Skip to main content
NCBI home page
Wiley Open Access Collection logoLink to Wiley Open Access Collection
. 2022 Apr 6;117(10):2602–2613. doi: 10.1111/add.15858

Prenatal smoking, alcohol and caffeine exposure and offspring externalizing disorders: a systematic review and meta‐analysis

Elis Haan 1,2,✉, Kirsten E Westmoreland 1, Laura Schellhas 1,2, Hannah M Sallis 1,2, Gemma Taylor 3, Luisa Zuccolo 2,4, Marcus R Munafò 1,2
PMCID: PMC10308447  PMID: 35385887

Abstract

Background and aims

Several studies have indicated an association between maternal prenatal substance use and offspring externalizing disorders; however, it is uncertain whether this relationship is causal. We conducted a systematic review to determine: (1) if the literature supports a causal role of maternal prenatal substance use on offspring externalizing disorders diagnosis and (2) whether these associations differ across externalizing disorders.

Methods

We searched Web of Science, Embase, PsycINFO and Medline databases. Risk of bias assessment was conducted using the Newcastle–Ottawa Scale (NOS), and where possible meta‐analysis was conducted for studies classed as low risk of bias. We included studies of any design that examined prenatal smoking, alcohol or caffeine use. Studies in non‐English language, fetal alcohol syndrome and comorbid autism spectrum disorders were excluded. Participants in the included studies were mothers and their offspring. Measurements included prenatal smoking, alcohol or caffeine use as an exposure, and diagnosis of attention‐deficit hyperactivity disorder (ADHD), conduct disorder (CD) and oppositional defiant disorder (ODD) in offspring as an outcome.

Results

We included 63 studies, 46 of which investigated smoking and ADHD. All studies were narratively synthesized, and seven studies on smoking and ADHD were meta‐analysed. The largest meta‐analysis based on genetically sensitive design included 1 011 546 participants and did not find evidence for an association [odds ratio (OR)1–9 cigarettes = 0.90, 95% confidence interval (CI) = 0.83–1.11; OR > 10 cigarettes = 1.04, 95% CI = 0.79–1.36). Studies on alcohol exposure in all the outcomes reported inconsistent findings and no strong conclusions on causality can be made. Studies on caffeine exposure were mainly limited to ADHD and these studies do not support a causal effect.

Conclusions

There appears to be no clear evidence to support a causal relationship between maternal prenatal smoking and offspring attention‐deficit hyperactivity disorder. Findings with alcohol and caffeine exposures and conduct disorder and oppositional–defiant disorder need more research, using more genetically sensitive designs.

Keywords: ADHD, alcohol, caffeine, conduct disorder, meta‐analysis, ODD, smoking, systematic review

INTRODUCTION

Several studies have indicated that maternal health behaviours during pregnancy, including smoking, alcohol and caffeine consumption, may contribute to offspring externalizing problems [such as attention deficit hyperactivity disorder (ADHD), conduct disorder (CD) and oppositional defiant disorder (ODD)] [1, 2, 3]. However, it remains unclear whether this reflects a true causal effect or residual confounding due to factors such as socio‐economic position, education, income and maternal age [4, 5, 6, 7, 8, 9]. This is of considerable public health importance as smoking, alcohol and caffeine consumption are common exposures, and although current UK guidelines recommend abstaining from smoking and alcohol consumption [10, 11] and limiting daily caffeine consumption to 200 mg during pregnancy [12], most women still use these substances at some point in pregnancy [13, 14].

A recent systematic review [15], focused upon alcohol exposure and various offspring mental health outcomes, found evidence of an association between low to moderate maternal prenatal alcohol use and offspring behavioural and conduct problems. Similarly, systematic reviews and meta‐analyses report an association between maternal prenatal smoking and offspring CD and ADHD [16, 17, 18]. However, these reviews are based on conventional observational studies which do not provide strong evidence of causality, given limitations such as unmeasured and residual confounding. The only review to date to triangulate evidence from different study designs, many of which are robust to confounding, concluded that there was no strong evidence for an effect of maternal prenatal alcohol use on behavioural phenotypes including ADHD [19]. In addition to socio‐economic confounding, the observed associations could also be explained by shared genetic influences (i.e. genetic confounding). Several studies report shared genetic liability between ADHD, CD and substance use [20, 21, 22] and maternal genetic risk for ADHD has been associated with smoking during pregnancy [23]. Therefore, it is possible that the association between maternal prenatal substance use and offspring externalizing disorders could be explained by genetic transmission. These reviews highlight the need for further investigation into the effect of maternal prenatal substance use on offspring externalizing problems and the use of genetically informative study designs to disentangle potential causal effects.

We systematically reviewed the evidence for association between prenatal smoking, alcohol and caffeine exposure and diagnosis of ADHD, CD and ODD. With our aim being to more clearly understand possible causal pathways, we specifically included studies accounting for genetic effects, in addition to conventional approaches. We chose to include these three highly comorbid [24] externalizing disorders to allow the interrogation of both common and specific effects of prenatal substance exposures, and prioritized clinical diagnoses over symptoms scales to avoid reporting bias.

METHODS

We followed Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) and Meta‐analysis of Observational Studies in Epidemiology (MOOSE) guidelines and registered the study protocol on the Open Science Framework (10.17605/OSF.IO/D9WZK) and PROSPERO (ID: CRD42018094810).

Search strategy

We searched Web of Science, Embase, PsycINFO and Medline databases via the Ovid platform up to 26 April 2021 using keyword and MeSH terms (the search strategy is shown in the Supporting information), and additionally checked the reference lists of previous reviews.

Inclusion and exclusion criteria

Inclusion criteria were: (1) publication in a peer‐reviewed journal in English language, (2) observational studies (cross‐sectional, case–control, longitudinal and cohort studies, which also included negative control studies), (3) maternal smoking, alcohol and caffeine use measured during pregnancy and (4) diagnosis of ADHD, CD and ODD in offspring.

Exclusion criteria for the study were: (1) animal studies, (2) reviews, (3) conference and/or meeting abstracts, (4) studies with no comparison group, (5) fetal alcohol spectrum disorder (FASD) studies, as several studies have shown an association between heavier drinking and FASD, and (6) studies with comorbid autism spectrum and tic disorders due to the different aetiology of coexistence of these disorders.

Study selection and data extraction

Selection of studies was carried out in three stages: (1) title and abstract screening, (2) full text screening and (3) data extraction and risk of bias assessment. Study selection and data extraction took place by three reviewers: E.H. (100%), K.W. (85%) and L.S. (15%). Any disagreements were resolved by a third author (G.T.).

If studies measured multiple exposures and outcomes, data were extracted separately for each exposure and outcome. If more than one follow‐up period was reported, data from the latest follow‐up period were extracted [25].

Risk of bias assessment

Risk of bias was assessed using the Newcastle–Ottawa Scale (NOS) for cohorts and case–control studies [26]. Studies were evaluated on three categories: (1) selection, (2) comparability and (3) outcome. Studies were ranked as low, medium or high risk of bias based on a rating system (maximum of 9 points, see the Supporting information for details). Risk of bias assessment was conducted by the review team and points given to each study are shown in Supporting information, Tables S1 and S2.

Meta‐analysis

We used random‐effects models to pool results from studies at low risk of bias, and computed I 2 statistics to quantify the between‐study heterogeneity for each analysis. Statistical analyses were conducted using the metan command in Stata version 15 [27].

RESULTS

Literature search

After removing duplicates, 5391 articles were identified, 393 of which were included in full text screening. Of these, 331 were excluded mainly due to non‐specific outcome measures (n = 38), wrong exposure (n = 36) or not meeting outcome criteria (n = 125). Excluded studies are listed in Supporting information, Table S3. Study authors were contacted if relevant details were missing. Studies excluded due to missing data are listed in Supporting information, Table S4. In total, 63 articles were included in the current review (Figure 1).

