Post on 28-Dec-2015
description
ORIGINAL CONTRIBUTION
Smoking during pregnancy and psychiatric disordersin preschoolers
Lise Carol Ellis • Turid Suzanne Berg-Nielsen •
Stian Lydersen • Lars Wichstrøm
Received: 20 June 2011 / Accepted: 18 June 2012 / Published online: 6 July 2012
� Springer-Verlag 2012
Abstract The overall objective of this study was to
determine whether smoking during pregnancy is related to
psychiatric disorders in 4-year-olds while controlling for a
wide range of potential confounding variables (i.e. parental
anxiety, depression, personality disorders, drug abuse, and
socio-economic characteristics). Parents of a community
sample of 4-year-olds (N = 995) residing in the city of
Trondheim, Norway were interviewed using the Preschool
Age Psychiatric Assessment, which includes information on
prenatal smoking. After adjusting for potential confounding
variables using the propensity score, smoking during
pregnancy was found to increase the odds for attention-
deficit/hyperactivity disorder (ADHD) OR = 2.59 (CI
1.5–4.34, p \ 0.001), oppositional defiant disorder (ODD)
OR = 2.69 (CI 1.84–3.91, p = 0.02) and comorbid OR =
2.55 (CI 1.24–5.23, p \ 0.001). Prenatal smoking during
pregnancy is associated with an increased risk for symp-
toms of ADHD and ODD independently of each other, in
4-year-olds.
Keywords Prenatal smoking � ADHD � ODD �Internalising disorders � Preschool children
Introduction
Prenatal smoking has been found to increase the risk of
attention-deficit/hyperactivity disorder (ADHD), opposi-
tional defiant disorder (ODD), conduct disorder (CD), poor
cognitive functioning, antisocial problems, aggression,
delinquency, substance abuse, and internalising problems
[1–7]. The majority of studies on this topic have examined
children during mid or late childhood. Children with an
early manifestation of disruptive behaviours have been
found to develop more serious long-term psychopatholo-
gies. For instance, approximately one-quarter of children
with ODD later develop conduct disorder (CD), and a few
of these children develop antisocial personality disorder in
adulthood [8, 9]. The short- and long-term costs of these
problems are grave not only for the patients and their
families, but also for society at large. Therefore, it is
important to establish whether prenatal smoking affects
early development. At present, only seven studies have
examined the effect of prenatal smoking on preschoolers
[5, 10–15]. Six of these studies used various rating scales to
measure the effects of prenatal smoking on symptoms
related to externalising problems. The drawback of this
technique is that high scores on rating scales do not nec-
essarily translate into disorders. One study [15] included a
structured diagnostic interview, but the final analyses were
performed on a composite of the results from rating scales
and symptom counts derived from this diagnostic inter-
view. At present, it is unknown whether prenatal smoking
merely increases the risk for elevated levels of externalis-
ing symptoms or if it also increases the risk of diagnosable
disorders. Thus, the current study addressed whether pre-
natal smoking increases the risk for disorders in a large
community of 4-year-olds using a state-of-the-art semi-
structured diagnostic interview.
L. C. Ellis (&) � L. Wichstrøm
NTNU Social Science, Department of Psychology,
Norwegian University of Science and Technology (NTNU),
7491 Trondheim, Norway
e-mail: lise.ellis@gmail.com; lise.carol.ellis@samfunn.ntnu.no
T. S. Berg-Nielsen � S. Lydersen
Regional Centre for Child and Adolescent Mental Health,
Norwegian University of Science and Technology,
Trondheim, Norway
L. Wichstrøm
Department of Child Psychiatry, Central Regional Health
Authority (RHA), St. Olavs Hospital, Trondheim, Norway
123
Eur Child Adolesc Psychiatry (2012) 21:635–644
DOI 10.1007/s00787-012-0300-y
The neurotoxicological mechanisms linking prenatal
smoking to behavioural disorders are not fully understood.
However, prenatal smoking has been found to affect the
foetus by stimulating nicotinic acetylcholine receptors
(nAChRs) in the developing brain, thereby altering axonal
and dendritic branching in several brain regions [16].
Studies have found that prenatal nicotine exposure can
create developmental disturbances in the serotonergic and
dopaminergic systems [17], which are implicated in the
regulation of emotion and behaviour.
Several prospective studies have demonstrated a dose–
response effect of prenatal smoking on externalising
behaviours [18, 19]. Such results support a causal interpre-
tation of the association. Despite these findings, the causal
relationship between maternal prenatal smoking and dis-
ruptive behaviours later exhibited by the children has been
challenged because numerous factors could confound the
association, including socioeconomic status, the use of other
substances during pregnancy, and other maternal or paternal
characteristics, such as education level, age, parental per-
sonality, ethnic background, and psychiatric history [20].
It has been suggested that mothers with antisocial traits,
conduct disorder or ADHD are more likely to smoke, and
therefore genes, rather than smoking per se, may cause the
observed associations [19]. Several quasi-experimental
studies have used innovative designs in order to attempt to
disentangle the effects of prenatal conditions from maternal
and offspring genomes [21], e.g., sibling designs, com-
paring offspring exposed to prenatal nicotine exposure to
siblings who had not been prenatally exposed [22–24]. The
results from these studies indicate that the risk of ADHD
and ODD in offspring appears to become weaker when
siblings are taken into account, indicating that the effects
may partly be due to genetic or other unmeasured con-
founds. Furthermore, a recent study by Thapar et al. [25] on
offspring conceived with assisted reproduction methods
involving both biological and non-biological mothers also
supported an effect of genes rather than smoking. Although
it is well established that ADHD is highly heritable [26], an
additional prenatal effect of smoking cannot be excluded
[4]. The consideration of this topic in either/or terms is
overly simplistic because it is probable that both genetic
and teratological effects contribute to the association
between prenatal smoking and behavioural disorders [27].
