The effects of tobacco exposure on children's behavioral and cognitive functioning:

Neurotoxicology and Teratology 24 (2002) 397 – 406 www.elsevier.com/locate/neutera

The effects of tobacco exposure on children’s behavioral and cognitive functioning: Implications for clinical and public health policy and future research Michael Weitzmana,b,*, Robert S. Byrdc, C. Andrew Aligneb, Mark Mossb a

b

American Academy of Pediatrics, Center for Child Health Research, Rochester, NY, USA Department of Pediatrics, The University of Rochester School of Medicine and Dentistry, Rochester, NY, USA c The University of California at Davis, Sacramento, CA, USA Received 24 July 2001; received in revised form 22 October 2001; accepted 19 December 2001

Abstract A growing body of literature indicates that maternal smoking during pregnancy is associated with neurotoxic effects on children. Both animal model studies and human epidemiologic studies demonstrate similar effects in terms of increased activity, decreased attention, and diminished intellectual abilities. Epidemiologic studies also suggest that prenatal tobacco exposure is associated with higher rates of behavior problems and school failure. These findings are explored and their implications for child health policy and practice, and for research, are discussed. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Tobacco exposure; Children’s behavioral and cognitive functioning; Clinical and public health policy; Research

1. Introduction Tobacco smoke exposure of fetuses and children is very common and its contribution to myriad child health problems, such as low birth weight, asthma, respiratory infections, otitis media, and sudden infant death syndrome, has been convincingly established [3,4]. Both animal model and human epidemiologic studies also strongly suggest that prenatal and early passive exposure to tobacco smoke leads to negative behavioral and neurocognitive effects in children, and there are plausible biologic mechanisms through which this may occur. A growing body of literature indicates that maternal smoking during pregnancy and early childhood is associated with neurotoxic effects on children. This literature suggests that this exposure results in increased rates of children’s behavior problems and psychiatric disorders, and may also lead to subtle intellectual decrements and neurocognitive impairments. This exposure is common, rarely confined to

* Corresponding author. Department of Pediatrics, The University of Rochester School of Medicine and Dentistry, Suite #130, 1351 Mount Hope Avenue, Rochester, NY 14620-3917, USA. Tel.: +1-716-275-1892. E-mail address: [email protected] (M. Weitzman).

the prenatal period, and may be associated with other factors that adversely affect behavioral and cognitive outcomes in children. Lower maternal educational and socioeconomic status, increased rates of maternal depression and anxiety disorder, and alcohol and psychoactive drug use are all more common among women who smoke during pregnancy or during the child bearing and rearing years. Each of these factors, and possibly others as yet uncovered, may compound or confound the negative effects of children’s tobacco exposure and our ability to isolate its independent effects on child development. Other environmental exposures, such as lead, cause neurodevelopmental problems that are subtle, but serious, and this has resulted in substantial clinical, public health, and environmental policy development and implementation, which in turn have been associated with profound reductions in children’s exposure. Children’s prenatal and early passive exposure to tobacco smoke may well result in neurocognitive and behavioral problems of a similar magnitude to that of lead and is extremely prevalent. This, we believe, raises important questions about the implications of such findings for clinical practice and public policy. This paper reviews the literature on the effects of tobacco exposure on children’s behavior and cognition, and begins

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the exploration of the important unanswered questions about this relationship and its implications for clinical and public health policies and services for children.

