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European Child & Adolescent Psychiatry

, Volume 23, Issue 10, pp 913–929 | Cite as

Prenatal nicotine exposure and child behavioural problems

  • Carla M. T. Tiesler
  • Joachim Heinrich
Open Access
Review

Abstract

In utero exposure to tobacco smoke has been related to numerous adverse health effects in new-borns, infants, children, adolescents and adults. The aim of this review was to summarise findings on prenatal nicotine exposure and its relationship with behavioural problems in the offspring. The majority of studies, and especially several recent epidemiological studies, observed a higher likelihood for attention-deficit/hyperactivity disorder (ADHD) or ADHD symptoms in exposed subjects. However, both human and animal studies have failed to provide clear evidence on causality. Existing literature on studies investigating the association between prenatal nicotine exposure and conduct or externalising problems in the offspring suggests a causal effect. The establishment of a final conclusion concerning the relationship between prenatal nicotine exposure and internalising problems in the offspring is complicated by insufficient data and mixed results in epidemiological studies. Prenatal nicotine exposure has been associated with altered brain structure and function in human offspring, and a proposed biological mechanism is related to nicotine’s adverse influence on neurotransmitter systems during brain development. In conclusion, establishing a statement on the causality of the relationship between prenatal nicotine exposure and behavioural problems in children remains a challenging task. Nevertheless, considering the results of an increasing number of studies which link prenatal exposure to nicotine to externalising problems applying different methodologies to account for confounding and in view of other adverse health effects known to be caused by this exposure, parents should consider smoking cessation.

Keywords

Tobacco smoke Attention-deficit/hyperactivity disorder Conduct problems Depression Anxiety Brain development 

Abbreviations

ACh

Acetylcholine

ADHD

Attention-deficit/hyperactivity disorder

CI

Confidence interval

CNS

Central nervous system

DALY

Disability-adjusted life year

ETS

Environmental tobacco smoke

nAChR

Nicotinic acetylcholine receptor

NRT

Nicotine replacement therapy

OR

Odds ratio

PFC

Prefrontal cortex

Introduction

Maternal smoking during pregnancy has been related to multiple adverse effects including pregnancy complications and risks of preterm delivery, lower birth weight, reduced lung function in infants and sudden infant death syndrome [1]. Another field of research links in utero exposure to tobacco smoke to behavioural problems such as attention-deficit/hyperactivity disorder (ADHD), conduct problems, depression and anxiety in the offspring.

The Global Burden of Disease study from 2010 estimated that mental and behavioural disorders cause around 185 million disability-adjusted life years (DALYs) [2]. Estimates for behavioural disorders in childhood were 5.8 million DALYs for conduct problems and half a million for ADHD [2]. However, even though a large number of studies support a relationship between intrauterine exposure to tobacco smoke and later behavioural problems and plausible biological mechanisms exist, some studies reported no association or only a weak one. Furthermore, many lifestyle, socioeconomic, cultural and genetic factors, in which smokers differ from non-smokers in non-random ways, complicate this relationship and make it difficult to come to a final conclusion on causality. Nicotine is just one component of tobacco smoke and smokeless tobacco products. However, there is increasing evidence for specific effects of prenatal nicotine exposure that leads to adverse health effects in new-borns, infants, children, adolescents and adults.

The objective of this review was to provide an overview on prenatal nicotine exposure and its relationship with offspring behaviour. As a broad range of symptoms and disorders is summarised under this term, we will summarise findings from previous reviews and complement them with relevant information from recent publications in the respective fields of research. First, main pathways of nicotine exposure during pregnancy are outlined. Then, the epidemiology of maternal smoking during pregnancy is covered including factors affecting the likelihood of smoking cessation. Subsequently, nicotine metabolism, methods of assessing prenatal exposure to nicotine and physical findings associated with this exposure are briefly described. The main section covers the specific topic of offspring behavioural problems following prenatal nicotine exposure. This section is subdivided into an overview of the literature covering (1) hyperactivity or inattention problems such as ADHD, (2) externalising problems such as conduct disorder and antisocial behaviour and (3) emotional or internalising problems such as depression and anxiety. Lastly, results from brain imaging studies and possible mechanisms of adverse effects of nicotine to the developing brain are discussed, followed by a final conclusion.

Definition of prenatal exposure to nicotine and its assessment

Active maternal smoking is just one pathway of foetal exposure to nicotine. Others include an exposure of the pregnant woman to environmental tobacco smoke (ETS) due to smoking behaviours of other people, maternal use of smokeless tobacco products such as chewing tobacco and maternal use of non-tobacco products containing nicotine such as medication during a nicotine replacement therapy (NRT). ETS consists of mainstream smoke exhaled by the smoker and sidestream smoke which is released by the smouldering cigarette [3]. Tobacco smoke itself is a complex mixture of gases and particulate matter components [3]. One of these constituents is nicotine. Furthermore, prenatal exposure to nicotine is often difficult to quantify as nicotine concentration in different tobacco products varies and is also dependent on individual smoking characteristics such as puffing intensity [4].

To date, human studies, which analysed the association between prenatal nicotine exposure and behavioural problems, have defined this exposure either by active maternal smoking or by ETS exposure of the mother during pregnancy.

Nicotine metabolism and its transfer from mother to the foetus

Nicotine is a chemical compound, an alkaloid, found in tobacco smoke, smokeless tobacco products and nicotine replacement products [5]. It can be absorbed through the mouth by chewing, the lungs as smoke or the skin via an NRT patch [5]. Once nicotine has entered the bloodstream, it is distributed throughout the body to various tissues such as the brain, lung and liver [5]. In the liver, it is metabolised and finally excreted in urine [5]. Nicotine’s major metabolite is cotinine whose main metabolic product in turn is trans-3′-hydroxycotinine [5]. By crossing the placental barrier, nicotine can be transferred from the maternal circulation to the foetus [6]. Cotinine measurements taken in the first trimester indicate an accumulation in foetal fluids: cotinine concentrations in amniotic fluid and foetal serum were higher than in maternal serum regardless of whether the mother is an active or passive smoker [7]. The main pathway of elimination of nicotine from the foetal circulation occurs by re-diffusion across the placenta into the maternal circulation [8].

Assessment of prenatal exposure to nicotine

Prenatal exposure to nicotine can be assessed via questionnaires asking, for example, about maternal smoking or ETS exposure during pregnancy. This method is often chosen for epidemiological studies as past, long-term and current exposures can be inexpensively assessed in large samples [3, 9]. However, this method has several drawbacks. First, this method is prone to exposure misclassification such as recall bias, under-reporting or concealment of smoking, which might be due to awareness of numerous negative health effects for children exposed to tobacco smoke in utero [3, 9]. Second, a single question on whether the mother smoked during pregnancy does not adequately address the amount of exposure and smoking patterns: a “yes” answer might include total abstinence after becoming aware of the pregnancy. Therefore, a detailed set of questions on numbers of cigarettes smoked per day during pregnancy or during certain trimesters and on smoking cessation should preferably be used.

A more objective method of ascertaining prenatal exposure is the measurement of exposure-specific biomarkers in biological matrices of mother and/or child. Candidate biomarkers with high specificity for active or passive tobacco smoking or usage of medication containing nicotine are nicotine itself and its metabolites, such as cotinine or trans-3′-hydroxycotinine [10, 11]. While nicotine has a short half-life of 2 h, the half-life of cotinine is on average 16 h [10]. Thus, measurements of nicotine or cotinine in blood, urine and saliva reflect recent exposures within the last few hours or last few days, respectively, and are susceptible to variations in exposure. This limits the usage for the assessment of long-term exposures. In new-borns, however, a longer half-life of nicotine and similar half-life of cotinine compared to adults have been reported which have been suggested to be due to differences in the sensitivity of the clearance rates of these two chemicals to alterations of hepatic blood flow [5]. Maternal matrices such as blood, urine, saliva and hair can be used for detection of the above-mentioned biomarkers to assess ETS exposure or active smoking [10, 12]. Llaquet et al. [13] provide an overview on possible biological matrices in the child for detection of prenatal ETS exposure. Measurements of nicotine or its metabolites in cord serum and neonatal urine reflect the exposure to ETS shortly before delivery [13]. Other matrices such as hair, nails, amniotic fluid and meconium, in which nicotine or its metabolites accumulate or are incorporated during formation, have longer detection periods ranging from first to last trimester [13]. It is often not feasible to differentiate clearly between children of mothers exposed to ETS during pregnancy and those who were not. Two studies [14, 15] reported no detectable levels of nicotine or its metabolites in amniotic fluid or meconium of new-borns whose mother was exposed to ETS during pregnancy. In another study, the measurement of trans-3′-hydroxycotinine (adjusted for creatinine) in urine of new-borns showed slight but significant differences between children of mothers exposed to ETS and those unexposed [16]. For detection of foetal tobacco smoke exposure in late pregnancy, the measurement of cotinine in cord serum seems to be the most promising biomarker due to its ability to distinguish between active maternal smoking, maternal ETS exposure and no exposure [13].