FIGURE 1.

FIGURE 1

Open in a new tab

Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) flow‐chart of search strategy

Characteristics of included studies

Included studies varied in terms of geographical region and study designs. The majority of studies assessed exposures retrospectively with variation in how exposures were categorized (binary versus categorical measures). Studies also differed in follow‐up time (from 2 to 37 years) and age at diagnosis (4–37 years). Narrative overview and full details of included studies are presented in the Supporting information methods and Tables S5 and S6.

Inclusion of confounding variables

The majority of studies adjusted for socio‐economic variables (social class, education, income, marital status), as well as for maternal age, offspring age and gender. Only a few studies adjusted for maternal mental health during pregnancy and none adjusted for partner's substance use (see Supporting information, Tables S7 and S8).

Summary of findings

An overview of results as reported in the studies is shown in Supporting information, Tables S5 and S6.

Prenatal smoking and ADHD

Of the 63 studies, 46 assessed the association between maternal prenatal smoking and offspring ADHD, of which 19 (41%) were cohort and longitudinal studies, four (9%) cross‐sectional and 23 (50%) case–control studies.

Of the included cohort and longitudinal studies, 13 (68%) found a positive association between maternal prenatal smoking and offspring ADHD. Three of these studies that did not report a positive association used a sample measured when offspring were in late adolescence (16–18 years) or adulthood (37 years) [28, 29, 30].

Seven studies which found a positive association used samples from prospective longitudinal cohorts and large registries (n = 5758–986 046) [31, 32, 33, 34, 35, 36, 37]. These studies enabled the authors to take into account environmental and/or genetic confounding by using quasi‐experimental designs (i.e. parental and sibling comparison designs). Six of these concluded that the association is most probably explained by confounding [31, 32, 33, 34, 35, 37]. Two studies claimed that the association was stronger, with maternal smoking compared to paternal smoking indicating a potential causal intra‐uterine effect [36, 38].

Seven other studies observed a positive association adjusted for birth weight or other perinatal factors that could be potential mediators or lead to spurious association because of collider bias [39, 40, 41, 42, 43, 44]. Additionally, two twin studies concluded that prenatal smoking was a common risk factor among monozygotic twins concordant for ADHD [45, 46].

All four cross‐sectional studies and 20 (87%) of the case–control studies found a positive association between maternal prenatal smoking and offspring ADHD. Of the three case–control studies that did not [47, 48, 49], two of these were conducted in small samples (n = 372–450) [47, 48]. Eight studies that observed a positive association adjusted for parental ADHD to account for potential genetic liability, but the association remained [50, 51, 52, 53, 54, 55, 56, 57]. However, another case–control study found that maternal prenatal smoking was shared between affected and unaffected siblings indicating that prenatal smoking is a weak risk factor for ADHD [58].

Seven studies examined the association with ADHD subtypes [48, 49, 51, 55, 59, 60]. One study conducted with girls only found an association with hyperactive–impulsive symptoms but not inattention symptoms [51]. In contrast, one study observed an indirect effect of prenatal smoking on inattention symptoms via memory span deficits [49]. Two other studies focused upon the inattention subtype and used the same sample [48, 55]; however, only one study found evidence for an association [55]. Two of the remaining studies investigated gene–environment interactions in the same sample of twins and found a positive effect between maternal prenatal smoking and child genotype in children with the combined ADHD subtype [59, 60]. Similarly, one study conducted in Chinese singletons found an interaction effect with all the ADHD subtypes [61]. However, two other studies that also investigated gene–environment interaction—but focused upon overall ADHD and used a sample of singletons—did not find an interaction effect [56, 62].

Of the six studies which investigated gender differences [29, 33, 34, 39, 63, 64], only two found evidence of a gender difference; however, one study found a stronger association among girls [39], while the other found a stronger association among boys [63]. Dose–response relationships were examined in 15 studies (33%), of which 12 studies observed a dose‐dependent association [33, 34, 35, 37, 40, 41, 43, 55, 65, 66, 67, 68].

Strength of evidence based on NOS score

In total, eight longitudinal and cohort studies were rated as low risk of bias (7–9 points). Six of these were based on quasi‐experimental designs [31, 33, 34, 35, 36, 37], one study used a twin sample [45] and another was based on a prospective cohort [69]. Seven studies concluded that the association between maternal prenatal smoking and offspring ADHD is unlikely to be causal. This was in contrast with three studies rated as very high risk of bias (0–3 points) [38, 40, 70], and three other studies rated as high risk of bias (4–5 points) (all cross‐sectional designs) [39, 42, 44] which found a positive association.

In total, nine case–control studies were rated as low risk of bias and eight of these studies found a positive association [47, 55, 56, 57, 64, 65, 68, 71, 72], but these studies do not account for genetic effects and can be prone to recall bias; therefore, conclusions about causality should be interpreted with caution.

Meta‐analysis based on NOS score

We conducted a meta‐analysis for studies which rated as low risk of bias (7–9 points). The pooled estimate of negative control studies in maternal prenatal smoking was 1.64 (1.33–2.02) and paternal smoking 1.28 (1.19–1.39), but between‐studies heterogeneity was high I 2 = 79.8%. The pooled estimate of sibling comparison studies in the full sample was OR1–9 cigarettes = 1.70 (1.52–1.91); OR> 10 cigarettes = 2.20 (1.78–2.73) and in the sibling matched sample OR1–9 cigarettes = 0.90 (0.83–1.11); OR> 10 cigarettes = 1.04 (0.79–1.38). The pooled estimate of nested case–control studies was OR = 1.61 (1.45–1.78). Results are presented in Figures 2, 3, 4.

FIGURE 2.

FIGURE 2

Open in a new tab

Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between maternal and paternal prenatal smoking and attention‐deficit hyperactive disorder (ADHD)

FIGURE 3.

FIGURE 3

Open in a new tab

Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for the association between full and sibling matched sample and attention‐deficit hyperactive disorder (ADHD). Studies by Obel, 2016 and Skoglund, 2014 reported results in hazard ratios and study by Lindblad, 2010 in ORs

FIGURE 4.

FIGURE 4

Open in a new tab

Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for the association between nested case–control studies. Study by Joelsson reported ORs and study by Linnet risk ratios (RRs)

Prenatal smoking and CD and ODD

Ten studies investigated the association between maternal prenatal smoking and offspring CD, of which five were cohort and longitudinal studies, two cross‐sectional studies and three case–control studies. Six studies (60%) found an association between maternal prenatal smoking and offspring CD [50, 73, 74, 75, 76, 77]. However, four of these studies used a clinical or hospital‐referred sample [29, 50, 76, 77]. One study observed an interaction effect between maternal prenatal smoking and child genotype [76]. In the three studies that did not find evidence of an association, two studies used a sample of offspring in late adolescence (16–18 years) [28, 29] and one study found an indirect effect via neuropsychological functioning [49].

Six studies investigated the association between maternal prenatal smoking and offspring ODD, of which three were cohort and longitudinal studies, one cross‐sectional study and two were case–control studies. Two studies (n = 798–995) found an association with maternal prenatal smoking [75, 78]. Among the studies that did not observe an association, one found an indirect effect via neuropsychological functioning, similar to the effect observed for ADHD and CD [49]. Two studies measured ODD in adolescence (15 years) and adulthood (21 years), where disorder manifestation could differ from childhood [77, 79]. One other study was conducted in a small sample (n = 215) and may have lacked power to detect an effect [38].

