https://orcid.org/0000-0003-1062-0097
Retraction
The PLOS One Editors retract this article [1] due to concerns about potential manipulation of the publication process. These concerns call into question the validity and provenance of the reported results and compliance with PLOS policies. We regret that the issues were not identified prior to the article’s publication.
All authors did not agree with the retraction.
17 Dec 2025: The PLOS One Editors (2025) Retraction: The association between maternal tobacco smoking during pregnancy and the risk of attention-deficit/hyperactivity disorder (ADHD) in offspring: A systematic review and meta-analysis. PLOS ONE 20(12): e0339089. https://doi.org/10.1371/journal.pone.0339089 View retraction
Figures
Abstract
Introduction
Maternal tobacco smoking during pregnancy is a significant public health concern with potential long-lasting effects on child development. ADHD, a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity, may be influenced by prenatal nicotine exposure. This systematic review and meta-analysis examine the association between maternal tobacco smoking during pregnancy and the risk of ADHD in offspring.
Methods
Following PRISMA guidelines, we searched databases including PubMed, Web of Science, Cochrane Central, Embase, Scopus, CINAHL, LILACS, SciELO, Allied and Complementary Medicine Database (AMED), ERIC, CNKI, HTA Database, Dialnet, EBSCO, LENS, and Google Scholar for studies up to November 1, 2024. We included peer-reviewed studies reporting quantitative effect size estimates for the association between maternal tobacco smoking and ADHD. Study quality was assessed using the Newcastle-Ottawa Scale (NOS).
Results
We identified 2,981 articles and included 55 studies (4,016,522 participants) in the analysis. The meta-analysis showed a significant association between maternal tobacco smoking during pregnancy and increased risk of ADHD in offspring (pooled Odds Ratio (OR) = 1.71, 95% CI: 1.55-1.88; P < 0.001). Egger’s test indicated no publication bias (p = 0.204), but Begg’s test did (p = 0.042). By employing the trim and fill method, the revised OR was estimated to be 1.54 (95% CI: 1.40–1.70; P < 0.001). The OR were 2.37 (95% CI: 1.72–3.28; P < 0.001) in cross-sectional studies, 1.72 (95% CI: 1.49–2.00; P < 0.001) in case-control studies, and 1.53 (95% CI: 1.34–1.74; P < 0.001) in cohort studies. Meta-regression showed study design and study region significantly influenced heterogeneity (P < 0.10). Sensitivity and subgroup analyses confirmed the robustness of these findings.
Conclusion
This systematic review and meta-analysis demonstrate a significant association between maternal tobacco smoking during pregnancy and increased odds of ADHD in offspring. These findings highlight the need for prenatal care guidelines and tobacco smoking cessation programs for pregnant women to reduce ADHD risk and promote optimal neurodevelopmental outcomes. Future research should explore underlying mechanisms and potential confounders further.
Citation: Mohammadian M, Khachatryan LG, Vadiyan FV, Maleki M, Fatahian F, Mohammadian-Hafshejani A (2025) RETRACTED: The association between maternal tobacco smoking during pregnancy and the risk of attention-deficit/hyperactivity disorder (ADHD) in offspring: A systematic review and meta-analysis. PLoS ONE 20(2): e0317112. https://doi.org/10.1371/journal.pone.0317112
Editor: Anthony A. Olashore, University of Botswana, BOTSWANA
Received: July 16, 2024; Accepted: December 22, 2024; Published: February 7, 2025
Copyright: © 2025 Mohammadian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Maternal tobacco smoking during pregnancy remains a pervasive public health issue worldwide, with significant implications for maternal and child health [1,2]. The prenatal period is a critical window of development where exposure to harmful substances, such as those found in tobacco smoke, can have lasting effects on the developing fetus [3–5]. One of the neurodevelopmental disorders of particular concern in this context is Attention-Deficit/Hyperactivity Disorder (ADHD) [6]. ADHD is characterized by patterns of inattention, hyperactivity, and impulsivity that are inconsistent with developmental levels and significantly impair functioning across various domains of life [7]. Globally, ADHD affects approximately 2–7% of children and adolescents, with prevalence varying depending on diagnostic criteria, age, and location [8]. ADHD significantly impacts individuals, families, and society [7]. Children with ADHD often struggle with academic performance, social interactions, and behavior management. These challenges frequently continue into adulthood, affecting job success and personal relationships [9,10]. The economic impact of ADHD is substantial, encompassing healthcare expenses, productivity losses, and special education services. The annual societal cost of ADHD in childhood and adolescence is conservatively estimated to be $42.5 billion, with a range of $36 billion to $52.4 billion [11].
The etiology of ADHD involves genetic and environmental factors, including prenatal tobacco smoke exposure through maternal smoking [12,13]. Nicotine and other toxic substances in tobacco can cross the placenta and disrupt fetal brain development [14]. Studies have shown that nicotine affects neurotransmitter systems, particularly dopamine and norepinephrine [15–17], and alters neural circuits related to attention and self-regulation [18,19]. Additionally, nicotine induces oxidative stress and inflammation, impacting brain development [20].
