participants did not complete the age 8-year visit.
Secondary Analysis of Second-Hand Smoke Exposure during Pregnancy In our analysis among children of mothers who reported not smoking during pregnancy (n = 208), the mean serum cotinine concentration was associated with a wider range of outcomes. Once again, we found no significant associations between maternal serum cotinine concentration and any of the BASC-2 scales (Table V). However, higher maternal mean serum cotinine concentration was significantly associated with higher scores on both the metacognition index (B = 1.22; 95% CI, 0.44-2.00; P = .003) and the global executive composite (B = 1.05; 95% CI, 0.29-1.82; 4
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P = .007) as well as the individual scales of initiate (B = 1.17; 95% CI, 0.47-1.87; P = .001), working memory (B = 1.20; 95% CI, 0.34-2.06; P = .007), plan/organize (B = 1.20; 95% CI, 0.44-1.96; P = .002), and organization of materials (B = 0.98; 95% CI, 0.23-1.73; P = .011).
Discussion In this study, we found that children’s early exposure to tobacco smoke was associated with poorer executive function at age 8 years, even after adjustment for important covariates. The areas of executive function associated with these exposures included initiation, working memory, and organization. We observed similar associations when examining exposures during different windows of early brain development (ie, during pregnancy and early childhood) and after excluding women who reported actively smoking during pregnancy. However, excluding mothers who reported active smoking revealed the greatest number of associations between early exposure to tobacco smoke and children’s later executive functions. Our findings highlight associations between children’s early exposure to tobacco smoke and later deficits in executive function tasks using the BRIEF. Specifically, early exposure to tobacco smoke was associated with scores in the area of initiation (ie, the ability to independently begin tasks and generate ideas), the organization of materials (ie, the ability to organize work, play, and storage spaces), and working memory (ie, the ability to retain critical information and complete specific tasks). These results are consistent with results reported by Piper and Corbett, who previously used the BRIEF to assess executive function in relation to pregnant mothers’ active smoking.24 Piper and Corbett also identified significantly higher scores on the BRIEF initiate scale when comparing children with high vs no exposure to prenatal tobacco smoke. They also identified additional elevated scores on the plan/
Table III. BASC-2 and BRIEF scores at 8 years of age (n = 239) Variables BASC-2 Externalizing problems Internalizing problems Behavioral symptoms index BRIEF Inhibit Shift Emotional control Initiate Working memory Plan/organization Organization of materials Monitor Behavioral regulation index Metacognition index Global executive composite
Minimum
Maximum
Mean
SD
32 31 31
90 81 80
49.5 48.3 49.7
9.4 8.8 9.0
36 36 35 35 35 33 32 28 33 31 31
83 91 78 79 86 85 73 81 79 83 84
49.1 47.3 47.4 48.6 51.0 48.4 48.8 46.3 47.6 48.4 48.1
10.0 9.9 9.9 9.6 11.7 10.9 10.2 10.7 9.9 10.9 10.6
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Table IV. Adjusted* change in BASC-2 and BRIEF scores for each doubling of serum cotinine concentration Maternal mean serum cotinine B
Variables BASC-2 Externalizing problems Internalizing problems Behavioral symptoms index BRIEF Inhibit Shift Emotional control Initiate Working memory Plan/organize Organization of materials Monitor Behavioral regulation index Metacognition index Global executive composite
95% CI
Child mean serum cotinine P value
B
95% CI
P value
0.05 0.23 0.01
0.35 to 0.44 0.61 to 0.15 0.37 to 0.39
.814 .241 .964
0.23 0.06 0.46
0.36 to 0.83 0.51 to 0.63 0.11 to 1.04
.443 .839 .117
0.19 0.11 0.09 0.44 0.35 0.36 0.43 0.09 0.07 0.34 0.26
0.24 to 0.62 0.32 to 0.54 0.52 to 0.35 0.03 to 0.85 0.15 to 0.86 0.09 to 0.82 0.01 to 0.87 0.55 to 0.38 0.35 to 0.49 0.12 to 0.81 0.19 to 0.71
.383 .622 .700 .038 .163 .115 .059 .715 .749 .146 .256
0.12 0.24 0.02 0.69 0.76 0.28 0.53 0.03 0.09 0.54 0.40
0.54 to 0.79 0.42 to 0.9 0.69 to 0.64 0.06 to 1.32 0.01 to 1.54 0.42 to 0.98 0.15 to 1.21 0.69 to 0.74 0.55 to 0.74 0.18 to 1.25 0.29 to 1.08
.715 .475 .950 .033 .055 .427 .131 .943 .777 .143 .256
Boldface values indicate statistically significant associations. *All models adjusted for child sex, maternal race, education, marital status, and maternal depression (measured with the BDI-II).