Lastly, indoor nicotine concentrations can be measured in the homes of pregnant women using active or passive air samplers [17, 18]. This approach is mainly relevant for the assessment of ETS exposure.

Epidemiology

Epidemiological studies using data from European birth cohorts reported maternal smoking prevalences between 14 and 38 % [19, 20, 21, 22, 23, 24]. The European Perinatal Health Report from 2010 estimates the prevalence of maternal smoking during pregnancy or in the last trimester to be above 10 % in many countries, varying between under 5 % in Sweden and Lithuania to 19 % in Scotland [25]. Compared to the report from 2004, a slight decrease of about 1–3 % of mothers who smoked in the third trimester was observed [25]. Cnattingius [26] reviewed the epidemiology of smoking during pregnancy and also concluded that the prevalence had declined. While one-fourth and one-fifth of pregnant women in Sweden and the USA, respectively, reported smoking around 1990, these values declined to about one-eighth in 2000. Denmark showed slightly higher but similarly declining rates of approximately one-third at the beginning and one-fourth at the end of the nineties [26]. In 2004–2005, Bloch et al. [27] conducted a study on tobacco use and ETS exposure of pregnant women in nine developing countries. Percentages of women who reported active smoking ranged from 3 % (Pakistan) to 18 % (Uruguay). Estimates for ETS exposure at home ranged between 17 % (Democratic Republic of Congo) and 92 % (Pakistan) [27].

A wide range of smoking cessation rates during pregnancy was reported with 27–47 % in Europe, 23–43 % in the USA, 62–70 % in Japan and 4–47 % in other countries [28].

However, in spite of declining prevalences of smoking during pregnancy in most developed countries, and potentially increasing prevalences in some developing countries, exposure to nicotine during pregnancy is still a problem worldwide.

Another important aspect of the epidemiology of smoking during pregnancy is the constellation of factors associated with likelihood of quitting. Chances of quitting are lower in mothers with lower social status, smoking partner, higher degree of addiction, higher parity [28] and psychological correlates such as a history of conduct problems in childhood [29].

Finally, since most epidemiological studies used questionnaire-based exposure assessment scenarios, it has to be kept in mind that the reported findings cannot be interpreted as effects of pure nicotine exposure but rather as those of tobacco smoke, which, apart from nicotine, contains numerous other toxicants.

Physical findings

Active maternal smoking is associated with a wide range of adverse health effects on the new-born. It is known to decrease birth weight, following a dose–response relationship [30, 31]. Other effects include increased risks for pregnancy complications and preterm delivery (<37 weeks of completed gestation), low birth weight (<2,500 g) and sudden infant death syndrome [1]. Maternal exposure to ETS during pregnancy is related to a similar range of outcomes. Salmasi et al. [32] conducted a meta-analysis on perinatal findings related to ETS exposure in pregnant women. Significant associations were found between ETS exposure and a lower birth weight, congenital anomalies and a longer birth length. ETS-exposed children further showed trends for smaller neonate head circumferences and risk for low birth weight [32]. Leonardi-Bee et al. [33] reported an increased risk for stillbirth of non-smoking women exposed to ETS while pregnant.

Nicotine exposure during pregnancy has been related to adverse effects on the lung and the respiratory system, including increased risks for asthma, wheeze and airway hyper-responsiveness in children [34, 35, 36]. Out of other components contained in tobacco smoke, nicotine has been suggested to be the main candidate concerning negative effects on pulmonary development [34]. Prenatal exposure to nicotine is related to structural as well as functional alterations in lung development, which are potentially related to an increased risk for obstructive lung disease and accelerated lung ageing in later years [34]. Finally, as prenatal nicotine exposure is a risk factor for low birth weight and as low birth weight is associated to adverse effects on lung development, nicotine might be indirectly related to adverse pulmonary development via low birth weight [37].

Bakker et al. [38] reviewed cardiovascular and metabolic influences of foetal smoke exposure. They reported that maternal smoking during pregnancy is associated with higher blood pressure in children. Furthermore, prenatal exposure to maternal smoking may directly or indirectly (via low birth weight) be related to obesity, adverse cardiovascular diseases and type 2 diabetes in later life [38]. While the association between maternal smoking during pregnancy and overweight or obesity in the children is suggested to be causal, no definitive conclusions for the outcomes of type 2 diabetes and the metabolic syndrome can be drawn from the small number of studies [39]. Moreover, there seems to be no association between smoke exposure during pregnancy and type 1 diabetes [39]. In short, findings for cardiovascular and metabolic effects of foetal smoke exposure are mixed and establishing statements about causality therefore stays difficult.

Neuropsychological, behavioural and psychiatric findings

Prenatal nicotine exposure is also associated with increases in behavioural and cognitive problems.

Briefly, no definitive conclusion can be drawn regarding the association between prenatal exposure to nicotine or tobacco smoke and impairment of cognitive function in the children [31, 40, 41]. Differing results may be explained by incomplete control for confounding variables such as maternal age, education, intelligence quotient and socioeconomic status [31]. Clifford et al. [41] reviewed observational studies between 2000 and 2011 on the association between active maternal smoking during pregnancy and cognitive outcomes in children; they concluded that the most consistent results were observed for reduced academic achievement and impaired intellectual abilities. Animal studies on the effects of developmental nicotine on cognitive function in offspring show a similarly inconclusive picture with conflicting results [31].

Two very recent studies in children from the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective UK birth cohort, related prenatal nicotine exposure to impaired reading performance [42] and increased risk of language impairment and poor performance on language tasks [43].

The main objective of this review was to provide an overview on the topic of prenatal nicotine exposure and child behavioural problems subdivided into attention, externalising and internalising problems. Literature search was performed between November 2013 and January 2014. Initially, the PubMed database was searched by using the following terms: (“nicotine” OR “tobacco” OR “cigarette” OR “smoking”) AND (“prenatal” OR “pregnancy” OR “gestational” OR “trimester” OR “in utero”) AND (“neonate” OR “infant” OR “child” OR “children” OR “adolescent”) in combination with keywords for (1) ADHD and symptoms of hyperactivity or inattention (“attention-deficit/hyperactivity disorder” OR “ADHD” OR “hyperactivity” OR “inattention”), (2) conduct or externalising behaviours and antisocial behaviour (“conduct problems” OR “conduct disorder” OR “oppositional defiant disorder” OR “externalizing” OR “externalising” OR “aggression” OR “antisocial”) and (3) depression, anxiety and internalising disorders (“depression” OR “anxiety” OR “internalizing” OR “internalising” OR “emotional problems” OR “emotional disorders”). Further articles were identified via reference lists from earlier review articles.

Due to the large number of publications published to date in this field, this review will provide a comprehensive but not exhaustive overview on the current knowledge by summarising the results of previous review articles combined with findings from key publications and relevant recent publications in the respective fields of research. Details of the original publications mentioned in the text can be found in Table 1.
Table 1

Details on original publications stated in the main text analysing the relationship between prenatal nicotine exposure on offspring behavioural problems (subdivided into publications on attention, externalising or internalising problems shown in chronological order)

References

Study name (location of recruitment), Country

Number of participants

Age (years)a

Assessment of child’s exposure to smoking in utero; coding of exposure variable; % smoking [m]others or exposed [c]hildren, if different

Assessment of symptoms

Covariates

Results

ADHD and symptoms of hyperactivity or inattention

Gatzke-Kopp [48]

Seattle, USA

133 Mothers and their 171 children

7–15

MSDP: reported; (a) no/yes/only ETS exposure; 16 % [m] smoked, 12 % [m] ETS (b) score based on packs/day summed across trimesters

CBCL and child symptom inventory

Household income, maternal and paternal antisocial symptoms, child BW, child GA at birth, maternal use of alcohol and other substances during pregnancy

Children exposed to MSDP or whose mother was exposed to second hand smoke during pregnancy had significantly higher ADHD symptom scores

a higher MSDP score was associated with more ADHD symptoms

D’Onofrio [52]

Offspring of National Longitudinal Survey of Youth (NLSY79), USA

8,889

4–10

MSDP: reported; 0/0.5/1.5/2.5 packs per day; 36 %

Behaviour problem index (subset of items from CBCL): 3 items for ADHP

Maternal intellectual ability, maternal years of education, income, maternal delinquency, maternal age at first birth, child gender

MSDP was related to ADHP when exposed offspring was compared to unrelated offspring who was not exposed to MSDP

MSDP was only related to small, non-significant effect on ADHP when siblings who were differentially exposed to MSDP were compared

Thapar [51]

