CONTEXT:

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood. Exploring the risk factors for ADHD is helpful in preventing ADHD.

OBJECTIVE:

To explore the association between maternal smoking during pregnancy and the occurrence of ADHD in offspring.

DATA SOURCES:

PubMed, Embase, and Cochrane Library were searched from inception to May 2017 for studies.

STUDY SELECTION:

Cohort or case-control studies in which the association between maternal smoking and ADHD in offspring were investigated were eligible if they included odds ratios (ORs), hazard ratios, or risk ratios and 95% confidence intervals (CIs).

DATA EXTRACTION:

Two investigators independently extracted data on definition of exposure and outcome, number of cases and total sample population, and potential confounders adjusted. Any dose-relationship data for smoking and ADHD risk were also extracted.

RESULTS:

Fifteen cohort studies and 5 case-control studies with 50 044 cases and 2 998 059 participants were included. Smoking during pregnancy increased the risk of offspring ADHD (OR: 1.60; 95% CI: 1.45–1.76). The risk of ADHD was greater for children whose mothers were heavy smokers (OR: 1.75; 95% CI: 1.51–2.02) than for those mothers were light smokers (OR: 1.54; 95% CI: 1.40–1.70).

LIMITATIONS:

The limitations of our study included different assessment tools of ADHD and a lack of objective biological measures for maternal smoking.

CONCLUSIONS:

With our meta-analysis, we provide evidence for an association between maternal smoking and offspring ADHD but do not solve the causality issues concerning potential confounding by other risk factors. More high-quality studies are needed to establish whether the association with smoking is causal.

Attention-deficit/hyperactivity disorder (ADHD), a common neurodevelopmental disorder, is characterized by inattention, impulsivity, and/or hyperactive or impulsive behaviors and often persists into adulthood, with worldwide prevalence estimates ranging from 3% to 10% of school-aged children.1,3 ADHD is associated with co-occurring psychiatric disorders in both boys and girls, including comorbid mood disorders (depression, anxiety), other disruptive behaviors (oppositional defiant disorder and conduct disorder), antisocial activities, poor verbal working memory, and substance abuse and dependency.4,5 In the United States, overall annual incremental costs of ADHD have been calculated at $143 billion to $266 billion, including productivity and income losses for adults and health care and education losses for ADHD children.6 The high prevalence, chronic nature, and heavy economic burden associated with ADHD make it a concern in public health.

Although the etiology of ADHD is poorly understood, a line of evidence suggests that this is a genetically- as well as environmentally-determined disorder. The authors of familial, twin, and adoption studies have indicated that there is a genetic component, with a heritability estimate of 70% to 80%.7 Environmental factors, including lead exposure, alcohol exposure, and cigarette smoking, and nutritional factors in pregnancy may also be related to the occurrence and severity of ADHD. The effect of cigarette smoking during pregnancy on the outcomes of offspring attracts extensive attention. It is reported that 4.9% of pregnant women still smoke during pregnancy8 in Japan. In the United States, the prevalence of maternal smoking during the third trimester of pregnancy was ∼10% in 2010.9 

The adverse effects of maternal smoking on pregnancy outcomes in the offspring include preterm delivery, low birth weight, placenta abruption, reduced fetal lung development, increased infection in infancy, sudden infant death syndrome, the development of obesity or overweight, and an increased probability of smoking.10,11 Evidence regarding the association between maternal smoking during pregnancy and the development of ADHD is inconsistent. Several studies have found that maternal smoking during pregnancy was a risk factor for the development of ADHD in offspring.12,13 Animal experiments have also revealed that the offspring of rats with prenatal nicotine exposure are hyperactive.14 However, the authors of other studies have failed to find an increased risk of ADHD in children whose mothers smoked during pregnancy, compared with those whose mothers did not smoke.15,17 Therefore, we performed the current study to systematically evaluate the association between maternal smoking during pregnancy and ADHD risk in offspring. Given the high prevalence of maternal smoking and ADHD, establishing whether maternal smoking during pregnancy and ADHD in offspring is associated is meaningful from a clinical and public health perspective. Additionally, the finding of a significant association would prompt efforts to advocate smoking cessation during pregnancy for the prevention of ADHD.