We have therefore controlled for a wide range of
potential confounding variables in the current study.
However, we have deliberately not controlled for various
parenting behaviours as recent studies have suggested [15],
as it does not seem logical or probable that parenting
behaviours after birth would influence whether a mother
smokes during pregnancy.
Most of the literature on maternal prenatal smoking
and disruptive behaviour have focused on ADHD and
behavioural problems in isolation [28]. Given the high
comorbidity between ADHD and ODD, including among
preschoolers [29], it is feasible that the association between
prenatal smoking and ODD could result from the effect on
ADHD (ODD route) or vice versa (ADHD route). Thus far,
the literature provides conflicting results; in support of an
ODD route, Nigg and Breslau [3] found that prenatal
smoking predicted ODD when ADHD was controlled, but
the reversed was not true. Similarly, Wakschlag et al. [28]
found that prenatal exposure was associated with ODD as
well as comorbid ADHD and ODD, but not with ADHD
only. However, Nomura et al. [30]. reached the opposite
conclusion, supporting an ADHD route. Specifically,
mothers who smoked during pregnancy were found to have
a significantly increased risk of having offspring with
comorbid ADHD/ODD and ADHD but no increase in the
risk of having offspring with ODD only. These latter results
are compatible with the finding of Mick et al. [31] that
prenatal smoking predicted ADHD even when CD had been
controlled for. Moreover, a prenatal effect of smoking could
potentially contribute to both ADHD and disruptive disor-
ders via similar neuroteratological mechanisms, which
would indicate a direct route to either disorder that is not
mediated through the other disorder. Such a direct route was
supported by the finding of Arnold et al. [32] that mothers
who smoked during pregnancy were more likely to have
children with ADHD and CD as well as comorbid ADHD
and CD. Similar results were found by Button et al. [4] who
reported that smoking had an independent effect on anti-
social behaviour and symptoms of ADHD. Additional
support for a direct route was provided by the finding of
Hutchinson et al. [12] of a dual effect for boys (but not for
girls) and the results of Biederman et al. [33] among sib-
lings of twins (but not among the twins). A direct route is
also supported by Huijbregts et al. [5], who found that
prenatal smoking predicted co-occuring hyperactivity–
impulsivity and physical aggression, which might be
indicative of behavioural problems. Taken as a whole, the
data in the literature appear to be conflicting. Furthermore,
as ADHD and ODD/CD are infrequent in the general pop-
ulation, a lack of statistical power may produce inconsistent
results. The data from the studies that supported a direct
effect route tended to have the most statistical power
because they involved the largest number of subjects.
If smoking during pregnancy has a dramatic impact on
the developing brain and increases the risk for diagnostic
disorders (i.e., ADHD and ODD), the detrimental effect
should be expected to manifest by the preschool years.
Therefore, it is hypothesised that (1) smoking during
pregnancy increases the risk for ADHD and ODD when
controlling for a wide range of potential confounding
variables, and (2) prenatal smoking increases the risk of
ADHD or ODD or both disorders.
636 Eur Child Adolesc Psychiatry (2012) 21:635–644
123
Methods
Participants
The present study was conducted as part of the Trondheim
Early Secure Study (TESS). All children living in Trond-
heim, Norway who were born in 2003–2004 and their
parents were invited to participate in the study. This study
was performed in collaboration with the community health
clinics, which routinely invite all children for a health
check-up when they reach 4 years of age.
The health clinic staff missed asking 166 families to
participate. Parents with a lack of proficiency in Norwegian
were excluded (n = 176). Of the 3,016 eligible parents,
2,475 (82.1 %) consented to participate in the study. The
children were divided into four strata according to their
scores on the Strengths and Difficulties Questionnaire
(SDQ) [34], resulting in the following probabilities
of selection into a further study: SDQ = 0–4, p = 0.37;
SDQ = 5–8, p = 0.48; SDQ = 9–11, p = 0.70; SDQ =
12–40, p = 0.89. According to this procedure, a subsample
of 1,250 parents was invited to participate in the study. Of
these parents, 995 (79.5 %) completed the interview. The
drop-out rate after providing consent at the health clinic did
not differ across the four SDQ strata (Chi-squared = 5.70,
df = 3, NS) or gender (Chi-squared = 0.23, df = 1, NS).
The sample, adjusted for stratification, was compared with
register information from Statistics Norway on all the par-
ents of the 4-year-olds in Trondheim in 2007 and 2008. The
sample contained significantly more divorced parents
(7.6 %) than the general population (2.1 %), and the edu-
cational level of the sample group was virtually identical to
that of the population. The mean age of the children was
53.0 months (range 46.3–63.0, SD = 2.1), and the mean
number of siblings was 1.3 (SD = 1.0); 12.8 % of the
children did not have siblings.
Procedure
The study was approved by the Regional Committee for
Medical and Health Research Ethics. The parents received
a letter of invitation with their scheduled appointment and
the SDQ before attending the public health check-up for
their 4-year-old child. The SDQ is a 31-item measure of
mental health problems in children aged 4–18 years. The
items relate to emotional symptoms, conduct problems,
hyperactivity, and peer problems. At the health clinic, the
nurse informed the parents about the study and obtained
their consent to participate. The SDQ was scored manually
at the health clinic, and a computer-based random number
generator determined whether the family should be invited
to participate in a further study.
After attending the health clinic and being selected for
the study, one of the parents was interviewed at home, at
work or at the University Clinic with a structured child-
diagnostic interview. The same parent was then invited to
attend the University Clinic with the 4-year-old for
observation and testing. Approximately 20 % of the
interviewed parents were fathers.
Measurements
Prenatal smoking
During the structured interview, the parent was asked a
series of pregnancy-related questions related to alcohol use
and smoking during pregnancy. If smoking was reported,
the mother was asked the frequency of cigarettes she
smoked during the first, second, or third trimester.