organize, and monitor subscales, whereas our results for prenatal exposures identified impairments only on the initiate subscale. These discrepancies could result from a number of factors, including random error, our quantitative measurement of serum cotinine (which is more accurate than the self-reported measures of exposure used by Piper and Corbett), or differences in prenatal exposure between the study samples (where they included direct maternal smoking and we included all sources of tobacco smoke exposure during pregnancy, dominated by second-hand smoke).24 In addition, we adjusted for maternal race and maternal depression in our analyses; these covariates were not considered by
Table V. Secondary analysis: adjusted* change in BASC-2 and BRIEF scores for each doubling of serum cotinine concentration among children with mothers who were not self-reported active smokers during pregnancy (n = 208) Maternal mean serum cotinines BASC-2 Externalizing problems Internalizing problems Behavioral symptoms index BRIEF Inhibit Shift Emotional control Initiate Working memory Plan/organize Organization of materials Monitor Behavioral regulation index Metacognition index Global executive composite
B
95% CI
P value
0.45 0.07 0.53
0.21 to 1.12 0.58 to 0.72 0.11 to 1.18
.181 .839 .108
0.74 0.48 0.37 1.17 1.20 1.20 0.98 0.70 0.61 1.22 1.05
0.07 to 1.48 0.26 to 1.22 0.38 to 1.12 0.47 to 1.87 0.34 to 2.06 0.44 to 1.96 0.23 to 1.73 0.08 to 1.47 0.12 to 1.34 0.44 to 2.00 0.29 to 1.82
.053 .205 .339 .001 .007 .002 .011 .078 .105 .003 .007
Boldface values indicate statistically significant associations. *All models adjusted for child sex, maternal race, education, marital status, and maternal depression (measured with the BDI-II).
Piper and Corbett.24 Overall, our findings and those of Piper and Corbett reveal similar associations between early life exposure to tobacco smoke and later deficits in executive functions. Our findings also provide some evidence that mother’s exposure to second-hand smoke during pregnancy may impair children’s later executive functions. In our secondary analysis, we excluded children whose mothers reported that they were active smokers during pregnancy. In addition to replicating the pattern of findings in our primary analysis, we observed significant associations with several additional dimensions of executive function (working memory, plan/ organize, the organization of materials, and significant associations with the composite metacognition and global executive composite indexes), and the overall effect sizes were larger. It is possible that this pattern emerged because including active smokers in the primary analysis did not account for unidentified confounding that masked the associations we observed after excluding active smokers. Assuming a causal effect of exposure to tobacco smoke on executive functions, it is possible that the greatest magnitude of impairments to executive functions occur with increases in the lowest levels of exposure. Indeed, this phenomenon has been reported previously for impairments to cognitive functions and associations with exposure to both second-hand smoke and lead during childhood.18,34 However, our sample may not be ideal for exploring this possibility given that our overall cotinine concentrations tended to be low. Nevertheless, our study was well-suited to study prenatal exposure to second-hand smoke because of the relatively small number of mothers who actively smoked and the inclusion of multiple measures of cotinine in pregnancy, capturing multiple sources of tobacco exposures. Overall, the associations we observed between tobacco smoke exposure and executive function were modest. Our largest detected association for pregnancy second-hand
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smoke exposure was a 1.22 score increase per each doubling of serum cotinine. This would reflect a change of 4.28 points for a change reflecting the interquartile range of this population, from 0.011 ng/mL (25th percentile of cotinine) to 0.123 ng/mL (75th percentile of cotinine), which is close to one-half a SD for the BRIEF. Bellinger notes that even slight effects of exposure may have a substantial impact at the population level by progressively shifting the population distribution of neurobehavioral traits.5 At the population level, this can increase the risk of neurodevelopmental disorders, such as learning disabilities. Because 90% of children in our sample had detectable exposure to second-hand smoke, this finding suggests that the majority of children regularly come into contact with second-hand smoke. Thus, our findings provide support for the implementation of policies to eliminate maternal smoking during pregnancy and to minimize children’s exposure to second-hand smoke during childhood. There are several limitations in our study. First, in this cohort study we can only report associations and cannot conclude a causal relationship between our measured variables. Second, our moderately sized sample (n = 239) may have limited our ability to detect