Strength of evidence based on NOS score

Only one study based on smoking and CD was rated as low risk of bias (8 points), and this study did not find evidence for an association between prenatal smoking and CD [28]. Two studies rated as very high risk of bias (2–3 points) did not find an association between prenatal smoking and ODD [38, 79]. Other studies rated as high risk of bias (4–6 points) found an association between prenatal smoking and offspring CD and ODD [29, 50, 63, 73, 74, 75, 76, 78], but two studies were based on cross‐sectional or case–control design which cannot prove causality [50, 74] and another four studies used a clinical or hospital‐referred sample [29, 63, 73, 76].

Prenatal alcohol and ADHD

Thirteen studies investigated the association between maternal prenatal alcohol consumption and offspring ADHD, of which eight were cohort, longitudinal and cross‐sectional studies (n = 679–34 503), one was a longitudinal twin study (n = 1936) and four were case–control studies (n = 372–2419). Two longitudinal studies found a positive association only with heavier alcohol use [46, 80] and one other longitudinal study found a positive association with alcohol use in all trimesters and with binge drinking [81], but this study was conducted in a small sample (n = 81). Three (33%) case–control studies found a positive association with maternal prenatal alcohol consumption [54, 66, 82], one of which used heavier drinking (drunkenness during the first 2 months) as the exposure [66]. Of the two other studies, one was conducted in a hospital‐referred sample [54] and the other failed to adjust for many relevant confounders [82].

Strength of evidence based on NOS score

Two studies based on alcohol exposure and ADHD were rated as low risk of bias (8–9 points) and these did not find evidence for an association [69, 83]. Four longitudinal cohort studies [41, 81, 84, 85] were rated as high risk of bias (4–6 points); however, only the highest scoring study (4 points) found evidence of an association [81]. Of four case–control studies rated as high risk of bias (5–6 points), three studies reported an association between prenatal alcohol exposure and offspring ADHD [54, 66, 82]. Due to the variability on exposure assessment, a meta‐analysis was not possible.

Prenatal alcohol and CD and ODD

Five cohort, longitudinal and cross‐sectional studies investigated the association between maternal prenatal alcohol consumption and offspring CD and ODD (n = 546–9719). Four studies were on CD [28, 80, 86, 87] and two on ODD [79, 80]. One study observed a positive association with heavier drinking and ODD [80], and two studies found an association between maternal prenatal alcohol consumption and offspring CD [86, 87]. However, these studies used heavier alcohol consumption and binge drinking phenotypes or were based on samples from culturally distinct populations [87].

Strength of evidence based on NOS score

Two studies based on alcohol exposure and CD were rated as low risk of bias (8 points). One of these studies did not find evidence for an association [28], but the other found evidence for an association with heavier alcohol use [86]. Both of these studies were based on prospective longitudinal birth cohorts. Two studies were rated as very high risk of bias (2 points); one study on CD found a positive association with binge drinking [87] while the other investigating ODD and using cross‐sectional design did not find evidence for an association [79].

Prenatal caffeine and ADHD and ODD

Three studies investigated the association between maternal prenatal caffeine consumption and offspring ADHD (n = 3627–24 156) [82, 88, 89]. One study examined the association with offspring ODD (n = 5924) [79]. No evidence for an association was observed between maternal prenatal caffeine consumption and offspring ADHD. Two of these studies used a longitudinal cohort design [88, 89] and one study used a case–control design [82]. A study of ODD based on a cross‐sectional sample found weak evidence for an association with maternal prenatal caffeine use in girls [79].

Strength of evidence based on NOS score

Two studies based on caffeine exposure and ADHD were rated as low risk of bias (8–9 points) [88, 89]. These studies found no evidence for an association. One case–control study rated as high risk of bias (4 points) also did not find evidence for an association [82]. Only one study on ODD rated as very high risk of bias (2 points) found weak evidence of an association in girls [79]. The studies at low risk of bias assessed caffeine consumption differently (one study in mg derived from coffee and tea/mate and other study in cups of coffee) and could not be meta‐analysed.

DISCUSSION

In this systematic review we examined whether there is evidence to support a causal effect of maternal prenatal smoking, alcohol and caffeine use on offspring ADHD, CD and ODD risk by synthesizing the results of existing research based on risk of bias assessment. Overall, our findings support stronger associations between prenatal smoking and ADHD and CD. However, evidence was less clear for the association with ODD and inconsistent on alcohol exposure for all outcomes. Our findings on caffeine exposure were limited to ADHD and there was a lack of evidence for other outcomes.

Our findings for smoking exposure indicate that maternal prenatal smoking is more strongly associated with ADHD and CD than with ODD. However, given that there were few studies on ODD, no strong conclusions can be drawn. Furthermore, some studies on ADHD with low risk of bias were able to take into account genetic effects, and indicate that shared genetics plays a substantial role in the association with prenatal smoking. This is supported by a previous systematic review based on genetically informed designs which also concluded that the association between maternal prenatal smoking and ADHD and CD symptoms is explained by familial confounding and shared genetics [90].

We identified relatively few studies that investigated the association between prenatal alcohol exposure and diagnosis of ADHD, CD and ODD in offspring. Evidence from these studies indicates that an association exists between heavier alcohol consumption and ADHD and CD. A recent review and meta‐analysis on low to moderate maternal alcohol consumption during pregnancy and offspring ADHD did not find evidence for an increased risk of ADHD symptoms [91], but studies on CD symptoms using quasi‐experimental designs have found evidence for a potential causal effect [92, 93]. However, these studies may be biased, as outcome measures are maternally reported [94]. Similarly to alcohol exposure, we only identified a few studies on prenatal caffeine exposure and these studies do not provide evidence for a causal effect with ADHD.

Several weaknesses and sources of heterogeneity between included studies emerged while we appraised the current research, as follows.

  1. Studies varied greatly on number of confounders adjusted in the multivariable analyses, thus raising the possibility of residual confounding. Although many studies adjusted for socio‐economic factors known to affect both exposures and outcomes, none of the studies adjusted for partner's substance use during pregnancy. There is evidence that assortative mating affects parental smoking and alcohol consumption and failure to take into account partner's substance use can lead to biased effect estimates [95]. Similarly, only a limited number of studies accounted for maternal mental health during pregnancy. For example, it has been shown that maternal depressive and anxiety symptoms during pregnancy increase the risk of offspring behavioural problems [96]. In contrast, many studies on smoking exposure adjusted for perinatal factors, such as birth weight, gestational age or other pregnancy and birth complications, which could be potential mediators in the pathway between prenatal smoking and ADHD. Adjusting for mediators induces collider bias in unpredictable directions, as showed in previous studies [97]. Therefore, estimates adjusted for birth weight may result in spurious association if there is an unmeasured common cause between birth weight and outcome [98].

  2. Maternal prenatal exposure assessment was mainly based on self‐reports and mothers may under‐report their prenatal substance use due to social desirability, which may lead to biased effect estimates in the studies. Furthermore, many studies assessed exposures after the child's birth or retrospectively when the outcome was already present, which may lead to recall bias (this is the case for all included cross‐sectional and for most case–control studies). In these studies, causality should be interpreted cautiously.

  3. Studies also differed in terms of how prenatal smoking, alcohol and caffeine consumption were categorized. Many studies used a binary measure which does not adequately capture effects of substance use where these are dose‐dependent. Some studies used a scale of low, moderate and high, but there is no clear definition of the level of consumption each of these categories represent.

  4. Studies also varied on timing of substance use, with the majority of studies using a single time‐point assuming that the effects of maternal substance use remain constant throughout pregnancy. One study on alcohol exposure reported that maternal prenatal alcohol consumption had a more harmful effect on offspring CD during the first trimester compared to the third trimester, indicating that prenatal alcohol exposure during the first pregnancy trimester may be more harmful [86].