Birth weight
During the interview, the mothers were asked to report
their offspring’s birth weight and gestational age.
Psychiatric diagnoses
The parents were interviewed using the electronic version
of the Preschool Age Psychiatric Assessment (PAPA) [35],
from which the DSM-IV diagnoses for ODD and ADHD as
well as a range of anxiety disorders (i.e., social phobia,
separation anxiety, generalised anxiety, and specific pho-
bia) and depressive disorders (i.e., major depression, dys-
thymia, and depression not otherwise specified) were
derived. Anxiety disorders and depressive disorders were
combined. The PAPA is a semi-structured, interviewer-
based diagnostic interview that is used to assess children
between 2 and 6 years of age. The questions are based on
the preceding 3-month period to promote accurate recall.
Diagnoses were computed by computer algorithms for
ADHD and ODD. ODD requires that the symptoms occur
‘‘often’’. ‘‘Often’’ was defined post hoc as occurring within
the highest 10 % in the current population, as determined
by frequency counts [36]. Because the primary interest was
whether prenatal smoking might cause symptoms of dis-
orders and not necessarily the resulting impairment or
distress, only the symptom criteria were applied.
The interviewers (n = 7) were trained by the developers
of the PAPA. They all had at least a bachelor’s degree in
relevant fields (i.e., psychologists, health nurses, social
workers, day care teachers) and extensive prior experience
with children and families. Regular meetings were held
with master coders. In addition, the interviews were
observed behind one-way mirrors to ensure adherence to
Eur Child Adolesc Psychiatry (2012) 21:635–644 637
123
the interview guide and to prevent rater drift. The main
interview duration was 2.25 h. Blinded raters recoded 9 %
of the interviews. The multivariate inter-rater reliabilities
between pairs of raters [37] were as follows: ADHD
k = 0.96 and ODD k = 0.89.
Confounders
Antisocial, schizoid, dependent, and borderline personality
symptoms were assessed during the DSM-IV and ICD-10
Personality Questionnaire (DIP-Q), which is a true/false
self-report questionnaire that is designed to measure all 10
DSM-IV personality disorders [38]. The DIP-Q has been
shown to discriminate well between different samples [39]
and has good validity [40]. The reliability coefficient theta
[41] for different scales varied between H = 0.71 and
H = 0.92. Parental depressive symptoms and anxiety
symptoms were assessed using the Beck Depression
Inventory-II (BDI-II; [42]) and Beck Anxiety Inventory,
respectively. Alcohol problems were assessed using the
Alcohol Use Disorders Identification Test (AUDIT) [43].
The parents’ level and type of occupation were coded
according to the International Classifications of Occupa-
tions [44]. If the parents were living together, the parent
with the highest-rated occupation was selected.
The interviewed parents were asked whether the tar-
geted child had siblings (yes/no), whether they were of
Norwegian origin, whether the birth of the target child was
easy or difficult on a scale of 1 (very easy) to 5 (very
difficult), and whether alcohol abuse occurred during the
pregnancy on a scale from 0 (did not drink) to 13 (drank
daily, including 6 ? alcohol units at least once a week).
Furthermore, the parents were asked whether the preg-
nancy had been stressful (yes/no), whether the pregnancy
had made them feel depressed (yes/no) and whether they
had been trying to become pregnant (yes/no). The parents
were also asked about ever having had a mental health
problem that resulted in a major breakdown in important
social roles (yes/no) and whether they ever (1) sought
psychiatric treatment (yes/no), (2) presently had drug/
alcohol problems (yes/no), (3) had ever been arrested (yes/
no), (4) had ever had alcohol/drug problems or both (yes/
no), (5) had ever used medication for mental health prob-
lems (yes/no), or (6) had ever been admitted to a hospital
for such problems (yes/no). Finally, the parents were asked
about their capacity to pay their bills on time (very capable/
quite capable/poor) (Table 1).
Statistical analysis
The odds of the children having psychiatric disorders,
according to the smoking status of the mother, were exam-
ined using a logistic regression. The number of ADHD
symptoms and the number of ODD symptoms were analysed
using linear regression. Because we oversampled children
with mental health problems, the data were weighted back
with the inverse of the drawing probabilities to yield true
population estimates and the Huber–White sandwich esti-
mator was used to provide robust standard errors. We used
propensity score analyses to adjust for potential confound-
ers. This was done in two steps: first, a propensity score
logistic regression model was constructed with the exposure
(smoking) as dependent variable, and selected potential
confounders as covariates. The predicted probability of
exposure is the propensity score. Second, the propensity
score was used as a covariate together with the exposure
variable in the final analysis. We used the quintiles of the
propensity score as a categorical variable in the main anal-
ysis. This typically removes 90 % of the bias [45]. In a
secondary analysis, we used the propensity score as an
untransformed scalar variable. We did not use propensity
score matching because there is no straight forward method
for matching in a weighted sample. These 24 variables were
considered as potential confounders: narcissistic personality
traits, histrionic personality traits, borderline personality
traits, schizotypal personality traits, paranoid personality
traits, avoidant personality traits, dependent personality
traits, OCD personality traits, parental alcohol use, parental
anxiety, parental depresion, alcohol use during pregnancy,
stress during pregnancy, depression during pregnancy,
planned pregnancy, parental feelings about pregnancy,
mothers’ feelings in the first month after birth, parental
experience of mental breakdown, parent requested medical
treatment, parent ever been arrested, parent ever been
indicted by police, parental ability to pay family expenses,
parent received medical treatment for psychological disor-
der, and parental admission to a mental health institution.
