The relationship of maternal smoking to psychological problems
in the offspring

There is strong evidence for an association between maternal smoking in pregnancy and
psychological problems in offspring. The problems most frequently associated are attention
problems, hyperactivity, and conduct problems, although there is some evidence for an association
with substance use problems as well. The nature of this association is unclear, but it is likely the
result of a number of different mechanisms. Animal studies provide evidence for a causal relationship,
in which exposure to nicotine has detrimental effects on foetal development. Other studies suggest
that factors that correlate with maternal prenatal smoking may be the real risk factors for behavioural
problems, although evidence that the associations remain after controlling for such risks goes some
way to dispel this as the only explanation.
Mick E, Biederman J, Faraone SV, Sayer J, Kleinman S. Case-control study of attention-deficit

hyperactivity disorder and maternal smoking, alcohol use, and drug use during pregnancy. J Am Acad

Child Adolesc Psychiatry 2002;41:378–85. [PubMed: 11931593]

Attention, hyperactivity, and related problems

Attention and hyperactivity-related problems encompass a variety of symptoms: inattention
(where children are easily distracted and unable to keep their mind on a single task for extended
periods of time); hyperactivity (often indicated by a child's constant restlessness); and
impulsivity, indicated by a lack of control or restraint. For the purpose of research, these
phenotypes are often defined operationally in terms of counts of the numbers of symptoms the
child has exhibited over a period of time, either for the individual phenotypes or for a composite
attention-hyperactivity-impulsivity score. In addition, classification may be by clinical
diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM based criteria) or
Hyperkinetic Disorder (ICD-10 based criteria). Consistent associations have been reported
between attention/hyperactivity problems and maternal prenatal smoking, that seem robust to
variations in methods of analysis, measures of child outcomes, or measures of maternal
smoking (e.g. any versus none; numbers of cigarettes smoked; or smoking in specific trimesters
of pregnancy). The strength of the association does differ slightly across studies, although generally it appears that the
children of smokers are approximately 3 times more likely to have clinical diagnoses of ADHD
than the children of non-smokers, with an increase in risk of between 2 and 4 times commonly
reported.
Milberger S, Biederman J, Faraone SV, Jones J. Further evidence of an association between maternal

smoking during pregnancy and attention deficit hyperactivity disorder: findings from a high-risk

sample of siblings. J Clin Child Psychol 1998;27:352–8. [PubMed: 9789194]

For example, one research group demonstrated that the mothers of ADHD probands
were twice as likely to smoke more than 20 cigarettes per day for at least 3 months of their
pregnancy as the mothers of control children; and a second research group showed that not
only were children of smokers at greater risk of ADHD than the children of non-smokers, but
that the siblings of ADHD probands were also four times more likely to have ADHD when
their mothers smoked during pregnancy. A similar association was demonstrated for
diagnoses of Hyperkinetic Disorder in 2 to 8 years olds. In this study children of prenatal
smokers were 3 times more likely to have hyperkinetic disorder than the children of mothers
who refrained from smoking, an association that remained significant even after controlling
for potentially confounding factors such as family psychiatric history, parental schooling,
employment, income, and co-habitation status (although inclusion of these controls did result
in a reduction of the risk estimate to two-fold).
Linnet KM, Wisborg K, Obel C, et al. Smoking during pregnancy and the risk for hyperkinetic disorder

in offspring. Pediatrics 2005;116:462–7.

Antisocial behaviour

The term ‘antisocial’ is also used in relation to a wide spectrum of problem behaviours. In
children it may refer to negativity and general behavioural problems such as lying, stealing, or
cheating on school tests, or to clinical diagnoses of Conduct Disorder in those with severe
difficulties. In adults it may refer to criminal behaviour (determined by arrest records or by
self report), or to clinically defined Antisocial Personality Disorder.
Evidence for an association between maternal prenatal smoking and disruptive and negative
behaviour in childhood has been demonstrated in children as young as age two, even after
controlling for confounding risks. Furthermore, this association is also found later in childhood,
in adolescence, and in adulthood. For example, rates of Conduct Disorder were twice as high
in the children of mothers who smoked at least 20 cigarettes per day during pregnancy as in
those who did not. Males whose mothers smoked more than 20 cigarettes per day during the
third trimester of pregnancy were 1.6 times more likely to be arrested for a non-violent crime,
1.8 times more likely to be ‘life-course persistent’ offenders, and twice as likely to be arrested
for a violent crime in adulthood than males whose mothers did not smoke during the third
trimester.
Wakschlag LS, Keenan K. Clinical significance and correlates of disruptive behavior in

environmentally at-risk preschoolers. J Clin Child Psychol 2001;30:262–75. [PubMed: 11393926]