  5. Considering that there is a high comorbidity between externalizing disorders, few studies took this into account. Although high rates of comorbidity are common among psychiatric disorders, it is plausible that a somewhat different aetiology may underlie externalizing disorders with and without comorbidities. For example, two studies that observed the association between maternal prenatal smoking and ADHD with comorbid conditions found that ADHD with comorbid CD/ODD had a stronger association with maternal prenatal smoking than ADHD without comorbidities [57, 71].

  6. Although externalizing disorders are more prevalent among boys than girls [99], few studies investigated gender effects. Some studies have shown that boys exposed to prenatal smoking and alcohol consumption may be at higher risk for developing behavioural problems than girls [100, 101], and it is possible that prenatal substance use may have distinct effects on boys and girls which needs more research.

  7. Studies varied greatly on age when ADHD, CD and ODD were assessed. Although several studies have shown that childhood externalizing disorder symptoms persist into adulthood [102, 103], other studies have found that childhood mental health problems change across development and persistence of externalizing disorders depends upon severity and comorbidity of symptoms [104, 105]. Previous studies on ADHD have reported that presentation of hyperactive–impulsive and inattention symptoms varies from preschool to early adulthood and inattention symptoms tend to be more persistent [106]. It is also suggested that child‐ and adulthood ADHD are two separate diagnoses, and future studies should investigate which underlying mechanisms could explain these different developmental paths [107].

  8. Several studies included in this review were mainly conducted in highly educated and generally affluent populations. This may underestimate any true effect of prenatal substance use on offspring externalizing disorders should these families be better able to mitigate the developmental consequences of early substance exposure.

  9. Relatively few studies used genetically informative designs, although it is well known that genetic confounding accounts for part of the association between maternal prenatal substance use and offspring externalizing disorders. Therefore, it is important to use different study designs to rule out alternative hypotheses when investigating causality [108]. Genetically informative designs (such as family‐based designs and natural experiments) can be particularly helpful when investigating causal hypotheses, as these designs enable integration of genetic and other epidemiological methods [109, 110, 111].

One major strength of this systematic review is including multiple prenatal exposures (smoking, alcohol and caffeine) and outcomes (ADHD, CD and ODD) which enabled us to synthesize whether the associations would differ across different exposure–outcome combinations. Secondly, conducting risk of bias assessments enabled us to account for potential weaknesses in study designs when interpreting the evidence supporting a causal relationship. Thirdly, in the studies that investigated the association between prenatal smoking and ADHD, we were able to take a triangulation approach. The main principle of the triangulation is that if the results from studies which have used different designs—and therefore rely upon different assumptions and have different sources of bias—align, then we can be more confident that the observed association reflects a true causal effect. For example, negative control studies rely upon the assumption that mothers and fathers share similar confounding structures, while sibling comparison studies rely upon the assumption that there is no bias because of unmeasured confounding and non‐shared environmental factors between siblings [19, 109]. Given that the results on smoking and ADHD were similar in both negative control and sibling comparison studies, this then gives more support on our conclusion that the association is unlikely to be causal.

However, this systematic review also has some limitations. First, we limited the searches to studies that used diagnosis as an outcome measure, and therefore excluded studies reporting on symptoms scores or other continuous scales. This may have caused bias in observed results, because response rates may be lower in studies that used diagnoses, compared with those that used symptoms scores. Furthermore, studies using diagnoses may be more selective by including individuals who have access to the psychiatric services or by including only individuals with more severe symptoms. This may lead to misclassification bias, as children with less severe externalizing disorder could have been left out, but this is likely to be a conservative and bias the effect estimate towards the null. Conversely, studies using maternal reported offspring externalizing disorder symptoms may be biased by maternal characteristics (mother's mental health, socio‐economic status) [112, 113] and therefore clinical diagnoses used by studies in this review may be more objective outcome measures. Secondly, due to the low number of studies included in the meta‐analysis, we were not able to assess publication bias [25]. Thirdly, we only included English language studies. However, it has been shown that the exclusion of non‐English studies has a little impact on overall findings [114].

CONCLUSION

Our review has shown that there is an association between maternal prenatal smoking and offspring ADHD, but studies that accounted for shared genetic and environmental confounders suggest that this association is unlikely to be causal. Given that majority of the identified studies investigated the association between ADHD and smoking exposure, findings with alcohol and caffeine exposures and CD and ODD need more research, especially using genetically sensitive designs. Future studies should use more prospective and quantitative exposure measures during each pregnancy trimester, as well as take into account comorbidities between externalizing disorders, gender differences and changes in presentation and manifestation of externalizing disorder symptoms across development.

DECLARATION OF INTERESTS

None.

AUTHOR CONTRIBUTIONS

Elis Haan: Conceptualization; data curation; formal analysis; investigation; methodology; project administration; resources; visualization. Kirsten Westmoreland: Data curation; formal analysis; investigation; methodology; project administration; resources; visualization. Laura Schellhas: Data curation; formal analysis; investigation; methodology; project administration; resources; visualization. Hannah Sallis: Data curation; formal analysis; investigation; methodology; supervision; visualization. Gemma Taylor: Data curation; formal analysis; investigation; methodology; supervision; visualization. Luisa Zuccolo: Data curation; formal analysis; investigation; methodology; supervision; visualization. Marcus Munafo: Conceptualization; data curation; formal analysis; investigation; methodology; project administration; supervision; visualization.

Supporting information

Supplementary Table S1. Risk of bias assessment scores based on NOS scale of cohort, longitudinal and cross‐sectional studies

Supplementary Table S2. Risk of bias assessment scores based on NOS scale of case–control studies

Supplementary Table S3. List of studies excluded

Supplementary Table S4. Studies not reporting all the results

Supplementary Table S5. Study characteristics and results of cohort, longitudinal and cross‐sectional studies

Supplementary Table S6. Study characteristics and results of case–control studies

Supplementary Table S7. Confounders included in the cohort, longitudinal and cross‐sectional studies

Supplementary Table S8. Confounders included in the case–control studies

Click here for additional data file. (191.3KB, docx)

ACKNOWLEDGEMENTS

This research was performed in the UK Medical Research Council Integrative Epidemiology Unit (grant number MC_UU_00011/7) and also supported by the National Institute for Health Research (NIHR) Bristol Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. L.Z. was supported by a UK Medical Research Council fellowship (grant number G0902144). H.M.S. is supported by the European Research Council (Grant ref: 758813 MHINT). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care. This research was also conducted as part of the CAPICE (Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe) project, funded by the European Union's Horizon 2020 research and innovation programme, Marie Sklodowska Curie Actions—MSCA‐ITN‐2016—Innovative Training Networks under grant agreement number 721567.

Haan E, Westmoreland KE, Schellhas L, Sallis HM, Taylor G, Zuccolo L, et al. Prenatal smoking, alcohol and caffeine exposure and offspring externalizing disorders: a systematic review and meta‐analysis. Addiction. 2022;117:2602–2613. 10.1111/add.15858

Funding information European Union Horizon 2020 research and innovation programme, Marie Sklodowska Curie Actions, Grant/Award Number: 721567; UK Medical Research Council Integrative Epidemiology Unit, Grant/Award Number: MC_UU_00011/7; UK Medical Research Council fellowship, Grant/Award Number: G0902144; Horizon 2020; European Union; Department of Health; National Institute for Health Research; European Research Council, Grant/Award Number: 758813 MHINT; University of Bristol; University Hospitals Bristol NHS Foundation Trust; Bristol Biomedical Research Centre