2. Characteristics of women associated with maternal smoking The prevalence of smoking during pregnancy is estimated to be between 15% and 30% of all pregnant women in the USA, with the estimates varying depending on the source of the data and maternal characteristics of the study population, and appears to be declining [21,22,95,129, 131]. In 1995, 40% of women between the ages of 25 and 44 who did not finish high school were smokers; 34% of high school graduates were smokers; 24% of those with some college were smokers; and only 14% of those who graduated from college were smokers [95]. Smoking during pregnancy varies by ethnicity: American Indians and Alaskan Natives (21.3%), Hawaiian Asians (15.3%), White (14.7%), Black (10.2%), Hispanic (4.3%), and Asian (3.3%). Prenatal smoking is greatest during late teen years (17.2%) [20]. The percentage of mothers 20 years of age and over who smoked varies greatly by education: 9– 11 years (31.1%), 12 years (18.0%), 13– 15 years (10.4%), and 16 or more years (2.6%). In addition, an estimated 50% of all US children are regularly exposed to environmental tobacco smoke as assessed by serum cotinine levels [108]. Many epidemiologic studies rely on parent report of smoking behavior rather than assessment of biomarkers to characterize fetal and child exposure. This is likely to result in underreporting of exposure, which introduces an important bias for studies because it likely misclassifies some children who are exposed or underestimates their exposure, thereby likely underestimating the effect of their exposure [100]. Infants who are exposed to maternal smoking during pregnancy are at increased risk for other toxic exposures. Smoking mothers are more likely to drink and use illicit drugs [53,55,87,96]. Women smokers differ from nonsmoking women in a number of psychosocial characteristics [65]. Higher rates of unwanted pregnancies [51], difficulties coping with stress, and lower self-esteem [120] are found among smoking women compared to nonsmoking women. Women who smoked during pregnancy have been found to be more likely to report marital difficulties and more likely to physically discipline their 1-year-old infants [88]. Smoking mothers are less likely to breastfeed their infants [70,99,100]. Women who smoke reportedly drink more coffee, are more anxious, change jobs more frequently, have less formal education, and divorce more often than women who do not smoke [138]. Associations of cigarette smoking and mental illness are not confined to women who smoke during pregnancy. Cigarette smoking is associated with psychiatric disorders among adolescents and adults in the general population

[16,45,52,62,138] Persons with mental illness are about twice as likely to smoke as other persons [14]. In addition, cigarette smoking may increase the risk of certain anxiety disorders during late adolescence and early adulthood [71]. Data are emerging that suggest that dopamine-related genes are associated with smoking [90,114]. Abnormalities in the dopaminergic reward pathways have been implicated in substance abuse and addictive behaviors [90]. Dopamine D2 receptor gene variants have been found to be associated with alcoholism, drug dependency, obesity, smoking, pathological gambling, attention-deficit hyperactivity disorder (ADHD), Tourette syndrome, as well as other related compulsive behaviors [11]. Linkage studies indicate that there are several possible smoking-associated genes, which include cytochrome P450 subfamily polypeptide 6 (CYP2A6), dopamine D(1), D(2), and D(4) receptors, dopamine transporter, and serotonin transporter genes [5,10,23 –25]. Genetic aspects of behavioral problems that are autosomally linked to smoking should be transmitted equally from smoking mothers and smoking fathers. Studies to date, however, have found that maternal smoking is more strongly associated with adverse developmental outcomes than is paternal smoking [33,128]. If parental smoking were simply a marker for genetically driven behavioral problems in children, then studies should have found that maternal and paternal smoking contribute equally to adverse outcomes in children, which has not been the case. A number of seminal epidemiologic studies of child development have demonstrated that the number of risk factors present in a particular child’s life increases the likelihood of adverse outcomes [32,115,117]. Both nature and nurture are responsible for developmental outcomes. Socioeconomic and familial factors sometime overshadow the role of biology in producing emotional difficulties and intellectual retardation [109]. The ‘‘transactional model’’ [116] of child development supposes that a child’s initial biological makeup, including genotype, is not fully expressed at birth, but only develops during an interactive process with the environment.

3. Potential pathway for adverse effects 3.1. Low birth weight In 1957, Simpson [119] reported on the adverse effect of maternal smoking on birth weight. Subsequent studies have confirmed this finding [63,67,79,80]. These studies show a direct dose response [63,64]. The effect of prenatal exposure on birth weight is more attributable to intrauterine growth retardation than to preterm delivery. Kramer et al. [68] estimated the effect of prenatal maternal smoking as a 5% reduction in relative weight per pack of cigarettes smoked per day. Cigarette smoking is the single most important factor affecting birth weight in developed countries