Offspring conceived with Assisted Reproductive Technologies, UK and USA

815

4–11

MSDP: reported; no/yes; 6 %

DuPaul ADHD scale

Child age and gender, multiple birth status, mother’s ADHD symptoms, father’s ADHD symptoms, family income

In related mother–child pairs, MSDP was associated with ADHD symptoms

in unrelated mother–child pairs, MSDP was not associated with ADHD symptoms

Nomura [50]

New York, USA

214

3–4

MSDP: reported; no/yes; 18 %

FSDP: reported; no/yes; 33 %

ADHD-Rating Scale-IV, Kiddie-SADS-PL

Gender, age, race and BW of child, maternal alcohol use during pregnancy, family SES, mother’s and father’s ADHD symptoms, partner smoking during pregnancy

MSDP associated with increased risk of diagnoses of ADHD and of comorbid ADHD and ODD, whereas FSDP had no influence

Tiesler [22]

LISAplus, Germany

1,654

10

MSDP: reported; no/yes; 14 %

SDQ hyperactivity/inattention

Sex, study centre, parental education level, maternal age at birth, TV/PC usage, single parent status

MSDP alone or in combination with child’s post-natal exposure to smoking at home was associated with hyperactivity/inattention problems

Langley [20]

ALSPAC, UK

8,324

7.5

MSDP: reported; no/yes; 18 %

FSDP: reported; no/yes; 32 %

MPSPb: reported; no/yes; 6 %

Development and well-being assessment

Sex, multiple births, mother’s education, family social class, ethnicity, mother’s alcohol use during pregnancy

MSDP and FSDP, where mother is a non-smoker, during pregnancy were associated with more ADHD symptoms

no association between MPSP and ADHD symptoms

Keyes [49]

Child Health and Development Study, USA

1,752

10

MSDP: reported; no/yes [0,1–9,10–19,20+], 33 %

PSDP: reported; no/yes [0,1–9,10–19,20+]; NA

8 Items on hyperactivity from a 100-item battery of child characteristics

Partner smoking during pregnancy, father’s education, manual job, maternal current smoking, paternal current smoking, offspring race/ethnicity, child gender, maternal cognition, maternal age and child age (in subgroup: maternal alcohol and coffeine use during pregnancy)

MSDP and PSDP were associated with higher hyperactivity score, but only the association with MSDP withstood adjustment for covariates

the MSDP dosage variable indicated a higher risk for a higher hyperactivity score for those who smoked 10–19 or 20+ cigarettes than for those who smoked 1–9 cigarettes compared to non-smokers

children exposed to PSDP but not MSDP showed no significantly increased hyperactivity scores

Silva [47]

Population-based, record linkage case–control study, Australia

1,688 Cases, 3,849 controls

<25 (age was a matching variable)

MSDP: record-based; no/yes; 19 %

Diagnosis with ADHD and prescription of stimulant medication

Cases and controls matched by gender, year of birth and SES maternal age, marital status, first pregnancy, complications of pregnancy, induced onset of labour, augmentation of labour, complications of labour, type of delivery, GA, BW, appropriate for GA, small for GA and large GA, child Apgar at 5 min

MSDP was associated with increased risk for ADHD in boys and girls

Conduct or externalising behaviours and antisocial behaviour

Gatzke-Kopp [48]

Seattle, USA

133 Mothers and their 171 children

7–15

MSDP: reported; (a) no/yes/only ETS exposure; 16 % [m] smoked, 12 % [m] ETS (b) score based on packs/day summed across trimesters

CBCL and child symptom inventory

Household income, maternal and paternal antisocial symptoms, child BW, child GA at birth, maternal use of alcohol and other substances during pregnancy

Children exposed to MSDP or whose mother was exposed to second hand smoke during pregnancy had significantly higher CD and aggression scores

higher MSDP score was associated with more CD symptoms after adjustment for covariates

D’Onofrio [52]

Offspring of National Longitudinal Survey of Youth (NLSY79), USA

8,889

4–10

MSDP: reported; 0/0.5/1.5/2.5 packs per day; 36 % [c]

Behaviour problem index (subset of items from CBCL): 7 for CP, 3 for ODP

Maternal intellectual ability, maternal years of education, income, maternal delinquency, maternal age at first birth, child gender

MSDP was related to CP and to ODP when exposed offspring was compared to unrelated offspring who was not exposed to MSDP

when siblings who differed in their exposure to MSDP were compared, the effect for both CP and ODP was substantially reduced and not significant

Stene-Larsen [56]

Norwegian Mother and Child Cohort Study, Norway

22,545

1.5

MSDP: reported; 0/1–9/10 + cigarettes per day; 13 %

8 items from CBCL/1.5–5y (oppositional behaviour [3], aggressive behaviour [2] and overly active behaviour [3] )

Mother’s level of education, single parent, maternal depressed mood, maternal alcohol use during pregnancy, maternal current smoking, child sex, BW <=2,500 g, GA <=37 weeks

Heavy MSDP (10+ cig./day) but not light MSDP (1–9 cig./day) was associated with an increased risk for externalising behaviour in the offspring

Brion [19]

Cohort 1: Pelotas, Brazil

Cohort 2: ALSPAC, UK

Cohort 1: 509

Cohort 2: 6,735

4

Cohort 1:

MSDP: reported; no/yes; 30 %

FSDP: reported; no/yes; 50 %

Cohort 2:

MSDP: reported; no/yes; 16 %

FSDP: reported; no/yes; 32 %

Cohort 1: CBCL (externalising scale)

Cohort 2: SDQ (conduct problems scale)

Maternal and paternal education, social class, family income, parental psychopathology, partner’s smoking during pregnancy, BW, GA, breastfeeding

MSDP was associated with conduct/externalising problems

FSDP was less strongly associated with conduct/externalising problems (significant only in Cohort 2 and lost significance after adjustment for parental psychopathology)

D’Onofrio [58]

Offspring of National Longitudinal Survey of Youth (NLSY79), USA

2,694 Mothers and their 6,066 children

14–17 (repeated assessments)

MSDP: reported; 0/0.5/1.5/2.5 packs per day; 27 % [c]

Offspring antisocial behaviour: self-reported delinquency scale reported criminal convictions

Gender, birth order, maternal teenage childbearing, maternal alcohol use during pregnancy, maternal adolescent antisocial behaviour, maternal intellectual abilities, maternal educational attainment, maternal income, maternal history of binge-drinking, maternal history of alcohol abuse/dependence, maternal adolescent substance use, family race/ethnicity

MSDP was associated to more antisocial behaviour and an increased risk for criminal convictions when exposed offspring was compared to unrelated offspring who was not exposed to MSDP

MSDP was not associated with antisocial behaviour or risk for criminal convictions when differentially exposed siblings were compared

Gaysina [59]

Study 1: Christchurch Health and Development Study, New Zealand

Study 2: Early Growth and Development study, USA

Study 3: Cardiff IVF Study, UK

Study 1: 1,124

Study 2: 310

Study 3: 842

Study 1: 6 and 7

Study 2: 4.5 and 6

Study 3: 4–10

MSDP: reported by birth mothers; 0/1–9/10 + cigarettes per day,

Study 1: 33 % [50 %] in genetically [un]related mothers

Study 2: 41 %

Study 3: 6 % [4 %] in genetically [un]related mothers

Parent- and/or teacher-reported child CP

Study 1: Rutter and Conners behaviour scales

Study 2: CBCL (externalising scale), Children’s Behaviour Questionnaire Short Form (impulsivity scale)

Study 3: SDQ

Child gender, ethnicity, BW, breast feeding, maternal age at birth, maternal education, family SES, family breakdown, placement age, parenting practices

MSDP (by birth mothers) was associated with increased offspring conduct problems in both genetically related and genetically unrelated mother–child pairs

O’Brien [57]

East Boston Family Study, USA

176

Three measurements (exact age NA), participant age 11–18

MSDP: repeated cotinine-corrected reports; 48 %

ODD and CD scales from Diagnostic Interview for Children Antisocial Behaviour Checklist

Age, maternal and paternal antisocial behaviour, harsh parenting

Significant gene (DAT1) × MSDP interaction for boys on latent externalising spectrum (DAT1 10r variant related to higher risk in presence of MSDP)

Depression, anxiety or internalising disorders

Höök [65]

Hässleholm and Western Blekinge, Sweden

1,428 (3 years), 677 (5.5 years)

3 and 5.5

MSDP: reported; 0/1–10/>10 cigarettes per day; 16 %

CBCL/2–3 (age 3) CBCL/4–18 (age 5.5)

None

MSDP was not associated with offspring internalising problems at 3 or at 5.5 years

Indredavik [62]

Subgroup of NICHD Study of Successive Small-for-Gestational Age Births, Norway

84

14

MSDP: reported; no/yes; 38 %

Youth self-report, CBCL and teacher report form, internalising and externalising scales