REFERENCES

  • 1. Dong TY, Hu WY, Zhou XJ, Lin HQ, Lan LW, Hang B, et al. Prenatal exposure to maternal smoking during pregnancy and attention‐deficit/hyperactivity disorder in offspring: a meta‐analysis. Reprod Toxicol. 2018;76:63–70. [DOI] [PubMed] [Google Scholar]
  • 2. Huizink AC, Mulder EJH. Maternal smoking, drinking or cannabis use during pregnancy and neurobehavioral and cognitive functioning in human offspring. Neurosci Biobehav Rev. 2006;30:24–41. [DOI] [PubMed] [Google Scholar]
  • 3. Mikkelsen SH, Obel C, Olsen J, Niclasen J, Bech BH. Maternal caffeine consumption during pregnancy and behavioral disorders in 11‐year‐old offspring: a Danish National Birth Cohort study. J Pediatr 2017;189:120−127. [DOI] [PubMed] [Google Scholar]
  • 4. Palmer RHC, Bidwell LC, Heath AC, Brick LA, Madden PAF, Knopik VS. Effects of maternal smoking during pregnancy on offspring externalizing problems: contextual effects in a sample of female twins. Behav Genet. 2016;46:403–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Russell AE, Ford T, Russell G. Socioeconomic associations with ADHD: findings from a mediation analysis. PLOS ONE. 2015;10:e0128248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. Kelly YJ, Sacker A, Gray R, Kelly J, Wolke D, Head J et al. Light drinking during pregnancy: Still no increased risk for socioemotional difficulties or cognitive deficits at 5 years of age? J Epidemiol Commun Health 2012;66:41–48. [DOI] [PubMed] [Google Scholar]
  • 7. Robinson M, Oddy WH, McLean NJ, Jacoby P, Pennell CE, de Klerk NH, et al. Low–moderate prenatal alcohol exposure and risk to child behavioural development: a prospective cohort study. Br J Obstet Gynaecol. 2010;117:1139–50. [DOI] [PubMed] [Google Scholar]
  • 8. Loomans EM, Hofland L, Van der Stelt O, Van der Wal MF, Koot HM, Van den Bergh BRH, et al. Caffeine intake during pregnancy and risk of problem behavior in 5‐ to 6‐year‐old children. Pediatrics. 2012;130:E305–13. [DOI] [PubMed] [Google Scholar]
  • 9. Berglundh S, Vollrath M, Brantsaeter AL, Brandlistuen R, Sole‐Navais P, Jacobsson B, et al. Maternal caffeine intake during pregnancy and child neurodevelopment up to eight years of age—results from the Norwegian Mother, Father and Child Cohort study. Eur J Nutr. 2021;60:791–805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Department of Health (DoH) . UK Chief Medical Officers' Low Risk Drinking Guidelines. London, UK: DoH; 2016. [Google Scholar]
  • 11. National Institute for Health and Care Excellence (NICE) . Smoking: Stopping in Pregnancy and After Childbirth (NICE Public Health Guideline). London, UK: NICE; 2010. [Google Scholar]
  • 12. Agostoni C, Canani RB, Fairweather‐Tait S, Heinonen M, Korhonen H, La Vieille S, et al. Scientific opinion on the safety of caffeine. EFSA J. 2015;13:4102. [Google Scholar]
  • 13. O'Keeffe LM, Kearney PM, McCarthy FP, Khashan AS, Greene RA, North RA, et al. Prevalence and predictors of alcohol use during pregnancy: findings from international multicentre cohort studies. BMJ Open. 2015;5:e006323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Lange S, Probst C, Rehm J, Popova S. National, regional, and global prevalence of smoking during pregnancy in the general population: a systematic review and meta‐analysis. Lancet Glob Health. 2018;6:E769–76. [DOI] [PubMed] [Google Scholar]
  • 15. Easey KE, Dyer ML, Timpson NJ, Munafò MR. Prenatal alcohol exposure and offspring mental health: a systematic review. Drug Alcohol Depend. 2019;197:344–353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Ruisch IH, Dietrich A, Glennon JC, Buitelaar JK, Hoekstra PJ. Maternal substance use during pregnancy and offspring conduct problems: a meta‐analysis. Neurosci Biobehav Rev. 2018;84:325–36. [DOI] [PubMed] [Google Scholar]
  • 17. Huang L, Wang Y, Zhang L, Zheng Z, Zhu T, Qu Y, et al. Maternal smoking and attention‐deficit/hyperactivity disorder in offspring: a meta‐analysis. Pediatrics. 2018;141:e20172465. [DOI] [PubMed] [Google Scholar]
  • 18. He Y, Chen J, Zhu LH, Hua LL, Ke FF. Maternal smoking during pregnancy and ADHD: results from a systematic review and meta‐analysis of prospective cohort studies. J Atten Disord. 2020;24:1637–47. [DOI] [PubMed] [Google Scholar]
  • 19. Mamluk L, Jones T, Ijaz S, Edwards H, Savovic J, Leach V et al. Evidence of detrimental effects of prenatal alcohol exposure on offspring birthweight and neurodevelopment from a systematic review of quasi‐experimental studies. Int J Epidemiol 2020;49:1972–1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Treur JL, Demontis D, Davey Smith G, Sallis H, Richardson TG, Wiers RW, et al. Investigating causality between liability to ADHD and substance use, and liability to substance use and ADHD risk, using Mendelian randomization. Addict Biol. 2021;26:e12849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Vilar‐Ribo L, Sanchez‐Mora C, Rovira P, Richarte V, Corrales M, Fadeuilhe C, et al. Genetic overlap and causality between substance use disorder and attention‐deficit and hyperactivity disorder. Am J Med Genet B. 2021;186:140–50. [DOI] [PubMed] [Google Scholar]
  • 22. Grant JD, Lynskey MT, Madden PAF, Nelson EC, Few LR, Bucholz KK, et al. The role of conduct disorder in the relationship between alcohol, nicotine and cannabis use disorders. Psychol Med. 2015;45:3505–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Leppert B, Havdahl A, Riglin L, Jones HJ, Zheng J, Davey Smith G, et al. Association of maternal neurodevelopmental risk alleles with early‐life exposures. JAMA Psychiatry. 2019;76:834–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Singh I. Science and society beyond polemics: science and ethics of ADHD. Nat Rev Neurosci. 2008;9:957–64. [DOI] [PubMed] [Google Scholar]
  • 25. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al., editors. Cochrane Handbook for Systematic Reviews of Interventions, version 6.1 (updated September 2020). Chichester, UK: John Wiley & Sons; 2020. [Google Scholar]
  • 26. Wells G, Shea B, O'Connell D, Peterson J, Welch V, Losos M et al. The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta‐analyses. 2013. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp [Google Scholar]
  • 27. StataCorp. Stata Statistical Software: Release 15. College Station, TX: StataCorp LLC; 2017. [Google Scholar]
  • 28. Fergusson DM, Woodward LJ, Horwood LJ. Maternal smoking during pregnancy and psychiatric adjustment in late adolescence. Arch Gen Psychiatry. 1998;55(8):721–7. [DOI] [PubMed] [Google Scholar]
  • 29. Weissman MM, Warner V, Wickramaratne PJ, Kandel DB. Maternal smoking during pregnancy and psychopathology in offspring followed to adulthood. J Am Acad Child Adolesc Psychiatry. 1999;38:892–9. [DOI] [PubMed] [Google Scholar]
  • 30. Ball SW, Gilman SE, Mick E, Fitzmaurice G, Ganz ML, Seidman LJ, et al. Revisiting the association between maternal smoking during pregnancy and ADHD. J Psychiatr Res. 2010;44:1058–62. [DOI] [PubMed] [Google Scholar]