The selection of variables for the propensity score was done
as follows: the variables mothers’ age, SES, and antisocial
personality traits were included, since these are a priori
known to be important candidate confounders. For the
additional variables, we first selected those with p \ 0.10
adjusted for the three-mentioned variables. Then, we used
backwards elimination to include in the final propensity
score model only those with p \ 0.10. All p values are two-
sided, and p \ 0.05 was considered significant unless
otherwise stated. Ninety-five percent confidence intervals
(CI) are reported were relevant. The analyses were per-
formed using SPSS 18 software.
Results
The estimated percentage of women in the population who
smoked during pregnancy was 14.0 %. Of the 148 mothers
who smoked during pregnancy, 69.6 % smoked less than
638 Eur Child Adolesc Psychiatry (2012) 21:635–644
123
Table 1 DemographicsSample characteristics Never smoked during
pregnancyAny smoking duringpregnancy
N % N %
Gender of child
Male 391 87.1 58 12.9
Female 396 83.5 78 16.5
Gender of the interviewed parent
Male 123 86.6 19 13.4
Female 661 85.1 116 14.9
Ethnic origin of the biological mother
Norwegian 722 84.7 130 15.3
Western Countries 24 96.0 1 4.0
Other Countries 36 92.3 3 7.7
Ethnic origin of the biological father
Norwegian 707 85.5 120 14.5
Western Countries 48 85.7 8 14.3
Other Countries 53 85.5 9 14.5
Biological parents’ marital status
Married 452 89.7 52 10.3
Cohabiting [6 months 240 81.9 53 18.1
Separated 11 68.8 5 31.3
Divorced 53 74.6 18 25.4
Widowed 3 100 0 0
Cohabitating \6 months 9 75.0 3 25.0
Never lived together 8 61.5 5 38.5
Interviewed parent’s socio-economic status
Leader 43 87.8 6 12.2
Professional, higher level 213 93 16 7.0
Professional, lower level 316 89.3 38 10.7
Formally skilled worker 162 72.0 63 28.0
Farmer/Fisherman 3 60.0 2 40
Unskilled worker 23 82.1 5 17.9
Interviewed parent’s highest completed education
Some education after junior high school 32 56.1 25 43.9
Senior high school 113 72.9 42 27.1
Some education after senior high school 22 73.3 8 26.7
Some college or university degree 57 82.6 12 17.4
Bachelor’s degree 53 93.0 4 7.0
College degree (3–4 years) 282 89.8 32 10.2
Master’s degree or similar 186 95.99 8 4.1
PhD Completed/ongoing 36 94.7 2 5.3
Household gross annual income
0–225,000 NOK (0–40,000 USD) 19 63.3 11 36.7
225,000–525,000 NOK (40,000–94,000 USD) 127 76.5 39 23.5
535,000–900,000 NOK (94,000–161,000 USD) 324 85 57 15
900,000 ? NOK (161,000 ? USD) 227 92.3 19 7.7
At least one parent has received treatment for mental health problems
None 533 87.5 76 12.5
Outpatient only 116 85.3 20 14.7
Hospitalised 69 82.1 15 17.9
Parents have received medical treatment for mental health problems
Yes 87 81.3 20 18.7
No 627 87.4 90 12.6
Eur Child Adolesc Psychiatry (2012) 21:635–644 639
123
10 cigarettes per day, and 30.4 % smoked 10 or more
cigarettes per day. A total of 34 children were diagnosed
with ADHD, 57 children were diagnosed with ODD, and
among these, 13 children had both ADHD and ODD.
The propensity score model for smoking during preg-
nancy included these ten potential confounders: borderline
personality traits, parental alcohol use, parental anxiety,
alcohol use during pregnancy, depression during preg-
nancy, planned pregnancy, mother’s feelings in the first
month after birth, parent ever been arrested, parental ability
to pay family expenses,parental admission to a mental
health institution. In addition, the variables mother’s age,
SES, and antisocial personality traits were included in the
propensity score model. Table 2 shows a clear increase in
proportion of smokers over the quintiles of the propensity
score, indicating that this propensity score is a suitable
summary measure for the confounders. The unadjusted OR
of having a child with ADHD for mothers who smoked
during pregnancy was 3.25 (CI 2.08–5.09, p \ 0.001).
After adjusting for quintiles of the propensity score as a
categorical variable, the OR was 2.59 (CI 1.50–4.34,
p \ 0.001), and 2.17(CI 1.30–3.61, p = 0.003) when using
the propensity score as a covariate. Further, the unadjusted
OR of having a child with ODD for mothers who smoked
during pregnancy was 3.12 (CI 2.30–4.24, p \ 0.001) and
2.69 (CI 1.84–3.91, p = 0.02) when adjusting for quintiles
of the propensity score as a categorical variable, and 2.46
(CI 1.66–3.63, p \ 0.001) when using the propensity score
as a covariate (Tables 2, 3).
To test whether the comorbidity between ADHD and
ODD could explain the effect of smoking on either disorder,
the children were divided into the following four groups:
those with neither ADHD nor ODD, those with only ADHD
(n = 21), those with only ODD (n = 44), and those with
comorbid ODD and ADHD (n = 13). Smoking during
pregnancy was predictive of comorbid ADHD and ODD.
The unadjusted OR was 3.67 (1.82–7.40, p \ 0.001). When
adjusting for quintiles of the propensity score as a cate-
gorical variable, the OR was 2.55 (1.24–5.23, p \ 0.001)
and 2.68 (1.84 to 3.91,p \ 0.001) when using the propen-
sity score as a covariate.