Gender, BW, SES, maternal age, single parent, mother’s present use of alcohol, mother’s mental health

MSDP was associated with higher scores on the internalising and externalising scales

Ashford [61]

Longitudinal general population study, Netherlands

396

5, 10–11 and 18

MSDP: reported; <10/10+ cigarettes per day; 7 % (10+)

CBCL/4–18 (ages 5,10–11) and CBCL/6–18 at age 18, internalising and externalising scales

Mother ill before pregnancy, mother ill during pregnancy, mother hospitalised during pregnancy, complications at birth, premature birth, low BW, child sex and SES, maternal mental health, child social and attention problems maternal mental health, child social and attention problems

MSDP was associated with increased internalising and externalising problems across all ages, even after control for co-occurrence of the two outcomes, across ages 5 to 18

Brion [19]

Cohort 1: Pelotas, Brazil

Cohort 2: ALSPAC, UK

Cohort 1: 509

Cohort 2: 6,735

4

Cohort 1:

MSDP: reported; no/yes; 30 %

FSDP: reported; no/yes; 50 %

Cohort 2:

MSDP: reported; no/yes; 16 %

FSDP: reported; no/yes; 32 %

Cohort 1: CBCL (internalising scale)

Cohort 2: SDQ (emotional symptoms scale)

Socioeconomic position (maternal and paternal education, social class, family income), parental psychopathology, partner’s smoking during pregnancy, BW, GA, breastfeeding

Neither MSDP nor FSDP were associated with emotional/internalising problems

Ekblad [64]

Population-based longitudinal register data, Finland

175,869

Inpatient episodes (up to 18–20), outpatient visits (9–11 to 18–20)

MSDP: reported; 0/<10/>10 cigarettes per day; 15 %

Children’s psychiatric diagnoses related to outpatient visits and inpatient care (classified by ICD-9 and ICD-10)

Child sex, GA, BW, 5-min Apgar score, maternal age, parity and psychiatric diagnosis before birth of child

MSDP was associated with an increased risk for any psychiatric diagnosis

dose–response relationships were observed for MSDP and the risks of mood disorders or the risks of behavioural and emotional disorders occurring in childhood and adolescence in total (also for subgroup of hyperkinetic disorders and subgroup of disorders of conduct and emotions regarded separately)

Menezes [63]

Pelotas, Brazil

4,106

18

MSDP: reported; no/yes; 33 %

PSDP: reported; no/yes; 50 %

Subjective happiness scale, mini-international neuropsychiatric interview (for depression)

Sex, family income, planned pregnancy, partner support during pregnancy, maternal alcohol use during pregnancy, type of delivery, maternal anxiety and depression symptoms, partner’s smoking during pregnancy

MSDP was associated with decreased happiness and an increased risk for depression

PSDP was associated with decreased happiness

ADHP Attention-deficit/hyperactivity problems, BW birth weight, CBCL Child Behaviour Checklist, CD conduct disorder, CP conduct problems, FSDP/PSDP father/partner smoking during pregnancy, GA gestational age, ICD International Classification of Diseases, MSDP maternal smoking during pregnancy, ODD oppositional defiant disorder, ODP oppositional defiant problems, SES socioeconomic status, SDQ Strengths and Difficulties Questionnaire

aAt time of outcome measurement

bNeither parent smoked but third person smoked at home or exposure to ETS at work

ADHD and symptoms of hyperactivity or inattention

An association between gestational exposure to nicotine or tobacco smoke and ADHD in children has been reported from many studies; results were summarised in several reviews (e.g. [31, 40, 44, 45, 46]). Linnet et al. [45] reviewed 24 studies published between 1975 and 2002 investigating the relationship between prenatal maternal smoking and ADHD or ADHD symptoms in the children. The authors concluded that most studies reported an increased risk for the development of such problems in children of smoking mothers, some even showing a dose–response effect in the association. However, as there were several serious shortcomings such as methodological issues related to retrospectively collected data, rough estimation of exposure by a dichotomous smoke exposure variable and statistical issues related to power, no final statement on causality was possible [45].

Latimer et al. [44] reviewed prenatal or early post-natal environmental risk factors associated with disruptive behaviour disorders. Eleven studies investigated the role of maternal smoking during pregnancy: eight of them, including population-based and case–control studies of good quality, supported the presence of a link to an increased risk for ADHD in the offspring.

Furthermore, results from about 1,600 children of the German birth cohort study LISAplus also support an association between maternal smoking during pregnancy and hyperactivity or inattention problems in 10-year-olds [22].

In a population-based record linkage case–control study of young non-Aboriginal Australians (about 1,700 cases and 3,850 controls), Silva et al. [47] recently observed that maternal smoking is a risk factor for clinically defined ADHD with additional prescription of stimulant medication. The association remained significant for both sexes even after adjustment for several characteristics related to pregnancy and birth (boys: odds ratio (OR) = 1.86, 95 % confidence interval (CI): 1.53–2.27; girls: OR = 1.67, 95 %CI: 1.07–2.61).

Thus, both the consistency of results across many studies and different study designs and the presence of dose–response relationships between exposure and outcome in some studies support the hypothesis of a causal association. A further aspect is related to the ETS exposure of women who are non-smokers during pregnancy. This exposure can be due to ETS exposure at home by the partner or other household members or it can be an exposure at the workplace. Several studies have compared the effects of active maternal smoking during pregnancy with those resulting from ETS exposure (e.g. [20, 48, 49, 50]).

Gatzke-Kopp et al. [48] observed a higher risk for ADHD symptoms not only in children exposed to maternal smoking during pregnancy but also in those whose mother did not smoke but was exposed to ETS during gestation.

A very recent study by Keyes et al. [49] compared the influence of maternal and/or paternal smoking on offspring hyperactivity at the age of 10 years. In unadjusted analyses, maternal as well as paternal smoking during pregnancy was related to increased offspring hyperactivity, respectively. After adjustment for partner’s smoking behaviour and accounting for several covariates, the association between maternal smoking and hyperactivity in the children remained stable, but the association with paternal smoking was attenuated to non-significance. Furthermore, no increased risk for hyperactivity could be observed in children whose father smoked during pregnancy and whose mother did not smoke. Nomura et al. [50] conducted a similar study in about 200 preschool children (3–4 years old). They observed an increased risk of ADHD symptoms only for children exposed to maternal smoking but not for those exposed to paternal smoking, even after adjustment for a series of confounders including ADHD symptoms of the parents, thereby decreasing the chance for confounding by genetic factors.

Langley et al. [20] used data from over 8,000 children of the ALSPAC prospective birth cohort study. They compared the risks of ADHD symptoms in children aged 7.5 years whose mother smoked during pregnancy, with those whose mother did not smoke but was exposed to the smoking behaviour of the father. Furthermore, they assessed the effect of passive smoking in families in which neither parent smoked but where the mother reported ETS exposure at work or living with household members who smoked. Maternal smoking and paternal smoking (even in the absence of maternal smoking) were both observed to be associated with increased ADHD symptoms in the offspring, while passive smoking was not. The authors concluded that the associations between maternal smoking and ADHD in the children may be confounded by genetic factors or factors on the household level and are to a lesser extent attributable to causal effects of an exposure in utero [20].

Further studies that were able to control for genetic factors suggest that the association between maternal smoking during pregnancy and ADHD might not be causal (e.g. [51, 52]).

Thapar et al. [51] tested the association with maternal smoking in children conceived with assisted reproductive technologies, comparing the ADHD risk of children genetically related and unrelated to the gestational carrier. In genetically related mother–child pairs, maternal smoking during pregnancy was related to an increased risk for ADHD symptoms in the offspring, while no association was observed for genetically unrelated pairs. This observation suggests that the effect might be rather attributed to inherited characteristics than to the exposure to prenatal smoking [51].

D’Onofrio et al. [52] compared the ADHD traits of siblings with and without prenatal maternal smoke exposure in order to account for familial and genetic effects. When children whose mother smoked during pregnancy were compared to unrelated children without prenatal smoke exposure, they showed a significantly increased risk for ADHD symptoms. However, in siblings who differed in their exposure to maternal smoking during pregnancy, the association between smoking and subsequent ADHD symptoms was small and not significant.