METHODS

Subjects were siblings of both sexes derived from two identically designed, longitudinal casecontrol
family studies conducted at the Clinical and Research Programs in Pediatric
Psychopharmacology and Adult ADHD at Massachusetts General Hospital (MGH). Briefly, these studies included male
and female youth probands with and without ADHD and their first-degree relatives (hereafter
referred to as the Boys and Girls ADHD study, respectively). For both studies, potential
probands were excluded if they had been adopted, if their nuclear family was not available, if
they had major sensorimotor handicaps (paralysis, deafness, blindness), if they had psychosis
or autism, or if they were unable to participate in the assessments due to language barriers or
an estimated IQ < 80. After a complete description of the study, parents provided written
informed consent for their children, and children and adolescents provided written assent. The
IRB at MGH approved this study.
We used a three-stage ascertainment procedure to select probands. For ADHD subjects,
the first stage was their referral, which resulted in a clinical diagnosis of ADHD. The second
stage confirmed the diagnosis of ADHD through a telephone questionnaire administered to the
mother. The third stage was a diagnostic assessment with a structured interview. Only patients
who received a positive diagnosis at all three stages were included. Controls were similarly
selected though a three-stage procedure. First, we ascertained them from consecutive referrals
to medical clinics for routine physical examinations at both the psychiatric and pediatric
sources. In stage two, the control mothers responded to the DSM-III-R ADHD telephone
questionnaire about their daughters. Eligible controls meeting study entry criteria were
recruited for the study and received the third stage, a diagnostic assessment with a structured
interview. Only subjects classified as not having ADHD at all three stages were included in
the control group.
To avoid the potential for bias resulting from studying referred samples, we utilized data from
the non-referred sibling samples of both sexes from both studies (n=303 from the Boys study
and n=274 from the Girls study). In the Boys study, the siblings were assessed at baseline and
at four and ten-year follow-ups. In the Girls study, the siblings were assessed at baseline and
at a five-year follow-up. The association between maternal smoking during pregnancy and
ADHD was previously tested using the baseline assessment of the sibling sample from the
Boys study (n=303, 53% of our total sample). The present study is unique because: 1) we are
examining other psychopathological outcomes, in addition to ADHD; 2) we are using both
baseline and follow-up assessments of the Boys sibling sample; and 3) we have included
additional subjects not examined previously. The age range of the sibling samples at baseline
were 5 to 37 (mean 13.5) and 6 to 29 (mean 13.3) for the Boys and Girls studies, respectively.
Maughan B, Taylor C, Taylor A, Butler N, Bynner J. Pregnancy smoking and childhood conduct

problems: a causal association? J Child Psychol Psychiatry 2001;42:1021–8. [PubMed: 11806683]
Bardone AM, Moffitt TE, Caspi A, Dickson N, Stanton WR, Silva PA. Adult physical health outcomes

of adolescent girls with conduct disorder, depression, and anxiety. J Am Acad Child Adolesc

Psychiatry 1998;37:594–601. [PubMed: 9628079]

Possible Mechanisms

A Direct cause and effect relationship
A variety of mechanisms might underlie these associations. The first key possibility is of a
direct cause and effect association, i.e. that some component of the smoked by the
mother (possibly the nicotine, or the carbon monoxide), may directly affect the developing
foetus. In the absence of experimental evidence, a variety of criteria can be applied to evidence
from observational (non-experimental) human studies to assess the likelihood that reported
associations reflect causal mechanisms. These are: strength and consistency of the reported
association, temporal ordering, a dose-response relationship, and biological plausibility, whereas cigarettes contain a large number of chemicals, each of which may impact on fetal development.
Nicotine exposure during gestation at low doses (0.75 or 1.5 mg/kg/d) significantly increased mRNA levels and density of neurons that express ENK in the hypothalamic paraventricular nucleus and central nucleus of the amygdala, OREXIN, and another orexigenic peptide, melanin-concentrating hormone, in the perifornical lateral hypothalamus in preweanling offspring. These effects persisted in the absence of nicotine, at least until puberty. During adolescence, offspring also exhibited significant behavioral changes, increased consumption of nicotine and other substances of abuse, ethanol and a fat-rich diet, with no changes in chow and water intake or body weight. These findings reveal a marked sensitivity during gestation of the orexigenic peptide neurons to low nicotine doses that may increase the offspring's propensity to overconsume substances of abuse during adolescence. Evidence from animal models suggests that the cognitive deficits may be a consequence of in utero nicotineexposure in the brain during critical developmental periods. However, maternal smoking exposes the fetus to not only nicotine but also a hypoxic intrauterine environment. Thus, both nicotine and hypoxia are capable of initiating cellular cascades, leading to long-term changes in synaptic patterning that have the potential to affect cognitive functions. This study investigates the combined effect of in utero exposure to nicotine and hypoxia on neuronal and glial elements in the hippocampal CA1 field. Fetal guinea pigs were exposed in utero to normoxic or hypoxic conditions in the presence or absence of nicotine. Hypoxia increased the protein levels of matrix metalloproteinase-9 (MMP-9) and synaptophysin and decreased the neural density as measured by NeuN immunoreactivity (ir). Nicotine exposure had no effect on these neuronal parameters but dramatically increased the density of astrocytes immunopositive for glial fibrillary acidic protein (GFAP). Further investigation into the effects of in utero nicotine exposure revealed that both GFAP-ir and NeuN-ir in the CA1 field were significantly reduced in adulthood.
Roy TS, Sabherwal U. Effects of gestational nicotine exposure on hippocampal morphology.