The analyses were performed again using linear regres-
sion with the number of ADHD symptoms and the number
of ODD symptoms as outcomes, and smoking during
pregnancy as the exposure variable. Smoking during preg-
nancy predicted ADHD symptoms (B = 0.67, SE = 0.13,
CI = 0.41–0.93, p = \0.001 (unadjusted). After adjusting
for quintiles of the propensity score as a categorical variable
(B = 0.50; SE = 0.15, CI = 0.20–0.80, p \ 0.001) and
(B = 0.40, SE = 0.14,CI = 0.12–0.68, p = 0.005) when
using the propensity score as a covariate. Smoking during
pregnancy predicted ODD symptoms (B = 0.36,
SE = 0.07, CI = 0.22–0.49, p \ 0.001 (unadjusted) and
(B = 0.34, SE = 0.09, CI = 0.18–0.51,p \ 0.001) when
adjusted for quintiles of the propensity score as a categor-
ical variable, and (B = 0.30, SE = 0.08, CI = 0.14–0.46,
p \ 0.001) when using the propensity score as a covariate
(Table 4).
Discussion
The principal findings of the present study were that
smoking during pregnancy predicted ADHD and ODD, and
comorbid ADHD and ODD in preschoolers. The associa-
tion beween smoking and ADHD/ODD could not be
attributed to a wide range of potential confounders or to the
comorbidity between the two disorders. Using propensity
score analysis, we could include more potential con-
founders in the analysis than we could have done by
adjustment for these confounders. The few studies that
have investigated younger children have examined aspects
of behavioural problems, for instance, physical aggression,
hyperactivity/impulsivity [5], externalising behaviours
[10, 14], or symptom counts of disruptive disorders [15];
diagnostic disorders have not previously been used as
Table 2 Propensity score quintiles and smoking during pregnancy
Propensity score quintile Smoking during pregnancy, n (%) Total
No Yes
1 158 (95.8) 7 (4.2) 165
2 157 (95.2) 8 (4.8) 165
3 149 (90.9) 15 (9.1) 164
4 134 (80.2) 33 (19.8) 167
5 108 (66.3) 55 (33.7) 163
Total 706 (85.7) 118 (14.3) 824
Table 3 Odds ratio (OR estimate, CI and p values) psychiatric disorders, for children exposed to smoking any time during pregnancy
Disorder
ADHD (n = 34) ODD (n = 57) ADHD and ODD (n = 13)
Unadjusted 3.25 (2.08–5.09), p \ 0.001 3.12 (2.30–4.24), p \ 0.001 3.67 (1.82–7.40), p \ 0.001
Adjusted for propensity score stratified in quintiles 2.59 (1.50–4.34), p \ 0.001 2.69 (1.84–3.91), p \ 0.001 3.69 (1.68–8.14), p \ 0.001
Adjusted for propensity score as covariate 2.17 (1.30–3.61), p = 0.003 2.46 (1.66–3.63), p \ 0.001 2.68 (1.84–3.91), p \ 0.001
640 Eur Child Adolesc Psychiatry (2012) 21:635–644
123
outcomes. However, the presence of a sufficient number of
symptoms to qualify for a disorder, which was the outcome
applied in the current study, is more likely to indicate the
prospect of a seriously altered life trajectory than an ele-
vated mean score of rating scale symptoms. For example, a
typical rating scale item for ADHD is ‘‘Can’t sit still,
restless or hyperactive’’. The informant (in this case, the
parent) must determine the definition of ‘‘restless’’, the
intensity of restlessness, how long the behaviour endures,
and how often the behaviour occurs before characterising a
child as ‘‘restless’’. Parents are likely to differ in their
evaluations of these symptoms. In an interviewer-based
interview, the trained interviewers ask the informant for
examples until they are satisfied that a child’s symptoms
meet the criteria, and then they ask for the duration, fre-
quency, and onset of the symptoms [46]. The present study
applied a more stringent measure of diagnostic disorders,
and yet, the effect of prenatal smoking on ADHD and ODD
remained.
To date, the literature is inconclusive on whether the
association between prenatal smoking and behavioural
disorders is caused by genetic transmission or the terato-
logical effect of nicotine during pregnancy. The present
design cannot exclude the possibility that the observed
association between smoking and disruptive disorders
results from genetic factors. Studies on the effect of pre-
natal nicotine exposure on rodents and primates support a
teratological effect of nicotine on the developing brain,
especially the hippocampus and areas in the prefrontal
cortex [47]. However, the possibility also exists that pre-
natal smoking may be a proxy for other environmental
effects (e.g., low socio-economic status) [4]. The present
study controlled for a wide range of such potential con-
founding variables, and the association remained. Recently,
evidence has been provided for genetic transmission [25];
however, strong genetic effects do not necessarily conflict
with environmental effects because of the possibility of
gene–environment interactions [48, 49].
Low birth weight is a well-replicated outcome of pre-
natal smoking and has been associated with disruptive
behavioural problems [3, 50], and associations between low
birth weight and prenatal nicotine exposure have also been
found in animal studies. Nonetheless, the current study did
not find significant differences in the birth weights of
nicotine-exposed children and non-exposed children.
However, nicotine at doses that do not cause intrauterine
growth retardation is still toxic to the developing brain [51].
Therefore, the level of smoking among mothers in the
current study was likely insufficient to cause retarded
growth but sufficient to cause an increased risk for disrup-
tive disorders.
Limitations
Several limitations of the present study should be taken into
account when evaluating the results. The main limitation of
this study is the inability to provide a rigorous test of
whether maternal smoking during pregnancy in fact causes
psychiatric disorders in children. Because a randomly
controlled study that assigns mothers to smoking and non-
smoking groups cannot be performed, other methods must
be applied. As mentioned previously, a recent study [25]
investigated mothers who either smoked or did not smoke
while undergoing assisted reproduction treatments as well
as their biological and non-biological offspring. This study
failed to identify an association between prenatal smoking
and ADHD. Several recent studies [15], however, may have
overcontrolled for a wide range of parenting behaviours that
are unlikely to influence whether a mother smokes during
pregnancy.