Abbott et al. [31] provided an overview on findings from animal studies exploring whether prenatal exposure to tobacco smoke is associated with ADHD-like symptoms. Most studies used nicotine instead of tobacco smoke and hyperactivity measured by increased locomotor activity was usually chosen as indicator for ADHD symptoms. Studies in mice mostly reported increased locomotor activity after prenatal nicotine exposure, but studies in rats were less consistent [31]. Furthermore, the authors stated that increased activity might not be representative of ADHD-like behaviour in rodents, as other symptoms such as inattention are not considered [31]. Moreover, several methodological issues complicate the transfer of results from rodent studies to humans. Dwyer et al. [53] mention three caveats: first, human foetuses are born at a more mature stage of brain development than are rodents. The first two trimesters of human development correspond approximately to the full gestational development of rodents, and the early post-natal period of rodents is used as model for the third trimester development of human foetuses. Second, the effects of a continuous exposure to nicotine as effected in rodent models might be different from an intermittent exposure related to variations in nicotine levels such as it is the case for human smoking. Third, animal models with a nicotine exposure do not reflect the exposure to tobacco smoke in humans as tobacco smoke contains numerous other chemicals besides nicotine [53].

In summary, the majority of studies, and especially several recent epidemiological studies, observed a higher likelihood for ADHD or ADHD symptoms in subjects prenatally exposed to nicotine. However, both human and animal studies have failed to provide clear evidence on causality.

Conduct or externalising behaviours and antisocial behaviour

Several review articles (e.g. [54, 55]) summarised the association between prenatal exposure to nicotine and conduct or externalising problems. The authors concluded that the existing literature strongly indicates an increased risk, but no causal association could be established due to methodological limitations.

Further support for an increased risk comes from the study of Gatzke-Kopp et al. [48] who observed that not only active maternal smoking, but also non-smoking mother’s ETS exposure, during pregnancy is related to higher symptom scores for conduct disorder in the offspring.

Two other studies investigated the association between maternal smoking during pregnancy and increased risk for externalising problems in relatively young children at an age of 18 months [56] and 4 years [19]. Using data from the population-based Norwegian Mother and Child Cohort Study with a large study sample (N > 22,500), Stene-Larsen et al. [56] reported a significantly increased risk for externalising problems for 18-month-old children whose mother smoked more than 10 cigarettes per day (OR = 1.32, 95 % CI: 1.03–1.70) but not for those who smoked less. The authors additionally reported no sex difference in the association [56]. Brion et al. [19] analysed the association of maternal smoking during pregnancy with conduct or externalising problems in 4-year-olds from two birth cohorts, one from a middle-income country (Brazilian Pelotas study) and one from a high-income country (British ALSPAC study). A significant effect was (1) present in both studies, (2) persisted even after adjustment for confounders such as socioeconomic status and parental psychopathology and (3) was also robust to adjustment for paternal smoking during pregnancy.

Recently, O’Brien et al. [57] reported a gene x environment interaction for a dopamine transporter gene (DAT1) variant that modifies the risk for externalising problems in male but not in female adolescents after prenatal exposure to maternal smoking which was assessed via repeated cotinine-corrected reports.

However, studies using specific designs to control for genetic confounding came to inconsistent results (e.g. [52, 58, 59]).

D’Onofrio et al. [58] recently assessed the relationship between maternal smoking during pregnancy and antisocial behaviour in adolescents aged 14–17 years. In unrelated individuals, the results show a significantly increased risk for antisocial behaviour symptoms and for a criminal conviction. However, the associations became smaller and lost statistical significance when comparing siblings who differed in their exposure to prenatal maternal smoking. This supports the influence of familial factors on the association between prenatal exposure to smoking and later development of antisocial behaviour. A similar result was observed in an earlier study from D’Onofrio et al. [52] who also did not observe any elevated risk for conduct problems or oppositional defiant problems in children exposed to prenatal maternal smoking compared to unexposed siblings.

However, a very new study by Gaysina et al. [59] shows a different picture. Using data from three studies, it supports a direct causal effect of prenatal maternal smoking on later conduct problems in the offspring. Three different genetic constellations for mother–child pairs were present: either genetically related (1) or genetically unrelated with an adoption of the child at birth (2) or at conception (3). Thus, the authors were able to assess the association in mother–child pairs who differed not only with respect to tobacco smoke exposure during pregnancy but also with respect to their genetic relationship. Children who were exposed to maternal smoking in utero were observed to have a higher risk of conduct problems, regardless of whether the mother was genetically related or unrelated to the child. This supports an adverse effect of the exposure and not of genetic factors. This association was also observed after adjustment for several potential confounders among which were maternal education, parenting practices and socioeconomic characteristics of the family. Furthermore, results of a meta-analysis across pairs in the three studies supported this finding [59].

A possible explanation for differences between the findings from the study of Gaysina et al. [59] and those from D’Onofrio et al. [52, 58] is proposed by Gaysina et al.: the inability of the latter two studies to account for the influence of passive gene–environment correlations. Contrary to a gene–environment interaction which refers to a different susceptibility to an environmental factor due to a certain genotype, gene–environment correlations are described by a probability of exposure to an environmental factor that differs with the genotype [60]. A passive gene–environment correlation refers to the situation that children with a certain genotype (that is inherited from the parents) are more likely to experience a certain environmental exposure occurring during childhood [60]. Gaysina et al. [59] mentioned that they were able to control for post-natal passive genotype–environment correlations by testing the association in a subgroup of children adopted at birth who share the post-natal environment, but no prenatal environmental nor genetic factors with the mother. The association between prenatal smoke exposure and children’s conduct problems was also present in this group.

In conclusion, existing literature suggests a causal effect of prenatal exposure to nicotine and conduct or externalising problems in the offspring.

Depression, anxiety or internalising disorders

Results are generally mixed on the association between maternal smoking during pregnancy and internalising symptoms, such as depression or anxiety, in children. Findings are therefore less consistent than the findings for externalising symptoms such as conduct problems or ADHD [61]. While some studies are supportive of a relationship (e.g. [61, 62, 63, 64]), others are not (e.g. [19, 65]).

One longitudinal study by Ashford et al. [61] investigated the association between maternal smoking during pregnancy and symptoms of internalising behaviour in nearly 400 children, assessed at ages 5, 10–11 and 18 years. The authors observed significant relationships with both externalising and internalising behaviours that were also robust to adjustment for potential confounders and also for co-occurring internalising and externalising behaviours, respectively. The authors state that their study has the advantage of controlling for comorbid externalising problems, as the association between maternal smoking during pregnancy and externalising problems is well established and internalising and externalising problems are often comorbid.

A similar result was observed from a small study of 84 children conducted by Indredavik et al. [62]. Maternally reported internalising scores at the age of 14 years were significantly higher for children whose mother smoked during pregnancy, and this association remained also after adjustment for confounders including socioeconomic status and maternal mental health.

Menezes et al. [63] recently reported results from 18-year-olds from the Pelotas cohort, showing a higher risk for lower levels of happiness and increased rates of depression among those prenatally exposed to maternal smoking (<20 cigarettes/day: OR = 1.38, 95 % CI: 1.03–1.84; ≥20 cigarettes/day: OR = 2.11, 95 % CI: 1.31–3.40). Smoking by the mother’s partner during pregnancy was associated with decreased adolescent happiness after adjustment for confounders, but did not show an association with offspring depression.

Ekblad et al. [64] studied the relationship between maternal smoking during pregnancy and psychiatric morbidity in young Finnish adults in a large (N > 175,000) population-based sample using registry-based data. The authors observed an increased risk for any psychiatric diagnosis. Dose–response relationships were observed for the risks of mood disorders, behavioural and emotional disorders occurring in childhood and adolescence, as well as disorders of conduct and emotion. However, while the study was able to adjust for a potential influence of maternal psychiatric morbidity on the relationship, information on other important factors such as socioeconomic factors, maternal alcohol consumption during pregnancy and post-natal exposure to tobacco smoke was not available. Therefore, the reported association should be interpreted with caution.

Other studies, however, do not observe a relationship between prenatal maternal smoking and internalising problems. Höök et al. [65] observed no such association in preschool children at 3 or at 5.5 years of age. A similar null finding was observed by Brion et al. [19] who studied the association in the British ALSPAC and the Brazilian Pelotas study. Another finding of this study was that paternal smoking during pregnancy was also unrelated to offspring internalising problems [19].

A small number of studies in rats on internalising behaviours after prenatal nicotine exposure reported consistent results of an increased anxiety-like behaviour in adolescent and also in adult rats [31].

In summary, the establishment of a final conclusion concerning the relationship between prenatal nicotine exposure and internalising problems in the offspring is complicated by insufficient data and mixed results in epidemiological studies.

Developmental aspects: neonate, infant, child, adolescent and adult

Taking together the results from above, maternal active or passive smoking during pregnancy correlates with behavioural problems in the offspring across the lifespan. However, even if no study had had the possibility to investigate the longitudinal association from birth to adulthood, the results from offspring at different ages seem to support a long-lasting relationship.