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[66] Meyer and Comstock [84] reported that the effect of maternal cigarette smoking on infant birth weight was an average reduction of 150 to over 300 g. Both maternal smoking and paternal smoking are associated with lower birth weight, but maternal smoking is associated with more of an effect on birth weight than paternal smoking [33,81]. Only one study we are aware of has found no effect of passive exposure to cigarette smoking among nonsmoking mothers [50]. A randomized controlled intervention study by Sexton and Hebel [118] demonstrated that reduction of smoking during pregnancy improves the birth weight of the infant. Prenatal maternal smoking affects the fetus in a number of ways that may result in chronic hypoxia and low birth weight. Placental vascular resistance is often increased when women smoke during pregnancy [54,72]. Along with the known direct vasoconstrictive effect of nicotine, nitric oxide, and prostacyclin deficiency may affect the uteroplacental blood flow and contribute to the impaired fetal nutrition and increased perinatal mortality of babies born to women who smoke [130]. Chronic maternal smoking is associated with alterations of protein metabolism and enzyme activity in fetal cord blood [56]. These may be secondary to irreversible changes in the cellular functions of the trophoblast and may contribute to fetal growth restriction. Cigarette smoking during pregnancy transiently lowers maternal uterine blood flow and reduces flow of oxygen from the uterus to the placenta [89]. Increased levels of carboxyhemoglobin are found in both maternal and fetal blood when the mother smokes during pregnancy, and this can lead to fetal hypoxia because it replaces oxyhemoglobin that normally releases oxygen to the fetal tissues [122]. The fetus suffers chronic hypoxic stress as a consequence of smoking, as evidenced by elevated hematocrit levels [17]. Similarities have been noted between various birth characteristics of smoking mothers and births at high altitudes [84]. These parallels include reduction in birth weight without a corresponding shortening of gestation, some increase in perinatal mortality, and an increase in the ratio of placental weight to fetal weight [48,57,76]. Poor intrauterine growth has a lasting effect on subsequent growth [50] and development of children [30]. Low birth weight infants are at increased risk of emotional and behavioral problems [7,82,107]. The sequelae of low birth weight also include lowered cognitive abilities and hyperactivity [12]. Breslau et al. [13] found an increase in neurologic soft signs among low birth weight children. These soft signs were in turn associated with increased risk for subnormal IQ and learning disorders among children with normal IQ. Low birth weight also is associated with increased risk for reading and math disabilities [59]. It remains unclear whether the modest decrements in birth weight associated with maternal smoking have neurobehavioral consequences among those who are not born prematurely or of substantially low birth weight, and this needs to be examined in more detail.

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3.2. In utero brain growth Maternal smoking increases the likelihood for a child to be born with a small head circumference [61]. Children born to smoking mothers experience catch-up growth in weight and partial catch-up growth in length, but the differences in head circumference persist to at least 5 years of age [132]. No difference in head circumference measurements was found when women who are pregnant stop smoking prior to 32 weeks gestation [77].

4. Neurocognitive and behavioral outcomes associated with maternal smoking Cigarette smoke is comprised of more than 2000 chemical compounds [60], only a relative few of these have been studied for their biologic activity [28,91]. Both animal model and human epidemiologic studies have focused primarily on nicotine. At least three comprehensive reviews of the animal model and epidemiologic studies of maternal prenatal tobacco smoke’s effects on brain development, behavior, and neurocognitive functioning of children have been published in the past 5 years [31,94,100]. The following sections on animal model and epidemiologic studies are not meant to be exhaustive or systematic reviews of this literature, but rather provide a summary of the findings to date so that the implications for policy, practice, and research of these findings can be better understood. 4.1. Animal models Animal studies provide experimental models where the toxic exposure can be isolated to the prenatal period and isolated to tobacco exposure. The majority of the animal research has focused on the toxic effects of nicotine and the findings of these studies have been quite similar, despite the wide variability of study designs employed [31]. Prenatal nicotine exposure increases adrenergic receptor binding significantly in the cerebral cortex of adult animals [97,98,105,127]. In mouse experiments where the dose and timing of nicotine were varied, Nasrat et al. [93] demonstrated that doses of nicotine equivalent to 20 cigarettes per day in humans resulted in shortening of the gestational period, especially so when that exposure was during the second and third trimester. Similar to the findings of human studies, prenatal exposure to nicotine in animal studies consistently is associated with lower birth weight in offspring [8,73,74,87]. Animal studies also demonstrate that in multiple species (rats, mice, and guinea pigs), there is increased motor activity associated with in utero nicotine exposure [2,45,58]. Such studies have also found attention and memory deficits in maze task performance [75,106,137] and mild deficits in learning [46,58,75]. In many cases, these studies have found alterations in attention, memory, and learning that are consistent with attention deficit/