  • 31. Gustavson K, Ystrom E, Stoltenberg C, Susser E, Suren P, Magnus P, et al. Smoking in pregnancy and child ADHD. Pediatrics. 2017;139:e20162509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Langley K, Heron J, Davey Smith G, Thapar A. Maternal and paternal smoking during pregnancy and risk of ADHD symptoms in offspring: testing for intrauterine effects. Am J Epidemiol. 2012;176:261–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Obel C, Olsen J, Henriksen TB, Rodriguez A, Jarvelin MR, Moilanen I, et al. Is maternal smoking during pregnancy a risk factor for hyperkinetic disorder? Findings from a sibling design. Int J Epidemiol. 2011;40:338–45. [DOI] [PubMed] [Google Scholar]
  • 34. Obel C, Zhu JL, Olsen J, Breining S, Li J, Gronborg TK et al. The risk of attention deficit hyperactivity disorder in children exposed to maternal smoking during pregnancy—a re‐examination using a sibling design. J Child Psychol Psychiatry 2016;57:532–537. [DOI] [PubMed] [Google Scholar]
  • 35. Skoglund C, Chen Q, D'Onofrio BM, Lichtenstein P, Larsson H. Familial confounding of the association between maternal smoking during pregnancy and ADHD in offspring. J Child Psychol Psychiatry. 2014;55:61–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Zhu JL, Olsen J, Liew Z, Li J, Niclasen J, Obel C. Parental smoking during pregnancy and ADHD in children: the Danish National Birth Cohort. Pediatrics. 2014;134:E382–8. [DOI] [PubMed] [Google Scholar]
  • 37. Lindblad F, Hjern A. ADHD after fetal exposure to maternal smoking. Nicotine Tob Res. 2010;12:408–15. [DOI] [PubMed] [Google Scholar]
  • 38. Nomura Y, Marks DJ, Halperin JM. Prenatal exposure to maternal and paternal smoking on attention deficit hyperactivity disorders symptoms and diagnosis in offspring. J Nerv Ment Dis. 2010;198:672–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Braun JM, Kahn RS, Froehlich T, Auinger P, Lanphear BP. Exposures to environmental toxicants and attention deficit hyperactivity disorder in US children. Environ Health Perspect. 2006;114:1904–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Koshy G, Delpisheh A, Brabin B. Childhood obesity and parental smoking as risk factors for childhood ADHD in Liverpool children. J Epidemiol Commun Health. 2011;65:21–28. [DOI] [PubMed] [Google Scholar]
  • 41. Pohlabeln H, Rach S, De Henauw S, Eiben G, Gwozdz W, Hadjigeorgiou C et al. Further evidence for the role of pregnancy‐induced hypertension and other early life influences in the development of ADHD: results from the IDEFICS study. Eur Child Adolesc Psychiatry 2017;26:957–967. [DOI] [PubMed] [Google Scholar]
  • 42. Schmitt J, Romanos M. Prenatal and perinatal risk factors for attention‐deficit/hyperactivity disorder. Arch Pediatr Adolesc Med 2012;166:1074–1075. [DOI] [PubMed] [Google Scholar]
  • 43. Sciberras E, Ukoumunne OC, Efron D. Predictors of parent‐reported attention‐deficit/hyperactivity disorder in children aged 6–7 years: a national longitudinal study. J Abnorm Child Psychol. 2011;39:1025–34. [DOI] [PubMed] [Google Scholar]
  • 44. Froehlich TE, Lanphear BP, Auinger P, Hornung R, Epstein JN, Braun J, et al. Association of tobacco and lead exposures with attention‐deficit/hyperactivity disorder. Pediatrics. 2009;124:e1054–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Lehn H, Derks EM, Hudziak JJ, Heutink P, van Beijsterveldt TCEM, Boomsma DI. Attention problems and attention‐deficit/hyperactivity disorder in discordant and concordant monozygotic twins: evidence of environmental mediators. J Am Acad Child Psychiatry 2007;46:83–91. [DOI] [PubMed] [Google Scholar]
  • 46. Knopik VS, Sparrow EP, Madden PA, Bucholz KK, Hudziak JJ, Reich W, et al. Contributions of parental alcoholism, prenatal substance exposure, and genetic transmission to child ADHD risk: a female twin study. Psychol Med. 2005;35:625–35. [DOI] [PubMed] [Google Scholar]
  • 47. Yoshimasu K, Kiyohara C, Minami T, Yoshikawa N, Kihira S, Toyonaga K, et al. Maternal smoking during pregnancy and offspring attention‐deficit/hyperactivity disorder: a case–control study in Japan. Atten Defic Hyperact Disord. 2009;1:223–31. [DOI] [PubMed] [Google Scholar]
  • 48. Ketzer CR, Gallois C, Martinez AL, Rohde LA, Schmitz M. Is there an association between perinatal complications and attention‐deficit/hyperactivity disorder‐inattentive type in children and adolescents? Rev Bras Psiquiatr 2012;34:321–328. [DOI] [PubMed] [Google Scholar]
  • 49. Wiggs K, Elmore AL, Nigg JT, Nikolas MA. Pre‐ and perinatal risk for attention‐deficit hyperactivity disorder: does neuropsychological weakness explain the link? J Abnorm Child Psychol. 2016;44:1473–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50. Biederman J, Monuteaux MC, Faraone SV, Mick E. Parsing the associations between prenatal exposure to nicotine and offspring psychopathology in a nonreferred sample. J Adolesc Health 2009;45:142–148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Gard AM, Owens EB, Hinshaw SP. Prenatal smoke exposure predicts hyperactive/impulsive but not inattentive ADHD symptoms in adolescent and young adult girls. Infant Child Dev. 2016;25:339–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52. Milberger S, Biederman J, Faraone SV, Chen L, Jones J. Maternal smoking during pregnancy a risk factor for attention deficit hyperactivity disorder in children? Am J Psychiatry. 1996;153:1138–42. [DOI] [PubMed] [Google Scholar]
  • 53. Milberger S, Biederman J, Faraone SV, Jones J. Further evidence of an association between maternal smoking during pregnancy and attention deficit hyperactivity disorder: findings from a high‐risk sample of siblings. J Clin Child Psychol. 1998;27:352–8. [DOI] [PubMed] [Google Scholar]
  • 54. Mick E, Biederman J, Faraone SV, Sayer J, Kleinman S. Case–control study of attention‐deficit hyperactivity disorder and maternal smoking, alcohol use, and drug use during pregnancy. J Am Acad Child Psychiatry. 2002;41:378–85. [DOI] [PubMed] [Google Scholar]
  • 55. Schmitz M, Denardin D, Silva TL, Pianca T, Hutz MH, Faraone S, et al. Smoking during pregnancy and attention‐deficit/hyperactivity disorder, predominantly inattentive type: a case–control study. J Am Acad Child Psychiatry. 2006;45:1338–45. [DOI] [PubMed] [Google Scholar]
  • 56. Altink ME, Slaats‐Willemse DIE, Rommelse NNJ, Buschgens CJM, Fliers EA, Arias‐Vasquez A, et al. Effects of maternal and paternal smoking on attentional control in children with and without ADHD. Eur Child Adolesc Psychiatry. 2009;18:465–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57. Arnold LE, Elliott M, Lindsay RL, Molina B, Cornelius MD, Vitiello B, et al. Gestational and postnatal tobacco smoke exposure as predictor of ADHD, comorbid ODD/CD, and treatment response in the MTA. Clin Neurosci Res. 2005;5:295–306. [Google Scholar]
  • 58. Oerlemans AM, Burmanje MJ, Franke B, Buitelaar JK, Hartman CA, Rommelse NNJ. Identifying unique versus shared pre‐ and perinatal risk factors for ASD and ADHD using a simplex–multiplex stratification. J Abnorm Child Psychol. 2016;44(5):923–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59. Todd RD, Neuman RJ. Rapid publication ‐ gene‐environment interactions in the development of combined type ADHD: Evidence for a synapse‐based model. Am J Med Genet B 2007;144:971–975. [DOI] [PubMed] [Google Scholar]
  • 60. Neuman RJ, Lobos E, Reich W, Henderson CA, Sun LW, Todd RD. Prenatal smoking exposure and dopaminergic genotypes interact to cause a severe ADHD subtype. Biol Psychiatry. 2007;61:1320–8. [DOI] [PubMed] [Google Scholar]