Central nervous system (CNS) findings

Bublitz et al. [66] reviewed the results from the small number of studies investigating the association between maternal smoking during pregnancy and brain structure and function in human offspring, and concluded that this exposure has adverse effects. Structural changes in the foetal or early post-natal period included smaller volumes of cerebellum and lateral ventricular system and a smaller frontal lobe [66]. Structural changes in children and adolescents exposed to gestational tobacco smoke included reduced grey matter volume in the cerebral cortex, smaller volume of the corpus callosum and thinning in the frontal, temporal and parietal regions [66]. Reduced volume of the corpus callosum and cerebellum was also observed in children with ADHD [67], thereby providing a potential link between in utero exposure to tobacco smoke and ADHD. Furthermore, comparative functional magnetic resonance imaging studies showed inferior frontal cortex underactivation in children with ADHD which is suggested to be disorder-specific for ADHD [68]. Imaging studies of conduct disorders showed dysfunctions of the paralimbic system which were disorder-specific when compared to children with ADHD [68].

Bublitz et al. [66] reported an increased rate of auditory brainstem responses in infants whose mother smoked during pregnancy, providing a link to cognitive deficits or language and learning impairments.

Mechanisms underlying teratogenesis and/or effects on the CNS

Nicotine is one of thousands of components of tobacco smoke, but it is this chemical that most probably has adverse effects on brain development [53]. The effects of nicotine are thought to occur via its action on nicotinic acetylcholine receptors (nAChRs). These receptors are ligand-gated ion channels expressed in the CNS, in the peripheral nervous system and also in non-neuronal cells that operate through binding and release of a signalling molecule which, in the case of nAChRs, is the endogenous neurotransmitter acetylcholine (ACh) [69]. Nicotine is an exogenous agonist of ACh, able to bind to and to desensitise these nAChRs and thereby mimics the action of ACh [53]. It is suggested that ACh through its action on nAChRs plays an important role in brain maturation in foetuses and infants up to adolescence [53]. These processes modulated by ACh can thus be perturbed by nicotine. Expression of nAChRs subunit mRNA is reported in the first trimester of human foetuses [70], and its expression varies among brain regions and time but seems to be comparable between humans and rodents [53]. Therefore, nicotine exposure at different periods of maturation could elicit different developmental deficits [53]. There is further evidence for the involvement of nAChRs in the control of CNS maturation by modulating, for example, gene expression, cell proliferation, differentiation and apoptosis [70]. Results from animal studies also suggest that gestational exposure to nicotine is related to cell death in neurons [70]. NAChRs are also thought to be involved in the development of the catecholamine neurotransmitter systems via regulation of neurotransmitter release [70]. This provides a link to behavioural problems in children as these may be a result from catecholaminergic dysfunction that could potentially be caused by nicotine that perturbed a proper development [53]. Arnsten and Rubia [68] reviewed the role of neurobiological circuits involved in the regulation of behaviour and cognitive function and their relationship to neurodevelopmental disorders in children. The prefrontal cortex (PFC) plays here an important role which is dependent on optimal levels of neurotransmitters such as the catecholamines dopamine and norepinephrine, serotonin and ACh [68]. A reduced function of the prefrontal cortex is related to symptoms of ADHD [71]. Treatment with methylphenidate, a stimulant medication for ADHD in children, increases the levels of dopamine and norepinephrine in the PFC by blocking transporters responsible for the clearance of these neurotransmitters and thereby improves the PFC’s function to control attention and working memory [68].

Moylan et al. [72] reviewed possible biological mechanisms that might be involved in the relationship between in utero tobacco smoke exposure and anxiety symptoms or disorder. Among these is a role of neurotransmitter systems, such as serotonin, noradrenaline and dopamine. As mentioned above, these systems might be affected by prenatal exposure to nicotine. Furthermore, dysfunction of norepinephrine and serotonin neurotransmitter systems has been related to depression and anxiety [73, 74].

Another approach for understanding the influence of maternal smoking on child behaviour problems is the investigation of epigenetic mechanisms [75, 76]. Prenatal smoking has been linked to alterations in placental DNA methylation and gene expression [77], decreased global DNA methylation in cord blood relative to cord serum cotinine levels [78] and to increased DNA methylation in the brain-derived neurotrophic factor-6 exon in adolescence [79]. However, the implications of these findings for behavioural outcomes in the offspring are not yet clear [75].

Conclusion

Many studies report relationships between maternal smoking during pregnancy and behavioural problems or impaired cognitive function in the offspring, and plausible biological mechanisms exist via which nicotine could affect the development of the foetus in utero. The link of prenatal smoke exposure with externalising problems or ADHD seems to be more consistent than that with internalising problems. However, establishing a statement on the causality of the relationship between prenatal nicotine exposure and behavioural problems in children remains challenging.

But, do we really need more research on the direct causality between prenatal exposure to nicotine and behavioural problems to recommend abstinence from smoking during pregnancy and the avoidance of a smoke exposure of the expectant mother? We think that further studies are likely unnecessary! This final statement is not only justified by an increasing number of studies which link prenatal exposure to nicotine to externalising problems applying different methodologies to account for confounding but also by other adverse health effects known to be caused by prenatal nicotine exposure. Therefore, parents should consider smoking cessation to prevent adverse health effects for their child.