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hyperactivity disorder, but not all studies have found such findings [9,104]. Nicotine suppresses DNA synthesis in newborn rat brains, especially in the cerebellum [121]. It also reduces dopaminergic activity in the offspring of nicotine-exposed pregnant females in the ventral tegmental area, nucleus accumbens, and striatum. Nicotine also reduces the uptake of serotonin [126] and is typically associated with rat hyperactive behavior [90,114]. Thus, nicotine in experimental animals has been shown to alter in utero growth, and offspring’s cognitive and motor performance, DNA synthesis, and neurotransmitter function associated with mood. 4.2. Epidemiologic studies Over the past several decades, considerable new data have become available concerning the developmental consequences of children’s prenatal and early passive exposure to tobacco smoke through a series of observational studies involving humans using both cross-sectional and longitudinal data. The samples used have been diverse in terms of ethnicity, culture, and potentially confounding social characteristics. These new data generally support the view that children’s behavior and cognition are adversely affected by prenatal and early childhood tobacco exposure. 4.3. Adverse behavior outcomes in children of smoking mothers Many of the epidemiologic studies discussed below employed multivariate statistical analyses to control for many potential confounders of the association between prenatal tobacco exposure and children’s behavior and cognition. Studies of children whose mothers smoked during pregnancy have consistently demonstrated that such children have higher rates of behavior problems than those not exposed. Olds [100], for example, notes in his paper of 1997 that 10 of 11 human studies reviewed found increased rates of child behavior problems and attention deficit/hyperactivity disorder-like behaviors even after controlling for many potential confounders [26,29,34,40,49,69,85,92,113,124,125,133 – 135]. These studies vary from the newborn period up through adolescence. 4.4. Newborns and preschoolers Fried et al. [42] reported increases in hypertonicity and heightened tremors and startles among neonates who were prenatally exposed to tobacco compared to neonates born to nonsmokers. Longo [78] found evidence for neonatal hyperactivity among offspring of smoking mothers. In a study by Brook et al. [15], maternal smoking during pregnancy was associated with negativity in 2-year-old children. Williams et al. [136] reported on a prospective longiudinal study of 5342 5-year-old children in which maternal smoking during pregnancy was associated with externalizing behavior prob-

lems. These studies, like the studies noted below of older children, suggest that prenatal tobacco exposure may increase the risk for attention deficit/hyperactivity disorder and oppositional defiant, conduct disorders. 4.5. School age children and adolescents Weitzman et al. [135] in a longitudinal study involving 2256 US children ages 4 –11 years found that those who were exposed postnatally and both prenatally and postnatally were more likely to have behavior problems, even after controlling for numerous potential confounders. In this study, there was evidence of a dose – effect response and the tobacco exposure effect was not limited to any particular area of children’s behavior, such as antisocial behaviors, anxiety, depression, hyperactivity, or easy distractibility. The concept of ‘‘dose –effect’’ response in this case refers to the fact that within this sample those with higher rates of reported exposure demonstrated greater rates of problem behaviors, in contrast to experimental studies where ‘‘dose – effect response’’ refers to greater effects when individual subjects are exposed to higher doses in controlled studies. Fergusson et al. [36] also found maternal smoking during pregnancy to be associated with increased rates of behavior problems in a longitudinal study of a birth cohort of 1265 children up to age 18 years in New Zealand. This study used both teacher and mother reports, thereby eliminating the potential problem that smoking mothers may be less tolerant of children’s behaviors and more likely to report them as abnormal. A clear dose – response relationship between amounts smoked during pregnancy and disruptive behaviors, conduct disorder, and attention deficit was found after adjusting for confounding variables. Rantakallio et al. [113] found an association between prenatal cigarette smoking and later delinquency in the Finnish birth cohort study, and Wakschlag et al. [133], in a more recent prospective study in the USA, found that boys ages 7 –12 were more likely to be referred for psychiatric care for conduct disorder if their mothers smoked during pregnancy. 4.6. Cognitive impairments Prenatal exposure to maternal smoking has been shown to adversely affect children’s performance on intelligence and achievement tests, as well as performance in school, although the findings in this area are not as consistent as those for increased rates of behavior problems. Butler and Goldstein [18] demonstrated that children whose mothers smoked an average of 10 or more cigarettes per day were on average between 3 and 5 months delayed in reading, mathematics, and general ability when compared to offspring of nonsmokers. A number of studies [29,34,37,38, 92,111,112] demonstrate similar effects, while some found effects to virtually disappear after controlling for confounders [6,35,83]. In families in which mothers smoked during some but not all pregnancies, exposed children performed worse on intelligence tests