A systematic search of PubMed, Embase, and Cochrane Library was conducted to locate related studies. The following keywords, including medical subject heading terms and free-text terms, were used in the search strategy: “attention-deficit/hyperactivity disorder” or “ADHD” or “attention deficit disorders with hyperactivity” or “hyperkinetic disorder” or “hyperkinetic syndrome and pregnancy” or ‘‘pregnancies” or “perinatal” or “gestation” or “prenatal” or “antenatal” or “maternal and smoke” or “smoking” or “tobacco” or “nicotine.” We limited all results to studies in humans that were published in English. No restrictions were placed on location of the study or age of the participants. The single study with the largest sample size was included if participants overlapped between studies. Clearly irrelevant studies were excluded by scanning the titles and abstracts. We also reviewed searches of references of key retrieved articles manually. Next, 2 investigators independently read the full text of the remaining articles to assess their eligibility according to our inclusion criteria. Disagreements on the inclusion eligibility were resolved by a third author when required.

Inclusion criteria for our study were as follows: (1) those with a cohort or case-control design, (2) those in which the association between maternal smoking during pregnancy and ADHD risk in offspring was reported, and (3) those in which the authors reported the total number of participants, number of cases, odds ratios (ORs), hazard ratios, or risk ratios and 95% confidence intervals (CIs). Exclusion criteria for the study were as follows: (1) case reports, conference abstracts, reviews, and animal studies; (2) studies with overlapping data; (3) studies on passive smoking; and (4) studies without raw data.

Two reviewers independently extracted data on the first author, publication year, country, study design, age, definition of exposure and outcome, number of cases and total sample population, and potential confounders adjusted. Any dose-relationship data for smoking and ADHD risk were also extracted.

The methodological quality of studies was examined by using the Newcastle-Ottawa Scale, which was recommended for quality assessment of cohort and case-control studies with a maximum score of 9. The quality of the study was divided into 3 categories: high quality (scored 7–9), moderate quality (scored 4–6), and low quality (scored 0–3).18 

The ORs were used as a measure of the association between maternal smoking and the risk of offspring ADHD among studies. The hazard and risk ratios were directly considered as ORs in the pooled analysis. We used a random effects model to calculate the pooled ORs. The I2 statistic19 (significance level, >50%) and Q statistic (significance level at P < .10) were used to assess heterogeneity among studies. Subgroup analyses were stratified by study design, study location, study quality, and the degree of smoking exposure. Additionally, we conducted the sensitivity analysis by excluding 1 study in each turn. The possibility of publication bias was visually assessed by using the Begg’s test (significance level, P < .05). We also performed the “trim-and-fill” procedure to further assess the possible effect of publication bias in our meta-analysis. Stata version 12.0 (StataCorp, College Station, TX) was used for all analyses.

A total of 650 articles were identified, with 300 from PubMed, 345 from Embase, and 5 from the Cochrane Database. Of these, 160 duplicates, 128 reviews, 11 animal experiments, and 273 irrelevant studies were excluded, resulting in 78 studies for full-text review. After careful screening, 20 studies12,13,15,20,36 were selected for final inclusion in this study (Fig 1).

FIGURE 1

Flow diagram of the study selection process.

FIGURE 1

Flow diagram of the study selection process.

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Characteristics of the 20 selected studies are shown in Table 1. The selected studies were published between 1998 and 2017. Of the 20 studies, there were 5 case-control studies and 15 cohort studies, with a total of 50 044 cases and 2 998 059 participants. In 5 of the selected studies,12,13,20,22,27 authors reported the ORs separately for boys and girls, including 634 229 boys and 576 170 girls. In the 3 cohort studies,20,27,36 the authors used sibling analysis to control for shared genetic and social confounding. The sample size of the studies ranged from 260 to 982 856. Seven studies were performed in the United States,15,23,30,31,33,35 9 were performed in Europe,12,13,20,21,24,25,27,28 1 was performed in Brazil,32 1 was performed in Japan,29 and 2 were performed in Australia.22,26 For the diagnosis of ADHD, the authors of most of the studies reported the criteria for the diagnosis of ADHD; only 1 study did not include this information.28 In 12 of the selected studies, researchers adopted the diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R)30,31,34,35 or the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),15,23,25,29,32,33 whereas the International Classification of Diseases, 10th Revision (ICD-10) was used as the diagnostic method for ADHD in only 3 studies.20,27,36 In 2 studies, the authors chose measures to assess ADHD, such as the Strengths and Difficulties Questionnaire (SDQ)13,21 and Child Behavior Questionnaire (Rutter B2).12 The information about smoking was generally collected by interviews or according to related registers. According to the Newcastle-Ottawa Scale, the overall methodological quality was good, with 15 studies that were high quality and 5 studies that were moderate quality (Supplemental Table 3).