associations between early exposure to tobacco smoke, child behaviors, and other domains of executive function. For example, a previous study documenting an association between early exposure to tobacco smoke and child behaviors used a sample of 1265 children, >5 times our sample.21 Third, although we adjusted for a variety of potential confounders, additional unmeasured covariates or confounders like substance use, psychosocial factors, or life experiences occurring between the ages of 4 and 8 years may explain some of our observed associations. It is also possible that other measures of either behavior or executive function that do not depend on parental report would show larger or smaller associations with exposure to tobacco smoke. Finally, we found that childhood tobacco exposures had a similar association with executive function as prenatal exposures. Still, it is possible that childhood exposures were partially confounded by prenatal exposures. This may occur because women who smoke during pregnancy may continue to smoke after delivery, leading to our observed collinearity between pregnancy and child mean serum cotinine concentrations (r = 0.79), so that we were not able to simultaneously adjust childhood associations for prenatal exposure to tobacco smoke. The results of this study suggest that early exposure to tobacco smoke, both during pregnancy and childhood, is associated with later deficits in children’s executive function. The specific executive function skills that were affected—task initiation, working memory, the planning/organization of tasks, and the organization of materials—are components of metacognition: a higher-level cognitive ability essential for monitoring and controlling thoughts.23 In contrast, we found no significant associations with behavioral regulation aspects of executive function. Thus, our findings are consistent with the possibility that tobacco smoke exhibits greater 6
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deleterious effects on metacognitive executive functions than on behavioral regulation. These findings highlight the need to increase public awareness to protect pregnant women and developing fetuses from tobacco smoke. This need is emphasized by the high prevalence of detectable tobacco smoke exposure in this sample, even at low levels, and significant associations between exposure levels and later executive functions. Future studies examining similar associations across cultural and geographic boundaries are needed to determine the generalizability of these findings. In addition, similar investigations in larger samples will help to assess the robustness of the more marginal associations we observed, and to corroborate our conclusion that early exposure to tobacco smoke is negatively associated with children’s executive functions. n We thank the staff and participants of the HOME Study and the Tobacco Laboratory at the Centers for Disease Control and Prevention for their contributions to this research. Submitted for publication Jul 22, 2019; last revision received Oct 31, 2019; accepted Nov 20, 2019. Reprint requests: Brandon F. Terrizzi, MS, PhD, 3333 Burnet Ave, Cincinnati, OH 45229. E-mail: [email protected]
Data Statement Data sharing statement available at www.jpeds.com.
References 1. Jamal A, Phillips E, Gentzke AS, Homa DM, Babb SD, King BA, et al. Current cigarette smoking among adults—United States, 2016. MMWR Morb Mortal Wkly Rep 2018;67:53-9. 2. Drake P, Driscoll AK, Mathews T. Cigarette smoking during pregnancy: United States, 2016. NCHS Data Brief 2018;305:1-8. 3. Centers for Disease Control and Prevention (CDC). Secondhand smoke: an unequal danger. CDC Vital Signs. Atlanta: CDC; 2015. 4. Luck W, Nau H, Hansen R, Steldinger R. Extent of nicotine and cotinine transfer to the human fetus, placenta and amniotic fluid of smoking mothers. Dev Pharmacol Ther 1985;8:384-95. 5. Bellinger DC. A strategy for comparing the contributions of environmental chemicals and other risk factors to neurodevelopment of children. Environ Health Perspect 2012;120:501-7. 6. Eskanazi BB, Jackie J. Passive and active maternal smoking during pregnancy, as measured by serum cotinine, and postnatal smoke exposure. I. Effects on physical growth at age 5 years. Am J Epidemiol 1995;142:S10-8. 7. Hanke W, Kalinka J, Florek E, Sobala W. Passive smoking and pregnancy outcome in central Poland. Hum Exp Toxicol 1999;18:265-71. 8. Herrmann M, King K, Weitzman M. Prenatal tobacco smoke and postnatal secondhand smoke exposure and child neurodevelopment. Curr Opin Pediatr 2008;20:184-90. 9. Kahn RS, Certain L, Whitaker RC. A reexamination of smoking before, during, and after pregnancy. Am J Public Health 2002;92:1801-8. 10. Makin JF, Peter A, Watkinson B. A comparison of active and passive smoking during pregnancy: long-term effects. Neurotoxicol Teratol 1991;13:5-12. 11. Salmasi G, Grady R, Jones J, McDonald SD, Knowledge Synthesis G. Environmental tobacco smoke exposure and perinatal outcomes: a systematic review and meta-analyses. Acta Obstet Gynecol Scand 2010;89: 423-41.