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than their unexposed siblings [35]. Similarly, children of women who quit smoking during pregnancy have been found to score higher on tests of cognitive ability than children whose mothers smoke throughout pregnancy [40]. The Ottowa Prenatal Prospective Study provided longitudinal data regarding auditory processing, reading, and language development. Fried and Watkinson [39] found that infants born to maternal smokers have decreased rates of auditory habituation and increased sound thresholds. The children in this study at 12 and 24 months showed decreased responsiveness on auditory-related items on the Infant Behavior Record of the Bayley Scales of Infant Development associated with prenatal cigarette exposure. By ages 3 and 4 years, language development as assessed using standardized tests was found to be adversely affected by maternal cigarette smoking [34]. These findings were dose-related, and persisted in follow-up studies through age 12 years [37,41,43,44]. A study by Olds et al. [102] estimated the effect of prenatal smoking on cognitive function, finding that 10 or more cigarettes per day during pregnancy was independently associated with decreased Stanford – Binet IQ scores an average of 4.35 points, when controlling for many potential confounders. The same investigators also demonstrated that the adverse effects of smoking during pregnancy seem to be prevented or ameliorated by smoking cessation [101]. They showed that intervention with quality, long-term nurse home visitation can offset the impairment in intellectual functioning associated with substantial maternal smoking during pregnancy. While Olds et al. were unable to estimate how much of the prevention in intellectual impairment was due to smoking, the data suggest that some of the increase in IQ was due to a reduction in maternal smoking during pregnancy. Denson et al. [27], in a case control study, showed hyperactivity to be associated with maternal smoking and this relationship had a dose response. Milberger et al. [85,86] also employed a case control study and found that prenatal tobacco exposure contributes to children’s attention deficit/ hyperactivity disorder. 4.6.1. School performance Rantakallio [111] reported data from a 1966 birth cohort of 1819 Finnish children that demonstrated that parental smoking was associated with lower mean scores on ‘theoretical subjects based on school reports.’ Byrd and Weitzman [19] demonstrated that children of smoking parents are more likely to repeat kindergarten or first grade, using the US National Health Interview Survey. This study, however, was cross-sectional, and did not distinguish prenatal from childhood passive exposure to tobacco.

5. Summary of animal model and human epidemiologic data A causal argument rests on the accumulation of evidence along five major domains: biologic plausibility, consistency,

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temporality, dose – response gradient, and strength of association. The studies presented here represent strong evidence in each of these domains, yet the knowledge base remains incomplete. Because of limitations in human epidemiologic research, the basis for biologic plausibility is rooted in the strength of the animal research. However, the epidemiologic studies provide a broad base of consistency across populations and across varying study designs and endpoint measures. The temporal sequence of exposure coming prior to outcome, while somewhat cloudy in some of the human studies is clearly evident in the animal models. Dose –response relationships remain unclear in many respects however, again, the animal data provide a basis for concern. In any causal argument, the strength of the association stands as a key criterion largely because strong associations are unlikely to be explained away by other factors. This is a very important consideration in the association between prenatal tobacco exposure and adverse behavioral and neurocognitive effects on children. As noted elsewhere in this paper, differences exist between smoking and nonsmoking mothers that might explain adverse outcomes among the offspring of smoking mothers, i.e. heavy and moderate smokers receive less prenatal care, recognize their pregnancies later, and report more symptoms of depression than do nonsmokers and light smokers [116]. These differences suggest that smokers are more likely to be depressed or antisocial and less likely to practice health promoting behaviors for themselves or their children. These suppositions ignore findings from the significant number of observational studies that have controlled for a large number of potential confounders, including depression and substance abuse. Intervention studies and animal models also potently contradict the contention that maternal smoking simply is a proxy for other factors responsible for the adverse neurocognitive and behavioral outcomes that have been found. The actual magnitude of the adverse behavioral and neurocognitive effects of tobacco exposure for children is not entirely clear at this time, and may be seemingly modest, i.e. a decrement of 4– 5 IQ points and an odds ratio of approximately 1.5 for adverse developmental or behavioral outcomes. Yet, we have directed considerable public resources to other problems that seem to have a similar magnitude of effect. It also is essential that we recognize that an insult of this type and magnitude, when coupled with other risks that tend to cluster among a significant percentage of our children, may have profound effects on children’s functioning and quality of life across the life span. While many questions still remain, both animal model and human epidemiologic data clearly point to a causal relationship between prenatal tobacco exposure and adverse behavioral and neurocognitive effects on children. There are those who remain skeptical [31,94,100,110] of research on the adverse effects of smoking during pregnancy, and offer hypothetical alternative interpretations that could explain some of the findings in this growing literature. Clearly, these questions form the basis for further research. Nevertheless,

