83307011

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: [email protected]; [email protected]

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


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


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


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


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.

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