TABLE 1

Characteristics of Included Studies of Maternal Smoking During Pregnancy and ADHD

StudyLocationDesignADHD Cases/Total ParticipantsAge (y)Ascertainment of SmokingAscertainment of ADHDDiagnosis of ADHDConfounding Factors
Milberger et al35  United States ML 140/260 6–17 Diagnostic interview for children and adolescents–parent version Children were interviewed by a specialist in child and adolescent psychiatry DSM-III-R Socioeconomic status, maternal IQ, maternal ADHD, paternal IQ, and paternal ADHD 
Mick et al34  United States ML 280/522 6–17 Collected by structured diagnostic interview and self-reported regarding her own psychiatric history Interviews with each parent and medical record DSM-III-R Maternal age at child’s birth, indicators of social adversity, parental history of ADHD, parental history of CD and/or ASPD, and comorbid CD 
Kotimaa et al12  Northern Finland 808/8478 Recorded at recruitment Parents and teachers completed questionnaires on the child’s development or behavior Child Behavior Questionnaire (Rutter B2) Sex, family structure, socioeconomic status, maternal age, and alcohol use during pregnancy 
Knopik et al33  United States 255/3872 14.4 Extracted from maternal interview data Interview with mother DSM-IV Birth wt, parental alcohol history, and maternal alcohol use during pregnancy 
Schmitz et al32  Brazil ML 100/200 6–18 Collected by direct interview with the biological mother Screened by SNAP-IV and diagnosed by child and adolescent psychiatrist DSM-IV Alcohol use during pregnancy, birth wt, maternal ADHD, and oppositional defiant disorder 
Wakschlag et al31  United States 78/448 Extract from maternal report on background interview Interview with parents and children DSM-III-R Drug use 
Nigg and Breslau30  United States ML 94/713 6 and 11 Collected by direct interview with the biological mother Interview with mothers DSM-III-R Maternal substance use disorders, birth wt, education level, and location 
Yoshimasu et al29  Japan ML 90/360 6–15 Investigated by a questionnaire Diagnosed by experienced psychiatrists or pediatricians DSM-IV Children’s sex, family income, maternal drinking during pregnancy, pregnancy-induced hypertension, birth wt, children’s iron intake, maternal tendency of ADHD, parental history of mental disorders, and maternal mental stress during pregnancy 
Ball et al15  United States 219/2024 Collected beginning with the initial prenatal assessment and prospectively up to the day of birth by interview Diagnosed by psychologists DSM-IV Ascertainment source, family psychopathology, maternal education, and sex of offspring 
Lindblad and Hjern28  Sweden 6496/982 856 6–19 Collected by the midwife at the first visit to the maternity health clinic, 8–12 wk after conception Swedish Prescribed Drug Register Not mentioned Age, year of birth, sex, county of residence, maternal age, birth order, maternal education, single parent, social assistance, maternal and/or paternal psychiatric and/or addictive disorders, small for gestational age, and low Apgar score 
Hutchinson et al13  United Kingdom 1199/13 654 Collected by interview Interview with mothers SDQs Mother’s age (y) at index, child’s birth; No. children in the household, mother’s ethnicity, and psychosocial and parenting domains 
Obel et al27  Finland C, sibling analysis 7023/868 449 NA Finnish Medical Birth Register Finnish Hospital Discharge Register ICD-10 Sex, year of birth, maternal age, gestational age at birth, and parity 
Sciberras et al26  Australia 64/3474 6–7 Investigated by a questionnaire Interview with the primary caregiver DSM-IV Maternal alcohol use during pregnancy, maternal postnatal depression, intensive care at birth, child’s birth wt, sociodemographic factors, maternal age at child birth, No. people in the household, primary caregiver education, and marital status 
Langley et al25  United Kingdom 121/5637 7.6 Collected at 18 and 32 weeks’ gestation by interview Interview with parents DSM-IV Child’s sex, ethnicity, multiple births (twins), maternal alcohol use during pregnancy, and social class 