  • 61. Wang Y, Hu D, Chen W, Xue H, Du Y. Prenatal tobacco exposure modulated the association of genetic variants with diagnosed ADHD and its symptom domain in children: a community based case–control study. Sci Rep. 2019;9:4274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62. Altink ME, Arias‐Vasquez A, Franke B, Slaats‐Willemse DIE, Buschgens CJM, Rommelse NNJ, et al. The dopamine receptor D4 7‐repeat allele and prenatal smoking in ADHD‐affected children and their unaffected siblings: no gene‐environment interaction. J Child Psychol Psychiatry. 2008;49:1053–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Talati A, Wickramaratne PJ, Wesselhoeft R, Weissman MM. Prenatal tobacco exposure, birthweight, and offspring psychopathology. Psychiatry Res. 2017;252:346–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. Silva D, Colvin L, Hagemann E, Bower C. Environmental risk factors by gender associated with attention‐deficit/hyperactivity disorder. Pediatrics. 2014;133:E14–22. [DOI] [PubMed] [Google Scholar]
  • 65. Gustafsson P, Kallen K. Perinatal, maternal, and fetal characteristics of children diagnosed with attention‐deficit‐hyperactivity disorder: results from a population‐based study utilizing the Swedish medical birth register. Dev Med Child Neurol. 2011;53:263–8. [DOI] [PubMed] [Google Scholar]
  • 66. Pineda DA, Palacio LG, Puerta IC, Merchan V, Arango CP, Galvis AY et al. Environmental influences that affect attention deficit/hyperactivity disorder—study of a genetic isolate. Eur Child Adolesc Psychiatry 2007;16:337–346. [DOI] [PubMed] [Google Scholar]
  • 67. Knopik VS, Heath AC, Jacob T, Slutske WS, Bucholz KK, Madden PA, et al. Maternal alcohol use disorder and offspring ADHD: disentangling genetic and environmental effects using a children‐of‐twins design. Psychol Med. 2006;36:1461–71. [DOI] [PubMed] [Google Scholar]
  • 68. Sourander A, Sucksdorff M, Chudal R, Surcel HM, Hinkka‐Yli‐Salomaki S, Gyllenberg D, et al. Prenatal cotinine levels and ADHD among offspring. Pediatrics. 2019;143:e20183144. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69. Sagiv SK, Epstein JN, Bellinger DC, Korrick SA. Pre‐ and postnatal risk factors for ADHD in a nonclinical pediatric population. J Atten Disord. 2013;17:47–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70. Schwenke E, Fasching PA, Faschingbauer F, Pretscher J, Kehl S, Peretz R, et al. Predicting attention deficit hyperactivity disorder using pregnancy and birth characteristics. Arch Gynecol Obstet. 2018;298:889–95. [DOI] [PubMed] [Google Scholar]
  • 71. Joelsson P, Chudal R, Talati A, Suominen A, Brown AS, Sourander A. Prenatal smoking exposure and neuropsychiatric comorbidity of ADHD: a Finnish nationwide population‐based cohort study. BMC Psychiatry. 2016;306. 10.1186/s12888-016-1007-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72. Linnet KM, Wisborg K, Obel C, Secher NJ, Thomsen PH, Agerbo E, et al. Smoking during pregnancy and the risk for hyperkinetic disorder in offspring. Pediatrics. 2005;116:462–7. [DOI] [PubMed] [Google Scholar]
  • 73. Wakschlag LS, Lahey BB, Loeber R, Green SM, Gordon RA, Leventhal BL. Maternal smoking during pregnancy and the risk of conduct disorder in boys. Arch Gen Psychiatry. 1997;54:670–6. [DOI] [PubMed] [Google Scholar]
  • 74. Braun JM, Froehlich TE, Daniels JL, Dietrich KN, Hornung R, Auinger P, et al. Association of environmental toxicants and conduct disorder in US children: NHANES 2001–2004. Environ Health Perspect. 2008;116:956–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75. Nigg JT, Breslau N. Prenatal smoking exposure, low birth weight, and disruptive behavior disorders. J Am Acad Child Psychology. 2007;46:362–9. [DOI] [PubMed] [Google Scholar]
  • 76. Talati A, Odgerel Z, Wickramaratne PJ, Weissman MM. Brain derived neurotrophic factor moderates associations between maternal smoking during pregnancy and offspring behavioral disorders. Psychiatry Res. 2016;245:387–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77. Biederman J, Martelon M, Woodworth KY, Spencer TJ, Faraone SV. Is maternal smoking during pregnancy a risk factor for cigarette smoking in offspring? A longitudinal controlled study of ADHD children grown up. J Atten Disord. 2017;21:975–85. [DOI] [PubMed] [Google Scholar]
  • 78. Ellis LC, Berg‐Nielsen TS, Lydersen S, Wichstrom L. Smoking during pregnancy and psychiatric disorders in preschoolers. Eur Child Adoles Psychol. 2012;21:635–44. [DOI] [PubMed] [Google Scholar]
  • 79. Russell AA, Johnson CL, Hammad A, Ristau KI, Zawadzki S, Villar LD, et al. Prenatal and neighborhood correlates of oppositional defiant disorder (ODD). Child Adolesc Soc Work. 2015;32:375–81. [Google Scholar]
  • 80. Lees B, Mewton L, Jacobus J, Valadez EA, Stapinski LA, Teesson M, et al. Association of prenatal alcohol exposure with psychological, behavioral, and neurodevelopmental outcomes in children from the adolescent brain cognitive development study. Am J Psychiatry. 2020;177:1060–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81. Pagnin D, Grecco MLZ, Furtado EF. Prenatal alcohol use as a risk for attention‐deficit/hyperactivity disorder. Eur Arch Psychiatry Clin Neurosci 2019;269:681–687. [DOI] [PubMed] [Google Scholar]
  • 82. Kim HW, Cho SC, Kim BN, Kim JW, Shin MS, Kim Y. Perinatal and familial risk factors are associated with full syndrome and subthreshold attention‐deficit hyperactivity disorder in a Korean community sample. Psychiatry Invest. 2009;6:278–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83. Weile LKK, Wu C, Hegaard HK, Kesmodel US, Henriksen TB, Nohr EA. Alcohol intake in early pregnancy and risk of attention‐deficit/hyperactivity disorder in children up to 19 years of age: a cohort study. Alcohol Clin Exp Res. 2020;44:168–77. [DOI] [PubMed] [Google Scholar]
  • 84. Eilertsen EM, Gjerde LC, Reichborn‐Kjennerud T, Orstavik RE, Knudsen GP, Stoltenberg C, et al. Maternal alcohol use during pregnancy and offspring attention‐deficit hyperactivity disorder (ADHD): a prospective sibling control study. Int J Epidemiol. 2017;46:1633–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85. Mitchell JM, Jeffri FJ, Maher GM, Khashan AS, McCarthy FP. Prenatal alcohol exposure and risk of attention deficit hyperactivity disorder in offspring: a retrospective analysis of the millennium cohort study. J Affect Disord. 2020;269:94–100. [DOI] [PubMed] [Google Scholar]
  • 86. Larkby CA, Goldschmidt L, Hanusa BH, Day NL. Prenatal alcohol exposure is associated with conduct disorder in adolescence: findings from a birth cohort. J Am Acad Child Psychol. 2011;50:262–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87. Whitbeck LB, Crawford DM. Gestational risks and psychiatric disorders among indigenous adolescents. Community Ment Hlt J. 2009;45:62–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88. Del‐Ponte B, Santos IS, Tovo‐Rodrigues L, Anselmi L, Munhoz TN, Matijasevich A. Caffeine consumption during pregnancy and ADHD at the age of 11 years: a birth cohort study. BMJ Open. 2016;6:e012749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89. Linnet KM, Wisborg K, Secher NJ, Thomsen P, Obel C, Dalsgaard S, et al. Coffee consumption during pregnancy and the risk of hyperkinetic disorder and ADHD: a prospective cohort study. Acta Paediatr. 2009;98:173–9. [DOI] [PubMed] [Google Scholar]
