Developmental consequences of prenatal tobacco exposure : Current Opinion in Neurology

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Developmental disorders: Edited by Bruce Shapiro

Developmental consequences of prenatal tobacco exposure

Cornelius, Marie D; Day, Nancy L

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Current Opinion in Neurology 22(2):p 121-125, April 2009. | DOI: 10.1097/WCO.0b013e328326f6dc
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Tobacco is the most commonly used substance during pregnancy [1]: up to 25% of pregnant women smoke [2,3].

Nicotine crosses the placenta and is concentrated in the fetal tissue. The direct effects of nicotine predict deficits in growth and neural development, which have long-term effects on brain function, cognition, and behavior. Indirectly, nicotine affects size through placental pathology [4].

Recent studies have improved on earlier methodologies with prospective designs, biological measures, and statistical control of confounders. Current research also uses more sophisticated assessments including objective neurobehavioral batteries, neuroimaging techniques, and measurement of genotypic variability.

Neonatal and infant outcomes

Most recent research on infants has focused on behavior. Using the Brazelton Neonatal Behavioral Assessment Scale, one study [5••] compared 25 infants of women who smoked at least five cigarettes per day to 25 infants of nonsmokers. Urine cotinine levels significantly correlated with infant irritability, attention, and decreased response to inanimate auditory stimuli. Paternal smoking, in the absence of maternal use, was also significantly correlated with infant cotinine level and irritability.

Another study [6] examined 962 mother/infant pairs from the Providence Cohort of the National Collaborative Perinatal Project using the Graham-Rosenblith Behavioral Examination of the Neonate. Prenatal tobacco exposure (PTE) was associated with increased irritability and hypertonicity controlling for maternal socioeconomic status (SES), age, race, and infant birthweight. This study represented the largest investigation of the effects of maternal smoking on examiner-assessed neonatal behavior.

In a pilot study, Stroud et al. [7] compared 28 infants with PTE to 28 infants of nonsmokers aged 10–27 days. Infants with PTE had a greater need for handling and scored lower on self-regulation. In contrast to prior studies, there were no effects of PTE on abstinence withdrawal symptoms or muscle tone. The authors concluded that effects at this age included poorer infant self-regulation and an increased need for external intervention.

Infant temperament at 9 months was studied in a cohort of over 18 000 infants [8•]. Infants of heavy smokers scored least well on the Carey Infant Temperament Scale, whereas women who quit smoking had infants with higher scores on the easy temperament scale. These findings remained robust after controlling for sociodemographic factors that correlated with maternal pregnancy smoking status.

Six-month-old infants with PTE had less focused attention, lowered reactivity to basic sensory stimulation, and more distractibility compared to nonexposed infants (Wiebe, unpublished data), and the author concluded that PTE leads to deficits in information processing and self-regulation. An additional study by the same author and colleagues evaluated the genetic aspects of PTE-associated neurobehavioral deficits [9•]. This study examined early infant neurobehavior of 119 mothers and their infants. PTE status was based on self-report and maternal and meconium cotinine. The dopamine receptor D2 genotypes of the infants were identified. Nonexposed infants with the A1+ genotype had a heightened response to novelty. Among PTE infants with this variant, however, the response to novelty was dampened, which suggests that genetic variability and PTE interact to affect infant development.

In a study of infant cognition, speech-processing ability was assessed between eight PTE and eight non-PTE infants [10•]. Using event-related potentials, exposed infants discriminated fewer syllables and processed them more slowly than nonexposed infants. Thus, PTE may lead to changes in brain physiology that affect basic perceptual skills.

A study from the animal literature reported on gestational exposure and visual recognition memory. Golub et al. [11•] examined rhesus monkeys that were exposed to environmental tobacco smoke (ETS) from gestation day 50 to delivery. In parallel with the human literature, the exposed group showed less novelty preference in the visual recognition task. However, unlike the human literature, no effects were found on the auditory function test. The authors concluded that ETS exposure during pregnancy had adverse effects on cognitive function in nonhuman primates.

Childhood outcomes

Studies of PTE effects in childhood dealt primarily with behavior as the outcome. In a study of 2-year-old children in New Zealand [12•], PTE was assessed retrospectively at the 6-week postpartum visit. The Child Behavior Checklist (CBCL) was completed by the mothers when their children were 24 months old. Tobacco-exposed children had higher rates of internalizing, externalizing, and total problem scores after controlling for prenatal alcohol exposure, sociodemographic factors, maternal health, and parenting practices.