The current smoking measurement was too crude to
allow for a dose–effect response. This study did not control
for genetic confounding variables, e.g., the presence of
ADHD in the mother. We were also unable to control for IQ
in the parent or offspring as we did not measure this
potential confounder in this study. Previous studies have
shown mixed results on whether prenatal smoking affects
cognitive development [13]. Information was only available
for one parent; therefore, the personality traits and potential
mental health problems of the other parent were unavail-
able. For instance, it may have been more difficult for the
mother to discontinue smoking if the father smoked [52].
The heritable factors that increased the odds of the father
smoking could also increase the odds of the disruptive
behaviour in the child. Moreover, approximately 20 % of
the parent responders were fathers who answered the
questions on smoking during pregnancy on behalf of the
Table 4 Linear regression with number of ADHD or number of ODD symptoms as dependent variable, and smoking during pregnancy as
covariate (B, CI, and p values)
Number of ADHD symptoms Number of ODD symptoms
Unadjusted 0.67 (0.41–0.93), p \ 0.001 0.36 (0.22–0.49), p \ 0.001
Adjusted for propensity score stratified in quintiles 0.50 (0.20–0.80), p = 0.001 0.34 (0.18–0.51), p \ 0.001
Adjusted for propensity score as covariate 0.40 (0.12–0.68), p = 0.005 0.30 (0.14–0.46), p \ 0.001
Eur Child Adolesc Psychiatry (2012) 21:635–644 641
123
mothers. The possibility therefore exists that these fathers
were unable to remember the details of the mother’s pre-
natal smoking. The mothers may also have underreported
their prenatal smoking because of the social stigma against
smoking during pregnancy. The reporting of prenatal
smoking data relied on retrospective recall 4 years after
pregnancy, which is a potential weakness. However, a study
by Pickett et al. [53] that compared the retrospective recall
in relation to prospective reporting and biological mea-
surements 10 years earlier found that women’s reports were
accurate and reliable, particularly for second and third tri-
mesters of pregnancy. This accuracy has not been investi-
gated for the reports of fathers, however, and could
therefore represent a source of error.
Although we used a semi-structured diagnostic inter-
view, we applied only symptom criteria while excluding
impairment criteria for ADHD and ODD. In addition, the
questions were based on the preceding 3-month period
rather than on the minimum 6-month period required by the
DSM-IV. We did not control for passive smoking. Few
studies have controlled for postnatal smoking. However, it
seems unlikely that the effect of prenatal smoking would
disappear after controlling for postnatal smoking. Direct
nicotine exposure occurs in higher concentrations in the
foetus than in the mother, and environmental exposure is
weaker and less likely to affect brain development [2].
Furthermore, it is difficult to separate the effects of prenatal
and postnatal exposure because they are highly correlated
[13]. Nevertheless, a few studies have reported an effect of
both prenatal and postnatal smoking, although prenatal
smoking appears to be more influential [54]. Finally, it was
the same interviewer asking for diagnoses as for prenatal
smoking. However, both pieces of information are derived
from the PAPA, which is a 2–3 h interview that obtains a
great deal of background information, of which prenatal
smoking represents a very small part. Furthermore, the
PAPA includes a set of prescribed questions and probes,
and thus, it is not likely that the knowledge of prenatal
smoking status would have influenced the results, although
this effect cannot be ruled out.
In summary, the present findings suggest that the dis-
ruptive symptoms found in preschoolers prenatally exposed
to nicotine map onto psychiatric diagnoses at 4 years of
age, even after numerous confounding variables are con-
trolled for. Furthermore, prenatal smoking may be a com-
mon risk factor for both ADHD and ODD. Targeting
younger women who smoke for preventive programs or
offering smoking cessation therapy to pregnant women
may reduce the risk of ADHD and ODD. Although a causal
effect of smoking on behavioural disorders cannot be
conclusively demonstrated by the current study, it is
nonetheless ethical to offer interventions to at-risk women
rather than waiting for further research. This is particularly
the case because assisting young pregnant women to quit
smoking has a wide range of other health benefits for both
mothers and offspring [55].
Acknowledgments This research was funded by grants
185519/V50, 185760/V50, and 190622/V50 from the Research
Council of Norway and from grant 4396 from the Liaison Committee
between the Central Norway RHA and Norwegian University of
Science and Technology.
Conflict of interest None.
References
1. Braun JM, Daniels JL, Kalkbrenner A, Zimmerman J, Nicholas
JS (2009) The effect of maternal smoking during pregnancy on
intellectual disabilities among 8-year-old children. Paediatr
Perinat Epidemiol 23:482–491
2. Linnet KM, Dalsgaard S, Obel C, Wisborg K, Henriksen TB,
Rodriguez A, Kotimaa A, Moilanen I, Thomsen PH, Olsen J et al
(2003) Maternal lifestyle factors in pregnancy risk of attention
deficit hyperactivity disorder and associated behaviors: review of
the current evidence. Am J Psychiatry 160:1028–1040
3. Nigg JT, Breslau N (2007) Prenatal smoking exposure, low birth
weight, and disruptive behavior disorders. J Am Acad Child
Adolesc Psychiatry 46:362–369
4. Button TMM, Thapar A, McGuffin P (2005) Relationship
between antisocial behaviour attention-deficit hyperactivity
disorder and maternal prenatal smoking. Br J Psychiatry 187:
155–160
5. Huijbregts SCJ, Seguin JR, Zoccolillo M, Boivin M, Treblay R
(2007) Associations of maternal prenatal smoking with early
childhood physical aggression, hyperactivity-impulsivity, and
their co-occurrence. J Abnorm Child Psychol 35:203–215
6. Brennan PA, Grekin ER, Mortensen EL, Mednick SA (2007)
Relationship of maternal smoking during pregnancy with crimi-
nal arrest and hospitalization for substance abuse in male and
female adult offspring. Am J Abnorm Child Psychol 35:203–215
7. Ashford J, van Lier PAC, Timmermans M, Cuijpers P, Koot HM
(2008) Prenatal smoking and internalizing and externalizing
problems in children studied from childhood to late adolescence.