Sagiv et al23  United States 75/601 Extract from a questionnaire administered 2 wk after birth Pediatric medical records DSM-IV Maternal age at child’s birth, maternal education, paternal education, maternal marital status and annual household income at child’s school age, maternal alcohol consumption during pregnancy, maternal illicit drug use in year before birth, maternal IQ, maternal depression symptoms, HOME score, children’s gestational age, sex, race, breastfeeding, type of school, No. siblings living in house 
Jaspers et al24  Netherlands 419/1816 1.5–4 Preventive Child Healthcare files Interview with parents DSM-IV Alcohol use during pregnancy, low birth wt, and birth defects 
Silva et al22  Australia ML 12 991/43 062 <25 Records of midwives notification system Monitoring of Drugs of Dependence system DSM-IV or ICD-10 Maternal age, marital status, first pregnancy, threatened abortion, threatened preterm labor, maternal UTI, preeclampsia, onset of labor induced, augmentation of labor, complications of labor, type of delivery, weeks’ gestation, and birth wt 
Melchior et al21  France 176/1113 Investigated by a questionnaire Interview with mothers SDQ Children’s sex, premature birth, birth wt, duration of breastfeeding, maternal age at birth, maternal psychological difficulties in pregnancy, maternal depression postpregnancy, maternal alcohol use in pregnancy, maternal smoking postpregnancy, paternal tobacco smoking during and postpregnancy, study center, parents’ educational attainment, family income, parental separation, No. siblings, and negative life events 
Obel et al20  Denmark C, sibling analysis 17 381/968 665 NA Medical Birth Register Medical Birth Register or medication record ICD-10 Sex, birth year, parity, and mother’s age 
Gustavson et al36  Norway C, sibling analysis 2035/104 846 5–15 Mother self-report Norwegian Patient registry ICD-10 Maternal and paternal age, maternal and paternal education, maternal and paternal ADHD symptoms, maternal (prepregnancy) and paternal BMI, maternal alcohol consumption during pregnancy, parity, child’s birth year, and geographical region 
StudyLocationDesignADHD Cases/Total ParticipantsAge (y)Ascertainment of SmokingAscertainment of ADHDDiagnosis of ADHDConfounding Factors
Milberger et al35  United States ML 140/260 6–17 Diagnostic interview for children and adolescents–parent version Children were interviewed by a specialist in child and adolescent psychiatry DSM-III-R Socioeconomic status, maternal IQ, maternal ADHD, paternal IQ, and paternal ADHD 
Mick et al34  United States ML 280/522 6–17 Collected by structured diagnostic interview and self-reported regarding her own psychiatric history Interviews with each parent and medical record DSM-III-R Maternal age at child’s birth, indicators of social adversity, parental history of ADHD, parental history of CD and/or ASPD, and comorbid CD 
Kotimaa et al12  Northern Finland 808/8478 Recorded at recruitment Parents and teachers completed questionnaires on the child’s development or behavior Child Behavior Questionnaire (Rutter B2) Sex, family structure, socioeconomic status, maternal age, and alcohol use during pregnancy 
Knopik et al33  United States 255/3872 14.4 Extracted from maternal interview data Interview with mother DSM-IV Birth wt, parental alcohol history, and maternal alcohol use during pregnancy 
Schmitz et al32  Brazil ML 100/200 6–18 Collected by direct interview with the biological mother Screened by SNAP-IV and diagnosed by child and adolescent psychiatrist DSM-IV Alcohol use during pregnancy, birth wt, maternal ADHD, and oppositional defiant disorder 
Wakschlag et al31  United States 78/448 Extract from maternal report on background interview Interview with parents and children DSM-III-R Drug use 
Nigg and Breslau30  United States ML 94/713 6 and 11 Collected by direct interview with the biological mother Interview with mothers DSM-III-R Maternal substance use disorders, birth wt, education level, and location 