A prospective study examined the role of PTE on child behavioral outcomes in a cohort of teenaged mothers and their offspring. In a report on 357 6-year-olds, PTE predicted increased activity, inattention, and behavior problems on the CBCL after controlling for the correlates of maternal smoking [13•]. In a later report [14•] on the same children at age 10, PTE predicted more activity, impulsivity, delinquent, and aggressive behaviors, and more deficits of selective attention and response on the Stroop test. These effects were found at PTE levels as low as 10 cigarettes per day after controlling for confounders.

A study of maternal smoking during pregnancy and maternal exposure to environmental tobacco smoking (ETS) during pregnancy [15••] found that 7–15-year-old offspring of mothers with only second-hand exposure during pregnancy also had more conduct disorder symptoms after effects of income, parental antisocial tendencies, prematurity, birthweight and parenting practices were controlled. This was the first study to demonstrate the effects of ETS on externalizing behavior in exposed offspring.

Langley et al. [16•] examined the roles of PTE, birthweight, and social class among children diagnosed with attention deficit hyperactivity disorder (ADHD). In this clinical population, hyperactive-impulsive symptoms and conduct disorder symptoms were significantly higher among those with PTE, compared to children with ADHD and no PTE.

Multifactorial studies

Several studies have identified factors that interact with the effects of PTE. Huijbregts et al. [17•] examined PTE, parental antisocial behavior, and childhood physical aggression in children aged 17–42 months. There was a significant direct effect of PTE on child aggression. The interaction of PTE and the mother's history of antisocial behavior also predicted increased childhood aggression, as did an interaction between PTE and lower family income.

Other outcomes

Lewis et al. [18] compared children with and without PTE on receptive, expressive, and total language scores. PTE was significantly related to lower receptive language scores but not expressive language scores.

In a study of somatic outcomes [19], the effects of PTE were explored among 8000 children who were exposed to tobacco prenatally only, postnatally only, and at both times. At 3 years, those exposed both prenatally and postnatally had more wheezing, used more bronchodilating drugs, and had more excessive crying. Those with only prenatal exposure used more bronchodilating drugs and suffered from more sleep problems. Children with only postnatal exposure had more rhinitis, used more cough medicines, and suffered from poorer sleep.

Contrary findings

In contrast to the studies above, Roza et al.[20•] found no increased risk of behavioral problems in a Dutch sample of 18-month-olds who were prenatally exposed to maternal and paternal smoking after controlling for the effects of SES and parental psychopathology.

In a longitudinal study [21•] of 11 192 offspring between the ages of 4–10 years, offspring with PTE were compared to siblings with no PTE. PTE did not predict delinquency or oppositional/defiant behaviors. There was a significant association between PTE, attention, and hyperactivity problems, however. These authors concluded that environmental factors accounted for the association between PTE and externalizing behavior problems.

Gilman et al.[22•] examined over 52 000 children from birth to age 7 years. Only low birth weight and higher odds for being overweight at age 7 were associated with PTE. Intelligence, academic achievement, conduct problems, and asthma were not associated with PTE. The authors argued that the effects of smoking during pregnancy may not be distinguishable from a broader range of familial factors associated with maternal smoking.

Adolescent outcomes

With the development of faster genetic mapping techniques, more studies have incorporated genetics into their designs.


Becker et al. [23••] genotyped 305 15-year-olds, focusing on the dopamine transporter DAT1 gene and assessed inattention, hyperactivity, impulsivity, oppositional defiant, and conduct disorders using the Kiddie-Schedule for Affective Disorders and Schizophrenia (K-SADS). Males with PTE who were homozygous for DAT1 10r had higher rates of hyperactivity and impulsivity than all other groups. This study showed the importance of multiple factors in explaining the nature of attention and hyperactivity disorders.

Neuman [24•] examined the DAT1 and DRD4 polymorphisms among 1540 twins age 7–19 years. The odds of a DSM-IV ADHD diagnosis were 2.9 times greater in twins with the DAT1 allele and 2.6 times greater in those with the DRD4 seven-repeat allele. The odds ratio for offspring with PTE and both alleles was 9.0. The authors suggested that PTE was associated with specific subtypes of ADHD in genetically susceptible children.

Wakschlag et al. [25] tested the effects of a polymorphism of the enzyme monoamine oxidase (MAOA) and PTE on antisocial behavior in 176 adolescents. PTE males with low activity MAOA 5′ had an increased risk of conduct disorder symptoms as measured by a face-processing task. There was no evidence of a gene–environment correlation among female adolescents. This study showed that MAOA genotype, PTE and sex interact to predict antisocial behavior.


Rivkin et al. [26•] examined the brain volume on MRI of 10–14-year-olds with PTE. PTE was associated with significant reduction in cortical gray matter and total parenchymal volumes and head circumference after adjustment for demographics and the other prenatal substance exposures.