Notes

Acknowledgments

We would like to thank Maia Smith for editorial assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    US Department of Health and Human Services (2004) The Health Consequences of Smoking: A Report of the Surgeon General. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, Atlanta, GAGoogle Scholar
  2. 2.
    Murray CJ, Vos T, Lozano R et al (2012) Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380(9859):2197–2223. doi: 10.1016/S0140-6736(12)61689-4 PubMedCrossRefGoogle Scholar
  3. 3.
    Öberg M, Jaakkola M, Prüss-Üstün A et al. (2010) Second-hand smoke: Assessing the environmental burden of disease at national and local levels. WHO Environmental Burden of Disease Series, No. 18. World Health Organization, GenevaGoogle Scholar
  4. 4.
    Djordjevic MV, Doran KA (2009) Nicotine content and delivery across tobacco products. Handb Exp Pharmacol 192:61–82. doi: 10.1007/978-3-540-69248-5_3 PubMedCrossRefGoogle Scholar
  5. 5.
    Benowitz NL, Hukkanen J, Jacob P 3rd (2009) Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol 192:29–60PubMedCrossRefGoogle Scholar
  6. 6.
    Pastrakuljic A, Schwartz R, Simone C et al (1998) Transplacental transfer and biotransformation studies of nicotine in the human placental cotyledon perfused in vitro. Life Sci 63(26):2333–2342. doi: 10.1016/S0024-3205(98)00522-0 PubMedCrossRefGoogle Scholar
  7. 7.
    Jauniaux E, Gulbis B, Acharya G et al (1999) Maternal tobacco exposure and cotinine levels in fetal fluids in the first half of pregnancy. Obstet Gynecol 93(1):25–29. doi: 10.1016/S0029-7844(98)00318-4 PubMedCrossRefGoogle Scholar
  8. 8.
    Dempsey DA, Benowitz NL (2001) Risks and benefits of nicotine to aid smoking cessation in pregnancy. Drug Saf 24(4):277–322. doi: 10.2165/00002018-200124040-00005 PubMedCrossRefGoogle Scholar
  9. 9.
    Florescu A, Ferrence R, Einarson T et al (2009) Methods for quantification of exposure to cigarette smoking and environmental tobacco smoke: focus on developmental toxicology. Ther Drug Monit 31(1):14–30. doi: 10.1097/FTD.0b013e3181957a3b PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Avila-Tang E, Al-Delaimy WK, Ashley DL et al (2013) Assessing secondhand smoke using biological markers. Tob Control 22(3):164–171. doi: 10.1136/tobaccocontrol-2011-050298 PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Heinrich J, Holscher B, Seiwert M et al (2005) Nicotine and cotinine in adults’ urine: the German Environmental Survey 1998. J Expo Anal Environ Epidemiol 15(1):74–80. doi: 10.1038/sj.jea.7500373 PubMedGoogle Scholar
  12. 12.
    Gray T, Huestis M (2007) Bioanalytical procedures for monitoring in utero drug exposure. Anal Bioanal Chem 388(7):1455–1465. doi: 10.1007/s00216-007-1228-9 PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Llaquet H, Pichini S, Joya X et al (2010) Biological matrices for the evaluation of exposure to environmental tobacco smoke during prenatal life and childhood. Anal Bioanal Chem 396(1):379–399. doi: 10.1007/s00216-009-2831-8 PubMedCrossRefGoogle Scholar
  14. 14.
    Köhler E, Avenarius S, Rabsilber A et al (2007) Assessment of prenatal tobacco smoke exposure by determining nicotine and its metabolites in meconium. Hum Exp Toxicol 26(6):535–544. doi: 10.1177/0960327107072391 PubMedCrossRefGoogle Scholar
  15. 15.
    Köhler E, Avenarius S, Rabsilber A et al (2010) Nicotine and its metabolites in amniotic fluid at birth-assessment of prenatal tobacco smoke exposure. Hum Exp Toxicol 29(5):385–391. doi: 10.1177/0960327110363326 PubMedCrossRefGoogle Scholar
  16. 16.
    Köhler E, Bretschneider D, Rabsilber A et al (2001) Assessment of prenatal smoke exposure by determining nicotine and its metabolites in maternal and neonatal urine. Hum Exp Toxicol 20(1):1–7PubMedCrossRefGoogle Scholar
  17. 17.
    Apelberg BJ, Hepp LM, Avila-Tang E et al (2013) Environmental monitoring of secondhand smoke exposure. Tob Control 22(3):147–155. doi: 10.1136/tobaccocontrol-2011-050301 PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Gehring U, Leaderer BP, Heinrich J et al (2006) Comparison of parental reports of smoking and residential air nicotine concentrations in children. Occup Environ Med 63(11):766–772. doi: 10.1136/oem.2006.027151 PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Brion MJ, Victora C, Matijasevich A et al (2010) Maternal smoking and child psychological problems: disentangling causal and noncausal effects. Pediatrics 126(1):e57–e65. doi: 10.1542/peds.2009-2754 PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Langley K, Heron J, Smith GD et al (2012) Maternal and paternal smoking during pregnancy and risk of ADHD symptoms in offspring: testing for intrauterine effects. Am J Epidemiol 176(3):261–268. doi: 10.1093/aje/kwr510 PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Rückinger S, Rzehak P, Chen CM 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 Persp 118(1):150–154. doi: 10.1289/ehp.0901209 Google Scholar
  22. 22.
    Tiesler CM, Chen CM, Sausenthaler S et al (2011) Passive smoking and behavioural problems in children: results from the LISAplus prospective birth cohort study. Environ Res 111(8):1173–1179. doi: 10.1016/j.envres.2011.06.011 PubMedCrossRefGoogle Scholar
  23. 23.
    Ward C, Lewis S, Coleman T (2007) Prevalence of maternal smoking and environmental tobacco smoke exposure during pregnancy and impact on birth weight: retrospective study using Millennium Cohort. BMC Public Health 7:81. doi: 10.1186/1471-2458-7-81 PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Duijts L, Jaddoe VW, van der Valk RJ et al (2012) Fetal exposure to maternal and paternal smoking and the risks of wheezing in preschool children: the generation R study. Chest 141(4):876–885. doi: 10.1378/chest.11-0112 PubMedCrossRefGoogle Scholar
  25. 25.
    Euro-Peristat project with SCPE and Eurocat (2013) European perinatal health report. The health of pregnant women and babies in Europe in 2010Google Scholar
  26. 26.
    Cnattingius S (2004) The epidemiology of smoking during pregnancy: smoking prevalence, maternal characteristics, and pregnancy outcomes. Nicotine Tob Res 6(Suppl 2):S125–S140. doi: 10.1080/14622200410001669187 PubMedCrossRefGoogle Scholar
  27. 27.
    Bloch M, Althabe F, Onyamboko M et al (2008) Tobacco use and secondhand smoke exposure during pregnancy: an investigative survey of women in 9 developing nations. Am J Public Health 98(10):1833–1840. doi: 10.2105/AJPH.2007.117887 PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Schneider S, Huy C, Schutz J et al (2010) Smoking cessation during pregnancy: a systematic literature review. Drug Alcohol Rev 29(1):81–90. doi: 10.1111/j.1465-3362.2009.00098.x PubMedCrossRefGoogle Scholar
  29. 29.
    Kodl MM, Wakschlag LS (2004) Does a childhood history of externalizing problems predict smoking during pregnancy? Addict Behav 29(2):273–279. doi: 10.1016/j.addbeh.2003.08.003 PubMedCrossRefGoogle Scholar
  30. 30.
    DiFranza JR, Aligne CA, Weitzman M (2004) Prenatal and postnatal environmental tobacco smoke exposure and children’s health. Pediatrics 113(4 Suppl):1007–1015PubMedGoogle Scholar
  31. 31.
    Abbott LC, Winzer-Serhan UH (2012) Smoking during pregnancy: lessons learned from epidemiological studies and experimental studies using animal models. Crit Rev Toxicol 42(4):279–303. doi: 10.3109/10408444.2012.658506 PubMedCrossRefGoogle Scholar
  32. 32.
    Salmasi G, Grady R, Jones J et al (2010) Environmental tobacco smoke exposure and perinatal outcomes: a systematic review and meta-analyses. Acta Obstet Gynecol Scand 89(4):423–441. doi: 10.3109/00016340903505748 PubMedCrossRefGoogle Scholar
  33. 33.
    Leonardi-Bee J, Britton J, Venn A (2011) Secondhand smoke and adverse fetal outcomes in nonsmoking pregnant women: a meta-analysis. Pediatrics 127(4):734–741. doi: 10.1542/peds.2010-3041 PubMedCrossRefGoogle Scholar
  34. 34.
    Maritz GS, Harding R (2011) Life-long programming implications of exposure to tobacco smoking and nicotine before and soon after birth: evidence for altered lung development. Int J Environ Res Public Health 8(3):875–898. doi: 10.3390/ijerph8030875 PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Burke H, Leonardi-Bee J, Hashim A et al (2012) Prenatal and passive smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis. Pediatrics 129(4):735–744. doi: 10.1542/peds.2011-2196 PubMedCrossRefGoogle Scholar
  36. 36.
    Neuman A, Hohmann C, Orsini N et al (2012) Maternal smoking in pregnancy and asthma in preschool children: a pooled analysis of eight birth cohorts. Am J Respir Crit Care Med 186(10):1037–1043. doi: 10.1164/rccm.201203-0501OC PubMedCrossRefGoogle Scholar
  37. 37.
    Pike K, Jane Pillow J, Lucas JS (2012) Long term respiratory consequences of intrauterine growth restriction. Semin Fetal Neonat M 17(2):92–98. doi: 10.1016/j.siny.2012.01.006 CrossRefGoogle Scholar
  38. 38.
    Bakker H, Jaddoe VW (2011) Cardiovascular and metabolic influences of fetal smoke exposure. Eur J Epidemiol 26(10):763–770. doi: 10.1007/s10654-011-9621-2 PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Behl M, Rao D, Aagaard K et al (2013) Evaluation of the association between maternal smoking, childhood obesity, and metabolic disorders: a national toxicology program workshop review. Environ Health Persp 121(2):170–180. doi: 10.1289/ehp.1205404 Google Scholar
  40. 40.
    Rosenthal DG, Weitzman M (2011) Examining the effects of intrauterine and postnatal exposure to tobacco smoke on childhood cognitive and behavioral development. Int J Ment Health 40(1):39–64. doi: 10.2753/IMH0020-7411400103 CrossRefGoogle Scholar
  41. 41.
    Clifford A, Lang L, Chen R (2012) Effects of maternal cigarette smoking during pregnancy on cognitive parameters of children and young adults: a literature review. Neurotoxicol Teratol 34(6):560–570. doi: 10.1016/j.ntt.2012.09.004 PubMedCrossRefGoogle Scholar