Yoshimasu et al29  Japan ML 90/360 6–15 Investigated by a questionnaire Diagnosed by experienced psychiatrists or pediatricians DSM-IV Children’s sex, family income, maternal drinking during pregnancy, pregnancy-induced hypertension, birth wt, children’s iron intake, maternal tendency of ADHD, parental history of mental disorders, and maternal mental stress during pregnancy 
Ball et al15  United States 219/2024 Collected beginning with the initial prenatal assessment and prospectively up to the day of birth by interview Diagnosed by psychologists DSM-IV Ascertainment source, family psychopathology, maternal education, and sex of offspring 
Lindblad and Hjern28  Sweden 6496/982 856 6–19 Collected by the midwife at the first visit to the maternity health clinic, 8–12 wk after conception Swedish Prescribed Drug Register Not mentioned Age, year of birth, sex, county of residence, maternal age, birth order, maternal education, single parent, social assistance, maternal and/or paternal psychiatric and/or addictive disorders, small for gestational age, and low Apgar score 
Hutchinson et al13  United Kingdom 1199/13 654 Collected by interview Interview with mothers SDQs Mother’s age (y) at index, child’s birth; No. children in the household, mother’s ethnicity, and psychosocial and parenting domains 
Obel et al27  Finland C, sibling analysis 7023/868 449 NA Finnish Medical Birth Register Finnish Hospital Discharge Register ICD-10 Sex, year of birth, maternal age, gestational age at birth, and parity 
Sciberras et al26  Australia 64/3474 6–7 Investigated by a questionnaire Interview with the primary caregiver DSM-IV Maternal alcohol use during pregnancy, maternal postnatal depression, intensive care at birth, child’s birth wt, sociodemographic factors, maternal age at child birth, No. people in the household, primary caregiver education, and marital status 
Langley et al25  United Kingdom 121/5637 7.6 Collected at 18 and 32 weeks’ gestation by interview Interview with parents DSM-IV Child’s sex, ethnicity, multiple births (twins), maternal alcohol use during pregnancy, and social class 
Sagiv et al23  United States 75/601 Extract from a questionnaire administered 2 wk after birth Pediatric medical records DSM-IV Maternal age at child’s birth, maternal education, paternal education, maternal marital status and annual household income at child’s school age, maternal alcohol consumption during pregnancy, maternal illicit drug use in year before birth, maternal IQ, maternal depression symptoms, HOME score, children’s gestational age, sex, race, breastfeeding, type of school, No. siblings living in house 
Jaspers et al24  Netherlands 419/1816 1.5–4 Preventive Child Healthcare files Interview with parents DSM-IV Alcohol use during pregnancy, low birth wt, and birth defects 
Silva et al22  Australia ML 12 991/43 062 <25 Records of midwives notification system Monitoring of Drugs of Dependence system DSM-IV or ICD-10 Maternal age, marital status, first pregnancy, threatened abortion, threatened preterm labor, maternal UTI, preeclampsia, onset of labor induced, augmentation of labor, complications of labor, type of delivery, weeks’ gestation, and birth wt 
Melchior et al21  France 176/1113 Investigated by a questionnaire Interview with mothers SDQ Children’s sex, premature birth, birth wt, duration of breastfeeding, maternal age at birth, maternal psychological difficulties in pregnancy, maternal depression postpregnancy, maternal alcohol use in pregnancy, maternal smoking postpregnancy, paternal tobacco smoking during and postpregnancy, study center, parents’ educational attainment, family income, parental separation, No. siblings, and negative life events 
Obel et al20  Denmark C, sibling analysis 17 381/968 665 NA Medical Birth Register Medical Birth Register or medication record ICD-10 Sex, birth year, parity, and mother’s age 
Gustavson et al36  Norway C, sibling analysis 2035/104 846 5–15 Mother self-report Norwegian Patient registry ICD-10 Maternal and paternal age, maternal and paternal education, maternal and paternal ADHD symptoms, maternal (prepregnancy) and paternal BMI, maternal alcohol consumption during pregnancy, parity, child’s birth year, and geographical region 