The thickness of the cerebral cortex was measured using MRI in 144 adolescents with PTE and 159 nonexposed adolescents [27•]. Orbitofrontal, middle frontal, and parahippocampal cortices were thinner in the exposed adolescents and more pronounced in females. There was no effect of PTE on IQ. Exposed adolescents scored lower on the Positive Youth Development (PYD), and their scores correlated with their orbitofrontal thickness.

Jacobsen et al. [28•] used MRI and diffusion tensor imaging (DTI) to examine effects of prenatal and adolescent tobacco exposure on structure of brain white matter. The sample included 67 adolescent smokers and nonsmokers with and without PTE. PTE and adolescent tobacco exposure were associated with increased fractional anisotropy in anterior cortical white matter. In another study of auditory and visual attention, females with PTE or adolescent smoking had reductions in auditory and visual attention performance accuracy: these deficits were largest in female smokers with PTE [29•]. Among males, combined exposure predicted deficits in auditory attention. PTE and exposure to nicotine during adolescence had sex-specific effects on auditory and visual attention.

Comparable differences by sex were seen in rats. Deficits associated with PTE in cerebrocortical choline acetyltransferase activity and hemicholinium-3 binding to presynaptic choline transporter were greater in males than females [30••]. Environmental tobacco exposure of the rats in adolescence also affected expression of 5HT in males. When animals were exposed at both periods, the effects were also found in females.


Four review articles on PTE were written over 2 years. Shea and Steiner [31] reviewed the animal and human data that linked PTE to neurodevelopmental outcomes. Pickett and Wakschlag [32] reviewed the perinatal consequences of PTE and cognition and behavioral problems linked to PTE. They discussed the inconsistencies in the literature and stressed that PTE should be viewed as a risk for vulnerability along with multiple factors that influence neurobehavioral outcomes. The Button et al. [33] paper focused on the effects of PTE on problem behaviors; attention, hyperactivity, and conduct problems. Slotkin [34••] summarized literature from animal and human studies of neurobehavioral and brain development that could alter the reward systems that reinforce subsequent susceptibility to nicotine addiction in later life.


Most studies demonstrate that PTE predicts adverse neurodevelopmental outcomes, although a few reports do not support this conclusion. This may result from differing methodologies, small sample sizes, and differing measurement of PTE, outcomes, and confounders. Imaging techniques continue to demonstrate an effect of exposure on brain function and structure. The mechanisms of PTE's effects on the developing brain are not yet known. It is clear, however, that the mechanism will be multifactorial, involving biological effects, genetic susceptibility, and environmental factors. Animal studies provide biological plausibility to relations found in human populations and corroborate the importance of environmental factors.


Funding: NIH: DA09275, DA03874, DA019482, DA008916, AA07453, AA08284, AA015728, DK066266, ES0112059, MH067924.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 000–000).