J Am Acad Child Adolesc Psychiatry 47:779–787
8. Moffit TE (1993) Adolescence-limited and life-course-persistent
antisocial-behavior—a developmental taxonomy. Psychol Rev
100:674–701
9. Hinshaw SP, Lee SS (2003) Conduct and oppositional defiant
disorders. In: Mash EJ, Barkley RA (eds) Child psychopathology.
Guildford, New York
10. Carter S, Peterson J, Gao WZ, Lusitini L (2008) Maternal
smoking during pregnancy and behaviour problems in a birth
cohort of 2-year-old Pacific children in New Zealand. Early Hum
Dev 84:59–66
11. Linnet KM, Obel C, Bonde E, Thomsen PH, Secher NJ, Wisborg
K, Henriksen TB (2006) Cigarette smoking during pregnancy and
hyperactive-distractible preschooler’s: a follow-up study. Acta
Paediatr 95:694–700
12. Hutchinson J, Pickett KE, Green J, Wakschlag LS (2009)
Smoking in pregnancy and disruptive behaviour in 3-year-old
boys and girls: an analysis of the UK Milennium Cohort Study.
J Am Acad Child Adolesc Psychiatry 48:283–289
13. Day NL, Richardson GA, Goldschmidt MA, Cornelius MD
(2000) Effects on prenatal tobacco exposure on preschoolers’
behavior. J Dev Behav Pediatr 21:180–188
642 Eur Child Adolesc Psychiatry (2012) 21:635–644
123
14. Stene-Larsen K, Borge AIH, Volrath ME (2009) Maternal
smoking in pregnancy and externalizing behaior in 18-month-old
children: results from a population-based prospective study. J Am
Acad Child Adolesc Psychiatry 48:283–289
15. Lavigne JV, Hopkins J, Gouze KR, Bryant FB, LeBailly SA,
Binns HJ, Lavigne PM (2011) Is smoking during pregnancy a risk
factor for psychopathology in young children? A methodological
caveat and report on preschoolers. J Pediatr Psychol 36:10–24
16. Heath CJ, Picciotto MR (2009) Nicotine-related plasticity during
development: modulation of the cholinergic system and long-
term consequences for circuits involved in attention and sesory
processing. Neuropharmacology 56:254–262
17. Muneoka K, Ogawa T, Kamei K, Muroka S, Tomiyoshi R,
Mimura Y, Kato H, Suzuki ME, Takigawa M (1997) Prenatal
nicotine exposure affects the development of the central seroto-
nergic system as well as the dopaminergic system in rat offspring:
involvement of route of drug administrations. Dev Brain Res
102:117–126
18. Weitzman M, Gortmaker S, Sobol A (1992) Maternal smoking
and behavior problems of children. Pediatrics 90:342–349
19. Maughan B, Taylor A, Caspi A, Moffitt TE (2004) Prenatal
smoking and early childhood conduct problems—testing genetic
and environmental explanations of the association. Arch Gen
Psychiatry 61:836–843
20. Ernst M, Moolchan ET, Robinson ML (2001) Behavioral and
neural consequences of prenatal exposure to nicotine. J Am Acad
Child Adolesc Psychiatry 40:630–641
21. Rice F, Harold GT, Boivin J, Hay DF, van der Bree M, Thapar A
(2009) Disentangling prenatal and inherited influences in humans
with an experimental design. Proc Natl Acad Sci 106:2464–2467
22. D0Onofrio BM, Van Hulle CA, Wladman ID, Rodgers JL, Harden
KP, Rathouz PJ, Lahey BB (2008) Smoking during pregnancy
and offspring externalizing problems: an exploration of genetic
and environmental confounds. Dev Psychopathol 20:139–164
23. Obel C, Olsen J, Henriksen TB, Rodriguez A, Jarvelin MR,
Moilanen I, Parner E, Linnet KM, Taanila A, Ebeling H, He-
iervang E, Gissler M (2011) Is maternal smoking during preg-
nancy a risk factor for hyperkinetic disorder?—Findings from a
sibling design. Int J Epidemiol 40:338–345
24. Lindblad F, Hjern A (2010) ADHD after fetal exposure to
maternal smoking. Nicotine Tob Res 12:408–415
25. Thapar A, Rice F, Hay D, Boivin J, Langley K, van der Bree M,
Rutter M, Harold G (2009) Prenatal smoking might not cause
attention-deficit/hyperactivity disorder: evidence from a novel
design. Biol Psychiatry 66:722–727
26. Das Banerjee T, Middleton F, Faraone SV (2007) Environmental
risk factors for attention-deficit hyperactivity disorder. Acta
Paediatr 96:1269–1274
27. Picket KE, Wood C, Adamson J, DeSouza L, Wakschlag LS
(2008) Meaningful differences in maternal smoking behaviour
during pregnancy: implications for infant behavioural vulnera-
bility. J Epidemiol Community Health 62:318–324
28. Wakschlag LS, Pickett KE, Kasza KE, Loeber R (2006) Is pre-
natal smoking associated with a developmental pattern of conduct
problems in young boys? J Child Psychol Psychiatr 45:461–467
29. Egger HL, Angold A (2006) Common emotional and behavioral
disorders in preschool children: presentation, nosology, and epi-
demiology. J Child Psychol Psychiatr 47:313–337
30. Nomura Y, Marks DJ, Halperin JM (2010) Prenatal exposure to
maternal and paternal smoking on attention deficit hyperactivity
disorders symptoms and diagnosis in offspring. J Nerv Ment Dis
198:672–678
31. Mick E, Biederman J, Faraone SV, Sayer J, Kleinman S (2002)
Case-control study of attention-deficit hyperactivity disorder and
maternal smoking, alcohol use, and drug use during pregnancy.