ASPD, antisocial personality disorder; C, cohort; CD, conduct disorder; HOME, home observation for measurement of the environment; ML, case control; NA, not applicable; SNAP-IV, Swanson, Nolan, and Pelham Teacher and Parent Rating Scale, UTI, urinary tract infection.

Smoking during pregnancy increased the risk of ADHD in offspring with a pooled adjusted OR of 1.60 (95% CI: 1.45–1.76), indicating the positive association between maternal smoking during gestation and ADHD in offspring (Fig 2).Statistically significant heterogeneity was found across studies (I2 = 79.2%; P < .001).

FIGURE 2

Adjusted ORs expressing the association between maternal smoking and offspring ADHD. Weights are from random effects analysis. ES, effect size.

FIGURE 2

Adjusted ORs expressing the association between maternal smoking and offspring ADHD. Weights are from random effects analysis. ES, effect size.

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To explore heterogeneity, we performed subgroup analyses stratified by adjustment for confounders, study design, study location, study quality, diagnosis of ADHD, and the degree of smoking exposure (Table 2). A lower pooled OR was observed in studies conducted in the United States (OR: 1.25, 95% CI: 1.07–1.47) or Europe (OR: 1.67, 95% CI: 1.50–1.86) than in studies conducted in other places (OR: 1.86, 95% CI: 1.57–2.21), including Japan, Australia, and Brazil. Notably, there seems to be a dose-response relationship between maternal smoking and ADHD in children. The sibling analysis failed to reveal the relationship between maternal smoking and AHDH in offspring with a pooled OR of 1.04 (95% CI: 0.95–1.15). The child whose mother is a heavy smoker (10 or more cigarettes per day) seems to have a greater risk for the development of ADHD (OR: 1.75, 95% CI: 1.51–2.02) compared with those whose mother is a light smoker (10 or fewer cigarettes per day; OR: 1.54, 95% CI: 1.40–1.70). The risk of developing ADHD is comparable for boys (OR: 1.51, 95% CI: 1.30–1.76) and girls (OR: 1.43, 95% CI: 1.15–1.78) whose mothers smoked during pregnancy. A stronger association was found in studies unadjusted for maternal alcohol (OR: 1.74, 95% CI: 1.57–1.92) than in studies that adjusted for this confounder (OR: 1.43, 95% CI: 1.31–1.57). The pooled OR of studies adjusted for parental ADHD (OR: 1.59, 95% CI: 1.44–1.75) was comparable to that of studies not adjusted for parental ADHD (OR: 1.58, 95% CI: 1.41–1.76). The overall pooled result did not vary substantially (Supplemental Table 4) after excluding 1 study in each turn.

TABLE 2

Pooled ORs and Heterogeneity in Subgroups Analyses

VariablesNo. StudiesOR (95% CI)I2%P for Heterogeneity
Study design 
 Cohort 15 1.35 (1.20–1.52) 59.5 .002 
 Case control 1.85 (1.57–2.19) .859 
Location 
 United States 1.25 (1.07–1.47) .452 
 Europe 1.67 (1.50–1.86) 85.2 <.001 
 Others 1.86 (1.57–2.21) .466 
Study quality 
 M 1.55 (1.25–1.91) 50.5 .088 
 H 15 1.62 (1.46–1.80) 79.6 <.001 
Sibling design 
 Yes 1.04 (0.95–1.15) 44.7 .164 
 No 17 1.50 (1.35–1.67) 37.7 .059 
Smoking categories of mother 
 Light 1.54 (1.40–1.70) 58.9 .03 
 Severe 1.75 (1.51–2.02) 77 .001 
Sex 
 Male 1.43 (1.15–1.78) 74.1 .004 
 Female 1.51 (1.30–1.76) .465 
Adjusted factors 
 Maternal alcohol 
  Yes 10 1.43 (1.31–1.57) .582 
  No 10 1.74 (1.57–1.92) 76.7 <.001 
 Parental ADHD 
  Yes 1.59 (1.44–1.75) .486 
  No 14 1.58 (1.41–1.76) 81.9 <.001 
VariablesNo. StudiesOR (95% CI)I2%P for Heterogeneity
Study design 
 Cohort 15 1.35 (1.20–1.52) 59.5 .002 
 Case control 1.85 (1.57–2.19) .859 
Location 
 United States 1.25 (1.07–1.47) .452 
 Europe 1.67 (1.50–1.86) 85.2 <.001 
 Others 1.86 (1.57–2.21) .466 
Study quality 
 M 1.55 (1.25–1.91) 50.5 .088 
 H 15 1.62 (1.46–1.80) 79.6 <.001 
Sibling design 
 Yes 1.04 (0.95–1.15) 44.7 .164 
 No 17 1.50 (1.35–1.67) 37.7 .059 
Smoking categories of mother 
 Light 1.54 (1.40–1.70) 58.9 .03 
 Severe 1.75 (1.51–2.02) 77 .001 
Sex 
 Male 1.43 (1.15–1.78) 74.1 .004 
 Female 1.51 (1.30–1.76) .465 
Adjusted factors 
 Maternal alcohol 
  Yes 10 1.43 (1.31–1.57) .582 
  No 10 1.74 (1.57–1.92) 76.7 <.001 
 Parental ADHD 
  Yes 1.59 (1.44–1.75) .486 
  No 14 1.58 (1.41–1.76) 81.9 <.001 

Others include Japan, Australia, and Brazil. Light referred to 1–9 cigarettes/d or 1–10 cigarettes/d; Severe referred to ≥10 cigarettes/d. H, high; M, moderate.