1 NSDUH Report (2005) Substance use during pregnancy: 2002 and 2003 update. Office of Applied Studies, Substance Abuse and Mental Health Services Administrations (SAMSA). US Department of Health and Human Services.
2 Arria A, Derauf C, Lagasse L, et al. Methamphetamine and other substance use during pregnancy: preliminary estimates from the infant development, environment, and lifestyle (IDEAL) study. Matern Child Health J 2006; 10:293–302.
3 Centers for Disease Control and Prevention. Prevalence of selected maternal behaviors and experiences, pregnancy risk assessment monitoring system. MMWR 51(SS-2), 2002.
4 Lambers D, Clark K. The maternal and fetal physiologic effects of nicotine. Semin Perinat 1996; 20:115–126.
5•• Mansi G, Raimondi F, Pichini S, et al. Neonatal urinary cotinine correlates with behavioral alterations in newborns prenatally exposed to tobacco smoke. Pediatr Res 2007; 61:257–261. Neonatal irritability was strongly correlated with maternal smoking during pregnancy and from paternal smoking around nonsmoking mothers as indicated by neonatal urine cotinine levels. Neonatal behavior was significantly altered in a dose–response manner even after modest exposure to tobacco smoke.
6 Stroud L, Paster R, Goodwin M, et al. Maternal smoking during pregnancy and neonatal behavior: a large-scale community study. Pediatrics, in press.
7 Stroud L, Paster R, Papandonatos G, et al. Maternal smoking during pregnancy and newborn neurobehavior: a pilot study of effects at 10 to 27 days. J Pediatr 2009; 154:10–16.
8• Pickett K, Wood C, Adamson J, et al. Meaningful differences in maternal smoking behaviour during pregnancy: Implications for infant behavioural vulnerability. J Epidemiol Commun H 2008; 62:318–324. Women who quit smoking during pregnancy had infants with higher scores of easy temperament as compared with infants of women who persisted with heavy smoking during pregnancy. These findings remained robust after controlling for sociodemographic factors and correlate of maternal pregnancy smoking status.
9• Wiebe S, Espy K, Stopp C, et al. Gene-environment interactions across development: exploring DRD2 genotype and prenatal smoking effects on self-regulation. Dev Psychol 2009; 45:31–44. Explored the interaction between DRD2 genotype and PTE in neonates and preschoolers. Children who had the higher risk A1+ genotype and whose mothers reported smoking during pregnancy had increased difficulties across all task conditions.
10• Key A, Ferguson M, Mofese D, et al. Smoking during pregnancy affects speech-processing ability in newborn infants. Environ Health Perspect 2007; 115:623–629. PTE exposed infants discriminated fewer syllables as measured by high density event-related potentials, and began to process more slowly.
11• Golub M, Slotkin T, Tarantal A, et al. Visual recognition memory and auditory brainstem response in infant rhesus monkeys exposed perinatally to environmental tobacco smoke. Brain Res 2007; 1151:102–106. ETS exposure pre and postnatally significantly affected less novelty preference in a visual recognition task among rhesus monkeys.
12• Carter S, Paterson J, Gao W, et al. Maternal smoking during pregnancy and behaviour problems in a birth cohort of 2-year-old Pacific children in New Zealand. Early Hum Dev 2008; 84:59–66. Noted PTE effects among 2-year-olds on behavioral outcomes of externalizing, internalizing and total problems. Interactions were found with nonpartnered mothers and child internalizing and externalizing among girls.
13• Cornelius M, Goldschmidt L, DeGenna N, et al. Smoking during teenage pregnancies: effects on behavioral problems in offspring. Nicotine Tob Res 2007; 9:739–750. This prospective study found effects of PTE on childhood behavioral outcomes including externalizing, inattention and increased activity after controlling for maternal psychosocial factors, other prenatal substance, and ETS exposure in childhood.
14• Cornelius M, Leech S, Goldschmidt L, et al. Effects of prenatal tobacco exposure on neurobehavioral outcomes in ten-year-old children of teenage mothers. Presentation at the Society for Research on Child Development, April 2009, Denver, CO. This study found effects of PTE on childhood behavioral outcomes from maternal report but also from neuroassessment battery indicating effects in response processing of selective attention and response inhibition.
15•• Gatzke-Kopp L, Beauchaine T. Direct and passive prenatal nicotine exposure and the development of externalizing psychopathology. Child Psychiatry Hum Dev 2007; 38:255–269. This was the first study to demonstrate that second hand smoke exposure predicts offspring externalizing vulnerability after control for appropriate covariates.
16• Langley K, Holmans P, Van den Bree M, et al. Effects of low birthweight, maternal smoking during pregnancy and social class on the phenotypic manifestations of Attention Deficit Hyperactivity Disorder and associated antisocial behaviour: investigation in a clinical sample. BMC Psychiatry 2007; 7:e26. Indicators of environmental risk including maternal smoking in pregnancy and lower social class independently predicted the clinical presentation of ADHD.
17• Huijbregts S, Seguin J, Zoccolillo M, et al. Maternal prenatal smoking, parental antisocial behavior and early childhood physical aggression. Dev Psychopathol 2008; 20:437–453. This study demonstrated that behavioral risks of PTE exposure were heightened when combined with having an antisocial parent.
18 Lewis B, Kirchner H, Short E, et al. Prenatal cocaine and tobacco effects on children's language trajectories. Pediatrics 2007; 120:e78–e85.