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the judgement concerning whether to take precautionary action now or await further research findings must be made. This review argues for precaution.

6. Implications What are the implications of this literature for clinical and public health policies for children, and what additional research is needed to begin to translate these findings into prudent public health and clinical policies and practices for children? Listed below are 10 suggestions for clinical and public health practices, and an additional 10 for research. These are not meant to be encyclopedic, but rather to build on the current knowledge base and begin to develop the process by which children and society benefit from it. 6.1. Clinical and public health policy implications (1) Developmental surveillance for cognitive, behavioral and social aberrations in children is a cornerstone of preventive services for all children. Children whose mothers smoke are at increased risk for such problems. This risk may be due to independent neurotoxic effects of tobacco smoke’s constituents on the developing brain, the effects of one or more of these constituents on vascular supply or oxygenation of the developing brain, and/or because of adverse maternal and familial characteristics that may occur more frequently among mothers who smoke. That is, as noted elsewhere in this article, maternal smoking frequently occurs in the context of other factors that place the child at increased developmental risk, such as poverty, and low parental education. From this perspective, tobacco smoke exposure represents an additional insult to children’s development. One implication of this is that the magnitude of the association between children’s exposure and functional impairments is likely to vary depending on the characteristics of the child and his environment which in turn implies that altering the social and educational environment may do great good for the child. (2) Home and educational environments may be potent modifiers of effects of children’s tobacco smoke exposure. This indicates the need for heightened vigilance and assiduous attention to long-term developmental surveillance of children of smokers. It also indicates the need to develop and implement better strategies to help parents stop smoking and new environmental control activities to reduce the exposure of children whose parents appear unable to stop. (3) Maternal smoking should be developed as a clinical child health diagnosis. This would aid with developing national guidelines for obstetricians and child health care providers (pediatricians, pediatric nurse practitioners, and family practitioners) for screening for maternal smoking and for the management of such mothers and children. Mechanisms whereby clinicians could bill for providing services for such children and their families also are needed and would be facilitated by fostering this as a clinical diagnosis.

(4) Children’s primary medical care providers should include a history of maternal smoking on the child’s medical record problem list. (5) While long-term developmental surveillance is indicated, maternal smoking should not be seen as necessarily indicating the need for diagnostic assessment or referral for early intervention or special education services. There is likely to be a substantial amount of interchild variability in the neurocognitive and behavioral effects of pre- and postnatal tobacco smoke exposure. That is, some children may have greater or lesser effects than others. This suggests that not all children with the same level of exposure should be considered as being at equivalent developmental risk. Maternal smoking should be considered a risk factor for neurodevelopmental problems, not as a diagnosis indicative of the need for developmental services. (6) Early intervention/stimulation programs should be considered on a case by case basis, when there is evidence suggesting cognitive, behavioral, or social problems. There is no reason to believe that children exposed to maternal smoke require early intervention services different from those provided to low birth weight children, and those that focus both on child stimulation and parent –child interaction may be most appropriate. (7) As the neurodevelopmental problems associated with maternal smoking are likely to be subtle, they are unlikely to be identified using a relatively insensitive screening tool, such as the Denver Developmental Screening Test. (8) Neurocognitive or behavioral problems may not become apparent until later in children’s lives. One implication of this is that developmental assessments conducted during children’s preschool or early school years may result in false negative results and fail to identify children who are at risk for later developmental. Thus, the need for developmental monitoring does not end when the child reaches school. Clinicians and educators need to be alert for behaviors that could interfere with academic achievement, or suggest ADHD. Again, as is the case for childhood lead poisoning [1], developmental surveillance probably should include special attention to critical transitional periods in children’s lives when subtle neurodevelopmental or behavioral problems may lead to functional impairments, such as in the first, fourth, and sixth/seventh grade. (9) Clinical and public health strategies aimed at the primary and secondary prevention of prenatal and postnatal tobacco exposure of children need to be developed and promulgated by professional organizations (i.e. the American Academy of Pediatrics), and appropriate federal agencies, such as the Centers for Disease Control. (10) At present, no public (e.g. the Centers for Disease Control or the federal Bureau of Maternal and Child Health) or professional group (e.g. the American Academy of Pediatrics) has offered recommendations for special monitoring, screening, or services for children who were prenatally or passively exposed to tobacco smoke early in childhood. The data about negative effects of such exposures on neuro-