Visual inspection of the funnel plot revealed a potential publication bias (Supplemental Fig 3), although the Begg’s test was not statistically significant (z score = 1.2; P = .23). We further undertook a sensitivity analysis by using the trim-and-fill method37 to estimate the number of missing studies that may have caused funnel plot asymmetry, and we imputed the hypothetical studies to produce a symmetrical funnel plot. No theoretical missing trials were incorporated, which reveals a remarkable association between maternal smoking during pregnancy and ADHD in offspring.

The results of our meta-analysis based on 20 observational studies with a total a total of 50 044 cases and 2 998 059 participants reveal that maternal smoking during pregnancy is associated with a 60% increased odds of ADHD in offspring in the pooled estimate, after adjusting for the potential confounders.

Our study also reveals that there may be a dose-response relationship between smoking during pregnancy and the risk of ADHD in offspring. The dose-related concentration of cotinine in cord serum and urine of newborns was observed, and the neonates with fetal exposure of consistently high daily nicotine had the most elevated cotinine level.38 

However, high heterogeneity was detected in this meta-analysis; therefore, further analysis was required. To explore the heterogeneity of the studies, we conducted subgroup analysis stratified by several key study characteristics, such as study design, location, and study quality. In the subgroup analysis, we found that the heterogeneity decreased significantly when studies were categorized by sibling design, revealing that different study analyses may contribute to the heterogeneity. The participants of sibling-analysis were limited to matched siblings, which were different from traditional case-control study or cohort study.

We found that lower pooled OR was observed in studies conducted in the United States or Europe. Smoking cessation rates during pregnancy that were relatively higher in the United States and Europe than in other regions may have led to the difference. The cessation rates during pregnancy were reported as 35% to 42.5% in the United States,39 27% to 47% in Europe,40 18% to 21% in Brazil,41 and 4% to 34.1% in Australia.40 

A key issue when investigating the role of a certain environmental factors in the development of ADHD is the possibility of confounding by genetics and other environmental factors. It was reported that the prevalence of parental ADHD was higher in children with ADHD,34 and children born to parents with ADHD had an increased risk of ADHD.42 We also noted that the authors of studies with a sibling design did not show the relationship between maternal smoking and ADHD,20,27,36 suggesting a key role for genetics in the development of ADHD. In those sibling-design studies, the authors suggested that the family context and genetic factors are similar in siblings. However, Frisell et al43 pointed out that in studies of pairs of siblings, more bias exists when there are nonshared factors. Although mothers shared some characteristics with siblings, differing characteristics such as maternal age, paternal age, parity, and gravidity still existed. All of these differences may result in biased conclusions regarding the relationship between maternal smoking and ADHD in sibling studies. Meanwhile, Mick et al34 found that the relationship between ADHD and maternal smoking was significant after adjustment for parental ADHD. Our subgroup analysis also found that there was no difference in the increased risk of offspring ADHD, regardless of whether parental ADHD was adjusted. Therefore, maternal smoking might be a risk factor for ADHD.

Smoking and alcohol consumption often coexist. Maternal alcohol consumption, an important perinatal factor, was reported to increase the risk of ADHD in several studies.12,16,44 However, the authors of other studies provided contradictory evidence.12,21 We searched the databases to locate studies on the association between alcohol consumption during pregnancy and ADHD. The pooled OR from the 10 included studies was 1.40 (95% CI: 1.22–1.61)* (Supplemental Fig 4). These findings revealed that alcohol consumption during pregnancy may be associated with offspring ADHD.

All of the included studies except the one conducted by Melchior et al21 were not adjusted for paternal smoking. Therefore, we could not complete a subgroup analysis for paternal smoking. Keyes et al45 found that there was no association between paternal smoking and offspring ADHD after adjustment for several covariates. In contrast, Gustavson et al36 reported that paternal smoking increased the risk of ADHD by 1.23 times. We searched the databases, and 7 related studies were included for further analysis.21,25,36,45,48 The pooled OR was 1.20 (95% CI: 1.08–1.32) (Supplemental Fig 5), revealing a potential association between paternal smoking and offspring ADHD. However, Zhu et al47 found that children born to smoking mothers and nonsmoking fathers had a higher risk of ADHD than those who born to nonsmoking mothers and smoking fathers, which suggested that maternal smoking was more important than paternal smoking in the development of ADHD.