19 Johansson A, Ludvigsson J, Hermansson G. Adverse health effects related to tobacco smoke exposure in a cohort of three-year-olds. Acta Paediatr 2008; 97:354–357.
20• Roza S, Verhulst F, Jaddoe V, et al. Maternal smoking during pregnancy and child behaviour problems: the Generation R study. Int J Epidemiol 2008 Sep 4. [Epub ahead of print] This study found that when controlling for parental psychopathology, the effects of maternal and paternal smoking on child behavioral problems disappeared.
21• D'Onofrio B, Van Hulle C, Waldman I, et al. Smoking during pregnancy and offspring externalizing problems: An exploration of genetic and environmental confounds. Dev Psychopathol 2008; 20:139–164. The authors used a genetically informed design comparing cognitive outcome of siblings with different exposure. When genetics and environmental characteristics shared by the siblings were controlled, the PTE effects on CD and ODP disappeared.
22• Gilman S, Gardener H, Buka S. Maternal smoking during pregnancy and children's cognitive and physical development: a causal risk factor? Am J Epidemiol 2008; 168:522–531. This study of over 50 000 children examined physical and cognitive outcomes. After adjustment, PTE predicted decreased birthweight and increased child overweight at age 7 years. Effects were nonexistent for APGAR, asthma, conduct problems, intelligence or academic achievement.
23•• Becker K, El-Faddagh M, Schmidt M, et al. Interaction of dopamine transporter genotype with prenatal smoke exposure on ADHD symptoms. J Pediatr 2008; 152:263–269. This study showed a significant interaction between DAT1 genotype and PTE emerged that indicated that males with PTE who were homozygous for DAT1 had higher hyperactivity–impulsivity than males from all other groups. This study showed the importance of multifactorial factors in the explaining the nature of attention hyperactivity disorder.
24• Neuman R, Lobos E, Reich W, et al. Prenatal smoking exposure and dopaminergic genotypes interact to cause a severe ADHD subtype. Biol Psychiatry 2007; 61:1320–1328. Utilizing dopaminergic genotypes, this study found an interaction with DAT1 and DRD4 and PTE on ADHD. The OR for PTE children with both alleles was 9.0. Study demonstrated that smoking during pregnancy is associated with specific subtypes of ADHD in genetically susceptible children.
25 Wakschlag L, Kistner E, Pine D, et al. Interaction of prenatal exposure to cigarettes and MAOA genotype in pathways to youth antisocial behavior. Mol Psychiatry, in press.
26• Rivkin M, Davis P, Lemaster J, et al. Volumetric MRI study of brain in children with intrauterine exposure to cocaine, alcohol, tobacco, and marijuana. Pediatrics 2008; 121:741–750. This MRI study showed that PTE is associated with reduction in cortical gray matter, head circumference, and total parenchymal volumes after control of other prenatal substance exposures.
27• Toro R, Leonard G, Lerner J, et al. Prenatal exposure to maternal cigarette smoking and the adolescent cerebral cortex. Neuropsychopharmacology 2008; 33:1019–1027. This MRI study of the cerebral cortex showed that oribitofrontal, middle frontal and parahippocampal corices were thinner in exposed versus nonexposed. Differences were more pronounced in females.
28• Jacobsen L, Picciotto M, Heath C, et al. Prenatal and adolescent exposure to tobacco smoke modulates the development of white matter microstructure. J Neurosci 2007; 27:13491–13498. This MRI study demonstrated that white matter microstructure was affected and auditory processing from both PTE and adolescent exposure to tobacco smoke after control of other prenatal substance exposures.
29• Jacobsen L, Slotkin T, Menci E, et al. Gender-specific effects of prenatal and adolescent exposure to tobacco smoke on auditory and visual attention. Neuropsychopharmacology 2007; 32:2453–2464. This FMRI study showed that PTE and exposure during adolescents exerts sex-specific deleterious effects on auditory and visual attention.
30•• Slotkin T, MacKillop E, Rudder C, et al. Permanent, sex-selective effects of prenatal or adolescent nicotine, exposure, separately or sequentially in rat brain regions: indices of cholinergic and serotonergic synaptic function, cell signaling and neural cell number and size at six months of age. Neuropsychopharmacology 2007; 32:1082–1097. This study on rats showed that prenatal or adolescent nicotine exposure evoke permanent changes in synaptic function. Prenatal exposure also sensitizes females to subsequent adverse effects of adolescent nicotine.
31 Shea A, Steiner M. Cigarette smoking during pregnancy. Nicotine Tob Res 2008; 10:267–278.
32 Pickett K, Wakschlag L. The short-term and long-term developmental consequences of maternal smoking during pregnancy. In: Preece P, Riley E, editors. Drugs in pregnancy: the price for the child: exposure to fetal teratogens and long term neurodevelopmental outcomes. London: Mac Keith Press, in press.
33 Button T, Maughan B, McGuffin P. The relationship of maternal smoking to psychological problems in the offspring. Early Hum Dev 2007; 83:727–732.
34•• Slotkin T. If nicotine is a developmental neurotoxicant in animal studies, dare we recommend nicotine replacement therapy in pregnant women and adolescents? Neurotoxicol Teratol 2008; 20:1–19. This study questions the utility and safety of recommending nicotine replacement therapy in pregnant women or adolescents after convincingly demonstrating from the animal and human literature the permanent adverse effects of nicotine on the developing brain.

development; pregnancy; tobacco

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