J Am Acad Child Adolesc Psychiatry 41:378–385
32. Arnold LE, Elliott M, Lindsay RL, Molina B, Cornelius MD,
Vitiello B, Hechtman L, Elliott GR, Newcorn J, Epstein JN et al
(2005) Gestational and postnatal tobacco smoke exposure as
predictor of ADHD, comorbid ODD/CD, and treatment response
in the MTA. Clin Neurosci Res 5:295–306
33. Biederman J, Monuteaux MC, Faraone SV, Mick E (2009)
Parsing the associations between prenatal exposure to nicotine
and offspring psychopathology in a nonreffered sample. J Ado-
lesc Health 45:142–148
34. Goodman R (1997) The strengts and difficulties questionnaire: a
research note. J Child Psychol Psychiatry 38:581–586
35. Egger HL, Ascher BH, Angold D (2004) The Electronic Pre-
school Age Psychiatric Assessment (ePAPA). Center for Devel-
opmental Epidemiology
36. Egger HL, Erkanli A, Keeler G, Walter BK, Angold A (2006)
Test-retest reliability of the Preschool Age Psychiatric Assess-
ment (PAPA). J Am Acad Child Adolsc Psychiatry 45:538–549
37. Janson H, Olsson U (2004) A measure of agreement for interval
or nominal multivariate observations by different sets of judges.
Educ Pscyhol Meas 64:62–70
38. Ottosson H, Bodlund O, Ekselius L, Grann M, von Knorring L,
Kullgren G, Lindstrom E, Soderberg S (1998) DSM-IV and ICD-10
personality disorders: a comparison of a self-report questionnaire
(DIP-Q) with a structured interview. Eur Psychiat 13:246–254
39. Bodlund O, Grann M, Ottosson H, Svanborg C (1998) Validation
of the self-report quesionnaire DIP-Q in diagnosing DSM-IV
personality diosrders: a comparison of three psychiatric samples.
Acta Psychiatr Scand 97:433–439
40. Ottosson H, Grann M, Kullgren G (2000) Test-retest reliability of
a self-report questionnaire for DSM-IV and ICD-10 personality
disorders. Eur J Psychol Assess 16:53–58
41. Armor DJ (1974) Theta reliability and factor scaling. In: Costner
H (ed) Sociological methodology. Jossey-Bass, San Francisco
42. Beck AT, Steer RA, Brown GK (1996) Manual of the Beck
Depression Inventory, 2nd edn. Psychological Corporation, San
Antonio
43. Saunders JB, Aasland OG, Babor TF, Delafuente JR, Grant M
(1993) Development of the alcohol-use disorders identification test
(AUDIT)—WHO collaborative project on early detection of per-
sons with harmful alcohol-consumption. Addiction 88:791–804
44. ILO (1990) International Standard Classification of Occupations:
ISCO-99. International Labour Office, Geneva
45. D0Agostino RB (1998) Propensity score methods for bias
reduction in the comparison of a treatment to a non-randomized
control group. Stat Med 17:2265–2281
46. Frick PJ, Barry CT, Kamphaus RW (2010) Clinical assessment of
child and adolescent personality and behavior. Springer, Boston
47. Slotkin TA, Pinkerton KE, Auman JT, Qioa D, Seidler FJ (2002)
Perinatal exposure to environmental tobacco smoke upregulates
nicotinic cholinergic receptors in monkey brain. Dev Brain Res
133:175–179
48. Neuman RJ, Lobos E, Reich W, Henderson CA, Sun LW, Todd
RD (2007) Prenatal smoking exposure and dopaminergic geno-
types interact to cause a severe ADHD subtype. Biol Psychiatry
61:13201328
49. Kahn RS, Khoury J, Nichols WC, Lanphear BP (2003) Role of
dopamine transporter genotype and maternal prenatal smoking in
childhood hyperactive–impulsive, inattentive, and oppositional
behaviors. J Pediatr 143:103–110
50. Wakschlag LS, Henry DB, Blair RJR, Dukie V, Burns J, Pickett
KE (2011) Unpacking the association: individual differences in
the relation of prenatal exposure to cigarettes and disruptive
behavior phenotypes. Neurotoxicol Teratol 33(1):145–154
51. Pauly JR, Slotkin TA (2008) Maternal tobacco smoking, nicotine
replacement and neurobehavioural development. Acta Paediatr
97:1331–1337
Eur Child Adolesc Psychiatry (2012) 21:635–644 643
123
52. Agrawal A, Knopik VS, Pergada ML, Waldron M, Bucholz KK,
Martin NG, Heath AC, Madden PAF (2008) Correlates of ciga-
rette smoking during pregnancy and its genetic and environ-
mental overlap with nicotine dependence. Nicotine Tob Res
10:567–578
53. Pickett KE, Kasza K, Biesecker G, Wright RJ, Wakschlag LS
(2009) Women who remember, women who do not: a method-
ological study of maternal recall of smoking in pregnancy. Nic-
otine Tob Res 11:1166–1174
54. Ruckinger S, Rzehak P, Chen CM, Sausenthaler S, Kolezko S,
Bauer CP, Hoffman U, Kramer U, Berdel D, von Berg A et al (2010)
Prenatal and postnatal tobacco exposure and behavioral problems
in 10-year-old children: results from the GINI-plus Prospective
Birth Cohort Study. Environ Health Perspect 118:150–154
55. Martin RP, Dombrowski SC, Mullis C, Wisenbaker J, Huttunen
MO (2006) Smoking during pregnancy: association with child-
hood temperament, behavior, and academic performance. J Pedi-
atr Psychol 31:490–500
644 Eur Child Adolesc Psychiatry (2012) 21:635–644
123
Copyright of European Child & Adolescent Psychiatry is the property of Springer Science & Business Media
B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright
holder's express written permission. However, users may print, download, or email articles for individual use.