The possible mechanism by which maternal smoking results in the onset of ADHD in offspring includes the direct adverse effects of tobacco smoke on the structure and function of the developing brain, as well as the relative gene alteration. Tobacco smoke contains more than 4000 different ingredients, and many of these compounds may have a potential adverse effect on neurodevelopment. As the major psychoactive chemical in tobacco, nicotine is the chemical that most probably adversely effects neurodevelopment.49 De Zeeuw et al50 compared brain volumes derived from anatomic magnetic resonance imaging scans and found that ADHD patients with a prenatal cigarette exposure history had a smaller cerebellum volume. Roy et al51 reported that a substantial decrease in cell size in the hippocampus and a reduction in the proportion of medium-sized pyramidal neurons in the somatosensory cortex were found in rats exposed to nicotine prenatally. Animal models also revealed that prenatal nicotine exposure disrupted the proliferation and differentiation of neuronal progenitors.

Our study has several merits. Because of the large sample size of our study, the possibility of reaching reasonable conclusions about the association between maternal smoking and ADHD was much greater. The positive association between maternal smoking during pregnancy and ADHD in offspring remained across a number of stratified analyses, which revealed the high reliability of our findings. By using the 2-level categorical smoking variable, we also found a positive dose-response relationship between maternal smoking and ADHD in children.

Limitations of our analysis also must be considered. First, the different assessments of ADHD used among studies may have led to misclassification bias. Diagnostic criteria have been identified as a factor associated with variability in the prevalence of ADHD. The ICD-10 and DSM-IV criteria include similar lists of symptoms, but the recommended methods for establishing a diagnosis were different. Polanczyk et al52 reported that the prevalence rates based on the DSM-III-R, ICD-10, and DSM-IV varied, with the highest estimated prevalence calculated by using the DSM-IV. The authors of further studies should attempt to adopt similar diagnostic criteria for the selection of the cases. Second, the important confounding factors were not fully adjusted in the included studies, which may have resulted in confusion in relation to the conclusion. Third, tobacco use during pregnancy was generally ascertained by self-report without objective biological measures, so there was a possibility that participants tended to narrow their smoking status, which may have led to the misclassification of maternal smoking. To avoid the misclassification bias, combining self-report with biological assessment may be the optimal method to ascertain the prevalence and degree of maternal smoking during pregnancy in future studies. Fourth, Gard et al53 reported that girls prenatally exposed to nicotine had greater hyperactivity and/or impulsivity symptoms. Joo et al54 also found that prenatal secondhand smoke exposure increased the risk of ADHD, especially in terms of hyperactivity and/or impulsivity. It seems that prenatal smoking and/or nicotine exposure may be more relevant to the hyperactivity components of ADHD. Knowing the specific symptom domain of ADHD associated with prenatal smoking and/or nicotine exposure may be helpful in understanding the toxicological mechanism. However, the authors of the included studies did not distinguish among the components of ADHD in reporting the effect of maternal smoking on offspring. More studies are needed to explore the relationship between prenatal nicotine exposures and the specific symptoms of ADHD.

On the basis of our analyses, we suggest that there is a link between maternal smoking during pregnancy and ADHD in offspring. However, the association between maternal smoking during pregnancy and ADHD in offspring should be interpreted cautiously, because it may be confounded by familial and genetic factors. There is a need for more high-quality studies in which potential confounding factors are adjusted for fully and in which standardized diagnostic approaches are adopted to establish whether the association with smoking is causal. The authors of future studies should also focus on the explicit mechanism of maternal smoking during pregnancy that increases the risk of ADHD in offspring.

     
  • ADHD

    attention-deficit/hyperactivity disorder

  •  
  • CI

    confidence interval

  •  
  • DSM-III-R

    Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised

  •  
  • DSM-IV

    Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition

  •  
  • ICD-10

    International Classification of Diseases, 10th Revision

  •  
  • OR

    odds ratio

  •  
  • SDQ

    Strengths and Difficulties Questionnaire

Drs Mu and Huang conceptualized the study, designed the study, and reviewed and revised the manuscript; Drs Wang and Zhang collected data, drafted the initial manuscript, and conducted the initial analyses; Drs Zheng, Qu, and Zhu designed the data collection instruments, coordinated and supervised data collection, and critically reviewed the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

*

Refs 12,16,21,26,30,3234,55,56.

FUNDING: Supported by the National Science Foundation of China (81330016 and 81630038); the National Key Research and Development Program (2017YFA0104200), the Major State Basic Research Development Program (2013CB967404, 2012BAl04B00), a grant from the Ministry of Education of China (IRT0935), grants from Science and Technology Bureau of Sichuan province (2014SZ0149, 2016TD0002), and a clinical discipline program (neonatology) grant from the Ministry of Health of China (1311200003303).

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

Supplementary data