  42. 42.
    Cho K, Frijters JC, Zhang H et al (2013) Prenatal exposure to nicotine and impaired reading performance. J Pediatr 162(4):713–718. doi: 10.1016/j.jpeds.2012.09.041 PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Eicher JD, Powers NR, Cho K et al (2013) Associations of prenatal nicotine exposure and the dopamine related genes ANKK1 and DRD2 to verbal language. PLoS One 8(5):e63762. doi: 10.1371/journal.pone.0063762 PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Latimer K, Wilson P, Kemp J et al (2012) Disruptive behaviour disorders: a systematic review of environmental antenatal and early years risk factors. Child Care Health Dev 38(5):611–628. doi: 10.1111/j.1365-2214.2012.01366.x PubMedCrossRefGoogle Scholar
  45. 45.
    Linnet KM, Dalsgaard S, Obel C 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(6):1028–1040. doi: 10.1176/appi.ajp.160.6.1028 PubMedCrossRefGoogle Scholar
  46. 46.
    Behnke M, Smith VC, Committee on Substance Abuse et al (2013) Prenatal substance abuse: short- and long-term effects on the exposed fetus. Pediatrics 131(3):e1009–e1024. doi: 10.1542/peds.2012-3931 PubMedCrossRefGoogle Scholar
  47. 47.
    Silva D, Colvin L, Hagemann E et al (2014) Environmental risk factors by gender associated with attention-deficit/hyperactivity disorder. Pediatrics 133(1):e14–e22. doi: 10.1542/peds.2013-1434 PubMedCrossRefGoogle Scholar
  48. 48.
    Gatzke-Kopp LM, Beauchaine TP (2007) Direct and passive prenatal nicotine exposure and the development of externalizing psychopathology. Child Psychiat Hum D 38(4):255–269. doi: 10.1007/s10578-007-0059-4 CrossRefGoogle Scholar
  49. 49.
    Keyes KM, Davey Smith G, Susser E (2014) Associations of prenatal maternal smoking with offspring hyperactivity: causal or confounded? Psychol Med 44(4):857–867. doi: 10.1017/S0033291713000986 PubMedCrossRefGoogle Scholar
  50. 50.
    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(9):672–678. doi: 10.1097/NMD.0b013e3181ef3489 PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Thapar A, Rice F, Hay D et al (2009) Prenatal smoking might not cause attention-deficit/hyperactivity disorder: evidence from a novel design. Biol Psychiat 66(8):722–727. doi: 10.1016/j.biopsych.2009.05.032 PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    D’Onofrio BM, Van Hulle CA, Waldman ID et al (2008) Smoking during pregnancy and offspring externalizing problems: an exploration of genetic and environmental confounds. Dev Psychopathol 20(1):139–164. doi: 10.1017/S0954579408000072 PubMedPubMedCentralGoogle Scholar
  53. 53.
    Dwyer JB, McQuown SC, Leslie FM (2009) The dynamic effects of nicotine on the developing brain. Pharmacol Ther 122(2):125–139. doi: 10.1016/j.pharmthera.2009.02.003 PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Wakschlag LS, Pickett KE, Cook E Jr et al (2002) Maternal smoking during pregnancy and severe antisocial behavior in offspring: a review. Am J Public Health 92(6):966–974. doi: 10.2105/AJPH.92.6.966 PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Herrmann M, King K, Weitzman M (2008) Prenatal tobacco smoke and postnatal secondhand smoke exposure and child neurodevelopment. Curr Opin Pediatr 20(2):184–190. doi: 10.1097/MOP.0b013e3282f56165 PubMedCrossRefGoogle Scholar
  56. 56.
    Stene-Larsen K, Borge AI, Vollrath ME (2009) Maternal smoking in pregnancy and externalizing behavior in 18-month-old children: results from a population-based prospective study. J Am Acad Child Adolesc Psychiatry 48(3):283–289. doi: 10.1097/CHI.0b013e318195bcfb PubMedCrossRefGoogle Scholar
  57. 57.
    O’Brien TC, Mustanski BS, Skol A et al (2013) Do dopamine gene variants and prenatal smoking interactively predict youth externalizing behavior? Neurotoxicol Teratol 40:67–73. doi: 10.1016/j.ntt.2013.09.002 PubMedCrossRefGoogle Scholar
  58. 58.
    D’Onofrio BM, Van Hulle CA, Goodnight JA et al (2012) Is maternal smoking during pregnancy a causal environmental risk factor for adolescent antisocial behavior? Testing etiological theories and assumptions. Psychol Med 42(7):1535–1545. doi: 10.1017/S0033291711002443 PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Gaysina D, Fergusson DM, Leve LD et al (2013) Maternal smoking during pregnancy and offspring conduct problems: evidence from 3 independent genetically sensitive research designs. JAMA Psychiatry 70(9):956–963. doi: 10.1001/jamapsychiatry.2013.127 PubMedCrossRefGoogle Scholar
  60. 60.
    Jaffee SR, Price TS (2007) Gene-environment correlations: a review of the evidence and implications for prevention of mental illness. Mol Psychiatry 12(5):432–442. doi: 10.1038/sj.mp.4001950 PubMedPubMedCentralGoogle Scholar
  61. 61.
    Ashford J, van Lier PA, Timmermans M et al (2008) Prenatal smoking and internalizing and externalizing problems in children studied from childhood to late adolescence. J Am Acad Child Adolesc Psychiatry 47(7):779–787. doi: 10.1097/CHI.0b013e318172eefb PubMedCrossRefGoogle Scholar
  62. 62.
    Indredavik MS, Brubakk AM, Romundstad P et al (2007) Prenatal smoking exposure and psychiatric symptoms in adolescence. Acta Paediatr 96(3):377–382. doi: 10.1111/j.1651-2227.2006.00148.x PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Menezes AM, Murray J, Laszlo M et al (2013) Happiness and depression in adolescence after maternal smoking during pregnancy: birth cohort study. PLoS One 8(11):e80370. doi: 10.1371/journal.pone.0080370 PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Ekblad M, Gissler M, Lehtonen L et al (2010) Prenatal smoking exposure and the risk of psychiatric morbidity into young adulthood. Arch Gen Psychiatry 67(8):841–849. doi: 10.1001/archgenpsychiatry.2010.92 PubMedCrossRefGoogle Scholar
  65. 65.
    Höök B, Cederblad M, Berg R (2006) Prenatal and postnatal maternal smoking as risk factors for preschool children’s mental health. Acta Paediatr 95(6):671–677. doi: 10.1080/08035250500538965 PubMedCrossRefGoogle Scholar
  66. 66.
    Bublitz MH, Stroud LR (2012) Maternal smoking during pregnancy and offspring brain structure and function: review and agenda for future research. Nicotine Tob Res 14(4):388–397. doi: 10.1093/ntr/ntr191 PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Krain AL, Castellanos FX (2006) Brain development and ADHD. Clin Psychol Rev 26(4):433–444. doi: 10.1016/j.cpr.2006.01.005 PubMedCrossRefGoogle Scholar
  68. 68.
    Arnsten AFT, Rubia K (2012) Neurobiological circuits regulating attention, cognitive control, motivation, and emotion: disruptions in neurodevelopmental psychiatric disorders. J Am Acad Child Adolesc Psychiatry 51(4):356–367PubMedCrossRefGoogle Scholar
  69. 69.
    Hurst R, Rollema H, Bertrand D (2013) Nicotinic acetylcholine receptors: from basic science to therapeutics. Pharmacol Ther 137(1):22–54. doi: 10.1016/j.pharmthera.2012.08.012 PubMedCrossRefGoogle Scholar
  70. 70.
    Smith AM, Dwoskin LP, Pauly JR (2010) Early exposure to nicotine during critical periods of brain development: mechanisms and consequences. J Pediatr Biochem 1:125–141. doi: 10.3233/JPB-2010-0012 PubMedPubMedCentralGoogle Scholar
  71. 71.
    Arnsten AF (2009) Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction. CNS drugs 23(Suppl 1):33–41. doi: 10.2165/00023210-200923000-00005 PubMedCrossRefGoogle Scholar
  72. 72.
    Moylan S, Jacka FN, Pasco JA et al (2013) How cigarette smoking may increase the risk of anxiety symptoms and anxiety disorders: a critical review of biological pathways. Brain Behav 3(3):302–326. doi: 10.1002/brb3.137 PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Ressler KJ, Nemeroff CB (2000) Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety 12(Suppl 1):2–19. doi: 10.1002/1520-6394(2000)12:1+<2::AID-DA2>3.0.CO;2-4 PubMedCrossRefGoogle Scholar
  74. 74.
    Goddard AW, Ball SG, Martinez J et al (2010) Current perspectives of the roles of the central norepinephrine system in anxiety and depression. Depress Anxiety 27(4):339–350. doi: 10.1002/da.20642 PubMedCrossRefGoogle Scholar
  75. 75.
    Knopik VS, Maccani MA, Francazio S et al (2012) The epigenetics of maternal cigarette smoking during pregnancy and effects on child development. Dev Psychopathol 24(4):1377–1390. doi: 10.1017/S0954579412000776 PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Suter MA, Anders AM, Aagaard KM (2013) Maternal smoking as a model for environmental epigenetic changes affecting birthweight and fetal programming. Mol Hum Reprod 19(1):1–6. doi: 10.1093/molehr/gas050 PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Suter M, Ma J, Harris A et al (2011) Maternal tobacco use modestly alters correlated epigenome-wide placental DNA methylation and gene expression. Epigenetics 6(11):1284–1294. doi: 10.4161/epi.6.11.17819 PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Guerrero-Preston R, Goldman LR, Brebi-Mieville P et al (2010) Global DNA hypomethylation is associated with in utero exposure to cotinine and perfluorinated alkyl compounds. Epigenetics 5(6):539–546PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Toledo-Rodriguez M, Lotfipour S, Leonard G et al (2010) Maternal smoking during pregnancy is associated with epigenetic modifications of the brain-derived neurotrophic factor-6 exon in adolescent offspring. Am J Med Genet B Neuropsychiatr Genet 153B(7):1350–1354. doi: 10.1002/ajmg.b.31109 PubMedCrossRefGoogle Scholar

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© The Author(s) 2014

Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

Authors and Affiliations

  1. 1.Helmholtz Zentrum München, German Research Centre for Environmental HealthInstitute of Epidemiology INeuherbergGermany
  2. 2.Institute for Medical Informatics, Biometrics and EpidemiologyLudwig-Maximilians-University of MunichNeuherbergGermany

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