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cognition and behavior are sufficiently concerning to warrant convening an interagency task force to draft such guidelines. Such a task force should include individuals from the National Institutes of Health, the Centers for Disease Control and Prevention, the Bureau of Maternal and Child Health, the Agency for Healthcare Research and Quality, the Environmental Protection Agency, the American Academy of Pediatrics, the American Academy of Family Practice, and leading scholars in neurodevelopment, neurotoxicology, child development, and child health care. We suggest that such efforts, similar to those that have gone into providing recommendations for the management of children exposed to unacceptable levels of lead, should be undertaken. 6.2. Research implications The literature to date on the neurocognitive and behavioral effects of prenatal and early childhood passive exposure to tobacco smoke also have clear implications for further research. Listed below are a series of 10 questions that emanate from the findings to date in this profoundly important field. (1) Are the adverse neurocognitive and behavioral effects associated with tobacco exposure due to prenatal or early childhood passive exposure, or to both prenatal and postnatal exposure? (2) Is there a unique neurobehavioral signature associated with prenatal and early passive exposure to tobacco smoke, or is it variable and does it vary by stage of development at which the fetus or child is exposed? (3) Do tobacco effects vary by whether the exposure is acute or chronic, and is there a critical period of exposure? (4) Do neurobehavioral problems change over the course of childhood, or are they static, and whether changing or static are their effects likely to be more deleterious at different stages of children’s lives? (5) There is evidence of a dose effect response between children’s tobacco exposure and various domains of behavior and neurocognitive functioning. Do the slopes of these relationships change over the range of exposure? (6) Are there children who are especially vulnerable to tobacco exposure, such as those growing up in poverty, or with mothers who are poorly educated or depressed, or children with intellectual impairments, such as already low IQ, ADHD, or specific learning disabilities? (7) Are the adverse neurocognitive and behavioral effects reversible if mothers reduce or stop smoking, and if yes, are there times when, or by when it is especially important to reduce or curtail exposure? For example, does reduction or curtailment of tobacco exposure lead to decreased rates of behavior problems or decrements in IQ? Similarly, are there environmental control mechanisms that effectively could reduce children’s exposure to tobacco smoke? (8) Are there parenting strategies or social support interventions that can overcome the biologic effects of tobacco exposure? What are the effects of early intervention on children who have been exposed to maternal smoking?

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(9) What additional information can be learned from animal model studies, what are the limitations of extrapolations from such data to effects on children, and what additional animal model studies are indicated? What hypotheses suggested by human studies can better be tested in animal studies? (10) What additional information can be derived from further human epidemiologic investigation, what samples and study designs are indicated, and how would we develop such studies? What hypotheses suggested by animal studies can be tested in epidemiologic studies? In summary, while many questions remain unanswered, this review demonstrates that there is sufficient scientific evidence to indicate that there are adverse behavioral and neurocognitive effects of children’s exposure to tobacco smoke. Thus, this domain of children’s functioning should be added to the list of deleterious effects of tobacco exposure on child health. It also suggests that these effects warrant concerted efforts on the part of the scientific, public health and medical communities to develop policies that more effectively reduce children’s exposure to tobacco smoke.

Acknowledgments The authors would like to acknowledge the help of Zarina Fershteyn in finding and organizing many of the articles cited in this paper.

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