  • 90. Rice F, Langley K, Woodford C, Davey Smith G, Thapar A. Identifying the contribution of prenatal risk factors to offspring development and psychopathology: what designs to use and a critique of literature on maternal smoking and stress in pregnancy. Dev Psychopathol. 2018;30:1107–28. [DOI] [PubMed] [Google Scholar]
  • 91. Porter MS, Maravilla JC, Betts KS, Alati R. Low‐moderate prenatal alcohol exposure and offspring attention‐deficit hyperactivity disorder (ADHD): systematic review and meta‐analysis. Arch Gynecol Obstet. 2019;300:269–77. [DOI] [PubMed] [Google Scholar]
  • 92. Murray J, Burgess S, Zuccolo L, Hickman M, Gray R, Lewis SJ. Moderate alcohol drinking in pregnancy increases risk for children's persistent conduct problems: causal effects in a Mendelian randomisation study. J Child Psychol Psychiatry. 2016;57:575–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93. D'Onofrio BM, Van Hulle CA, Waldman ID, Rodgers JL, Rathouz PJ, Lahey BB. Causal inferences regarding prenatal alcohol exposure and childhood externalizing problems. Arch Gen Psychiatry. 2007;64:1296–304. [DOI] [PubMed] [Google Scholar]
  • 94. Collishaw S, Goodman R, Ford T, Rabe‐Hesketh S, Pickles A. How far are associations between child, family and community factors and child psychopathology informant‐specific and informant‐general? J Child Psychol Psychiatry. 2009;50:571–80. [DOI] [PubMed] [Google Scholar]
  • 95. Madley‐Dowd P, Rai D, Zammit S, Heron J. Simulations and directed acyclic graphs explained why assortative mating biases the prenatal negative control design. J Clin Epidemiol. 2020;118:9–17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96. Leis JA, Heron J, Stuart EA, Mendelson T. Associations between maternal mental health and child emotional and behavioral problems: does prenatal mental health matter? J Abnorm Child Psychol. 2014;42:161–71. [DOI] [PubMed] [Google Scholar]
  • 97. Schisterman EF, Cole SR, Platt RW. Overadjustment bias and unnecessary adjustment in epidemiologic studies. Epidemiology. 2009;20:488–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98. Hernandez‐Diaz S, Schisterman EF, Hernan MA. The birth weight ‘paradox’ uncovered? Am J Epidemiol. 2006;164:1115–20. [DOI] [PubMed] [Google Scholar]
  • 99. Merikangas KR, Nakamura EF, Kessler RC. Epidemiology of mental disorders in children and adolescents. Dialogues Clin Neurosci. 2009;11:7–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100. Niclasen J, Nybo Andersen AM, Teasdale TW, Strandberg‐Larsen K. Prenatal exposure to alcohol, and gender differences on child mental health at age seven years. J Epidemiol Community Health. 2014;68:224–32. [DOI] [PubMed] [Google Scholar]
  • 101. Hutchinson J, Pickett KE, Green J, Wakschlag LS. Smoking in pregnancy and disruptive behaviour in 3‐year‐old boys and girls: an analysis of the UK millennium cohort study. J Epidemiol Community Health. 2010;64:82–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102. Reef J, Diamantopoulou S, van Meurs I, Verhulst FC, van der Ende J. Developmental trajectories of child to adolescent externalizing behavior and adult DSM‐IV disorder: results of a 24‐year longitudinal study. Soc Psychiatry Psychiatr Epidemiol. 2011;46:1233–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103. Kuja‐Halkola R, Lichtenstein P, D'Onofrio BM, Larsson H. Codevelopment of ADHD and externalizing behavior from childhood to adulthood. J Child Psychol Psychiatry. 2015;56:640–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 104. Bunte TL, Schoemaker K, Hessen DJ, van der Heijden PG, Matthys W. Stability and change of ODD, CD and ADHD diagnosis in referred preschool children. J Abnorm Child Psychol. 2014;42(7):1213–24. [DOI] [PubMed] [Google Scholar]
  • 105. Caye A, Swanson J, Thapar A, Sibley M, Arseneault L, Hechtman L, et al. Life span studies of ADHD—conceptual challenges and predictors of persistence and outcome. Curr Psychiatry Rep. 2016;18:111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 106. Dopfner M, Hautmann C, Gortz‐Dorten A, Klasen F, Ravens‐Sieberer U, BELLA Study Group . Long‐term course of ADHD symptoms from childhood to early adulthood in a community sample. Eur Child Adolesc Psychiatry. 2015;24:665–73. [DOI] [PubMed] [Google Scholar]
  • 107. Moffitt TE, Houts R, Asherson P, Belsky DW, Corcoran DL, Hammerle M, et al. Is adult ADHD a childhood‐onset neurodevelopmental disorder? Evidence from a four‐decade longitudinal cohort study. Am J Psychiatry. 2015;172:967–77. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108. D'Onofrio BM, Class QA, Lahey BB, Larsson H. Testing the developmental origins of health and disease hypothesis for psychopathology using family‐based quasi‐experimental designs. Child Dev Perspect. 2014;8:151–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 109. Gage SH, Munafò MR, Smith GD. Causal inference in Developmental Origins of Health and Disease (DOHaD) research. Annu Rev Psychol. 2016;67:567–85. [DOI] [PubMed] [Google Scholar]
  • 110. D'Onofrio BM, Lahey BB, Turkheimer E, Lichtenstein P. Critical need for family‐based, quasi‐experimental designs in integrating genetic and social science research. Am J Public Health. 2013;103:46–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 111. Jami ES, Hammerschlag AR, Bartels M, Middeldorp CM. Parental characteristics and offspring mental health and related outcomes: a systematic review of genetically informative literature. Transl Psychiatry 2021;11:197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 112. Najman JM, Williams GM, Nikles J, Spence S, Bor W, O'Callaghan M, et al. Bias influencing maternal reports of child behaviour and emotional state. Soc Psychiatry Psychiatric Epidemiol. 2001;36(4):186–94. [DOI] [PubMed] [Google Scholar]
  • 113. Lavigne JV, Dahl KP, Gouze KR, LeBailly SA, Hopkins J. Multi‐domain predictors of oppositional defiant disorder symptoms in preschool children: cross‐informant differences. Child Psychiatry Hum Dev. 2015;46:308–19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 114. Morrison A, Polisena J, Husereau D, Moulton K, Clark M, Fiander M, et al. The effect of English‐language restriction on systematic review‐based meta‐analyses: a systematic review of empirical studies. Int J Technol Assess. 2012;28:138–44. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Table S1. Risk of bias assessment scores based on NOS scale of cohort, longitudinal and cross‐sectional studies

Supplementary Table S2. Risk of bias assessment scores based on NOS scale of case–control studies

Supplementary Table S3. List of studies excluded

Supplementary Table S4. Studies not reporting all the results

Supplementary Table S5. Study characteristics and results of cohort, longitudinal and cross‐sectional studies

Supplementary Table S6. Study characteristics and results of case–control studies

Supplementary Table S7. Confounders included in the cohort, longitudinal and cross‐sectional studies

Supplementary Table S8. Confounders included in the case–control studies

Click here for additional data file. (191.3KB, docx)

Articles from Addiction (Abingdon, England) are provided here courtesy of Wiley

RESOURCES