Neurotoxicol Teratol 1998;20:465–73. [PubMed: 9697973]

C. Dose-response relationship—If a causal association exists between a risk factor and
an outcome, we would expect that the higher the level of exposure, the more pronounced the
risk. Almost all of the studies described in this review have demonstrated a dose-response
relationship, with a linear relationship between the extent of smoking in pregnancy and severity of problem outcomes in offspring.

C. Biological Plausibility—To identify biological mechanisms by which smoking in
pregnancy might cause psychological problems in offspring, we have looked briefly at the
limited evidence from human studies, and then at results from animal studies,, which (as noted
above) allow for clearer manipulation and control.
A single study of human fetal development demonstrated that the fetuses of mothers who
smoked more than 10 cigarettes per day suffered from reduced blood flow to the brain due to
increased resistance in uterine, umbilical and fetal middle cerebral arteries than the fetuses of
non-smokers. Lack of blood to the brain of the developing fetus may thus provide a
mechanism by which smoking during pregnancy may impact upon the psychological
development of children.
Studies of the effects of nicotine on the brains of animals are more common, and have pointed
to a variety of mechanisms that may account for effects on psychological outcomes. Prenatal
exposure to nicotine in rats reduces the neuronal area of various regions of the hippocampus,
resulting in alterations to the brain cell structure which persist to young adulthood. Nicotine
exposure also results increased serotonin transporter density in the rat brain, which would
influence the activity of serotonin, a neurotransmitter that has been strongly linked to
behavioural problems in humans. Prenatal nicotine exposure also appears to lead to reduction
in both dopamine and serotonin turnover in the brains of rats.
Albuquerque CA, Smith KR, Johnson C, Chao R, Harding R. Influence of maternal tobacco smoking

during pregnancy on uterine, umbilical and fetal cerebral artery blood flows. Early Hum Dev

2004;80:31–42. [PubMed: 15363837]
Muneoka K, Ogawa T, Kamei K, Mimura Y, Kato H, Takigawa M. Nicotine exposure during

pregnancy is a factor which influences serotonin transporter density in the rat brain. Eur J Pharmacol

2001;411:279–82. [PubMed: 11164385]

C. Post natal smoking—Mothers who smoke during pregnancy are also more likely to
smoke after their pregnancy. Once again, it may be this, rather than smoking during pregnancy,
that influences some aspects of the child's behaviour, especially, perhaps, outcomes reflecting
the child's own use of substances. Although it is possible that there are chemical effects of
maternal smoking predisposing a child to smoke, learned behaviour modelled on the mother
seems more likely. Mechanisms underlying other behavioural outcomes are less certain.
Evidence from one study, for example, showed that that if a mother smoked during
pregnancy but gave up shortly after the child's birth, the child's risk of antisocial behaviour
was not much higher than that of children whose mothers refrained from smoking during
pregnancy.
Maughan B, Taylor C, Taylor A, Butler N, Bynner J. Pregnancy smoking and childhood conduct

problems: a causal association? J Child Psychol Psychiatry 2001;42:1021–8. [PubMed: 11806683]

CONCLUSION

Our data suggest that prenatal exposure to nicotine and hypoxia not only alters synaptic patterning acutely during fetal development, but that nicotine also has long-term consequences that are observed well into adulthood. Moreover, these effects most likely take place through distinct mechanisms. These findings suggest that prenatal nicotine exposure can be responsible for a number of changes to the structure and functioning of the brain of the developing fetus, and ultimately the live progeny. Each of these effects may impact, either additively or even interactively, on the psychological development of exposed offspring, although not all such effects will necessarily contribute to problematic development. Stop smoking during pregnancy!