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ORIGINAL ARTICLES 22. Gerard A, Gioia PKI, Guy SC, Kenworthy L. Behavior Rating Inventory of Executive Function Professional Manual. Lutz (FL): PAR; 1996. 23. Diamond A. Executive functions. Annu Rev Psychol 2013;64:135-68. 24. Piper BJ, Corbett SM. Executive function profile in the offspring of women that smoked during pregnancy. Nicotine Tob Res 2011;14: 191-9. 25. Benowitz NL. Cotinine as a biomarker of environmental tobacco smoke exposure. Epidemiol Rev 1996;18:188-204. 26. Braun JM, Kalloo G, Chen A, Dietrich KN, Liddy-Hicks S, Morgan S, et al. Cohort profile: the Health Outcomes and Measures of the Environment (HOME) study. Int J Epidemiol 2017;46:24. 27. Bernert JT, McGuffey JE, Morrison MA, Pirkle JL. Comparison of serum and salivary cotinine measurements by a sensitive high-performance liquid chromatography-tandem mass spectrometry method as an indicator of exposure to tobacco smoke among smokers and nonsmokers. J Anal Toxicol 2000;24:333-9. 28. Cole SR, Chu H, Nie L, Schisterman EF. Estimating the odds ratio when exposure has a limit of detection. Int J Epidemiol 2009;38:1674-80. 29. Beck AT, Steer RA, Brown GK. Beck depression inventory-II. San Antonio (TX): The Psychological Corporation; 1996. 30. Wechsler W. Wechsler abbreviated scale of intelligence. San Antonio (TX): The Psychological Corporation; 1999. 31. Caldwell BM, Bradley RR. Home observation for the measured environment. Little Rock: University of Arkansas at Little Rock; 1984. 32. System for children (BASC-2) handout. Circle Pines, MN: AGS Publishing; 2004. 33. Gioia GA. Behavior Rating Inventory of Executive Function: professional manual. Lutz (FL): Psychological Assessment Resources, Incorporated; 2000. 34. Lanphear BP, Hornung R, Khoury J, Yolton K, Baghurst P, Bellinger DC, et al. Low-level environmental lead exposure and children’s intellectual function: an international pooled analysis. Environ Health Perspect 2005;113:894-9.
Associations Between Early Low-Level Tobacco Smoke Exposure and Executive Function at Age 8 Years
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Figure. Bivariate association between mean prenatal maternal and child serum cotinine concentrations (ng/mL) and T-scores on the BRIEF’s Initiate subscale.
Table II. Serum cotinine concentrations (ng/mL) in maternal and child samples Variables Maternal cotinine (prenatal) 16 weeks 26 weeks Delivery Prenatal mean Child cotinine (postnatal) 1 year 2 years 3 years 4 years Postnatal mean
No.
Minimum
Maximum
Geometric mean (95% CI)
%>LOD*
%>3†
234 229 211 239
0 0 0 0.0005
349.0 252.0 282.0 291.7
0.075 (0.052-0.106) 0.06 (0.041-0.088) 0.05 (0.035-0.073) 0.078 (0.055-0.109)
70.9 65.5 61.1 70.2
9.8 10.9 10.0 11.3
186 147 157 128 238
0 0 0.002 0.003 0.002
35.3 10.5 21.6 14.9 20.2
0.114 (0.085-0.153) 0.094 (0.068-0.13) 0.071 (0.052-0.097) 0.06 (0.043-0.084) 0.126 (0.098-0.162)
89.2 89.8 77.1 75.8 89.9
7.5 6.8 7.0 3.1 7.1
*Limit of detection (LOD) = 0.015 ng/mL. †A value of 3 ng/mL is commonly used as an indicator of active smoking.
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