Emerging research highlights the role of epigenetic mechanisms in mediating the association between maternal tobacco smoking and ADHD risk. Studies suggest that tobacco smoke exposure can alter DNA methylation patterns, potentially modifying gene expression related to neurodevelopment and increasing the risk of various psychiatric disorders, including ADHD [21–23]. These epigenetic modifications can disrupt the precise regulation of gene expression necessary for typical brain development, potentially contributing to ADHD symptoms [24]. This epigenetic perspective provides a crucial framework for understanding the enduring impact of prenatal nicotine exposure.
Epidemiological studies investigating the association between maternal tobacco smoking during pregnancy and ADHD in offspring have yielded diverse results [25–30]. Some large, well-designed observational studies report a positive correlation, finding that children exposed to tobacco smoke in utero through maternal tobacco smoking during pregnancy face an elevated risk of subsequently receiving an ADHD diagnosis in childhood [29,31–34]. These findings are supported by experimental research conducted on animals and human cells, which provide biological plausibility for the neurotoxic and disruptive effects of nicotine on fetal brain development pathways that are believed to be associated with ADHD [15,16].
However, not all epidemiological studies have found a statistically significant association between prenatal smoking exposure and ADHD [35,36]. Some smaller or earlier studies did not find a relationship or attributed the observed associations mainly to potential confounding factors. These factors include familial, genetic, and psychosocial factors that are correlated with both maternal tobacco smoking and the risk of ADHD. Examples of such factors are parental ADHD, low socioeconomic status, inadequate prenatal care, and other environmental factors [28,35–38]. The inconsistencies in study findings have created ongoing uncertainty regarding the true nature and magnitude of the potential effect.
Given the significant public health implications of clarifying this relationship, it is essential to conduct a rigorous evaluation and synthesis of the totality of evidence from the existing epidemiological literature. A systematic review and meta-analysis provide a robust methodological framework to quantitatively integrate data from multiple observational studies, critically appraise the quality of included research, and estimate the overall effect size while accounting for heterogeneity. This approach offers the best available means to address the knowledge gaps and inform clinical guidance and public health policy on this important issue [39,40].
In this systematic review and meta-analysis, we aim to investigate the association between maternal tobacco smoking during pregnancy and the risk of ADHD in offspring. We have three objectives: (1) to synthesize the existing epidemiological evidence on this association(2) to assess the influence of confounding factors and study quality on reported findings, and (3) to offer evidence-based insights that can guide clinical practice and public health policies aimed at reducing prenatal exposure to tobacco smoke and minimizing the risk of ADHD.
While previous meta-analyses have examined this association [1,2], our study expands upon prior work by encompassing a broader and more comprehensive search strategy across a wider range of databases, enabling the inclusion of a more complete set of relevant studies. Furthermore, we will employ advanced statistical techniques, including meta-regression and subgroup analyses stratified by factors such as ADHD diagnostic criteria and tobacco smoking ascertainment methods, to explore potential sources of heterogeneity and provide a more nuanced understanding of this complex relationship. By addressing these limitations of previous reviews, our study will offer a more robust and comprehensive evaluation of the impact of maternal tobacco smoking on ADHD risk, with implications for prenatal care guidelines, tobacco smoking cessation interventions, and public health initiatives promoting optimal neurodevelopmental outcomes. Ultimately, a clearer understanding of this association is essential for developing targeted interventions to improve child health and well-being and reduce the societal burden of ADHD.
Materials and methods
Study design and search strategy
This systematic review and meta-analysis were designed to examine the association between maternal direct tobacco smoking during pregnancy and the risk of ADHD in children. We adhered strictly to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure a transparent and reproducible methodology [41,42].
Comprehensive literature search.
An exhaustive literature search was conducted across multiple electronic databases, including PubMed, Web of Science, Cochrane Central, Embase, Scopus, CINAHL, LILACS, SciELO, Allied and Complementary Medicine Database (AMED), ERIC, CNKI, HTA Database, Dialnet, EBSCO, LENS, and Google Scholar. The search covered all publications from the inception of these databases up to November 1, 2024. This extensive time frame was selected to encompass the most recent and relevant research available.
To identify pertinent studies, we employed a combination of Medical Subject Headings (MeSH) terms and keywords related to maternal tobacco smoking, pregnancy, and ADHD. These terms included “Maternal tobacco smoking”, “pregnancy”, “prenatal”, “ADHD”, “Attention-deficit/hyperactivity disorder”, and their synonyms. Boolean operators (AND, OR) were used to combine these terms, ensuring a comprehensive retrieval of relevant articles.
Inclusion and exclusion criteria
Eligibility criteria.
To ensure the inclusion of high-quality studies, we established strict eligibility criteria. We included original research articles that explored the relationship between maternal tobacco smoking during pregnancy and ADHD in children. The studies had to be published in peer-reviewed journals to ensure the reliability and comprehensibility of the findings.
We considered various study designs, including case-control, cross-sectional, and retrospective/prospective cohort studies. These designs are well-suited for examining associations between exposure (maternal tobacco smoking) and outcomes (ADHD in children).
Eligible studies were required to report quantitative effect size estimates, such as odds ratios (ORs), hazard ratios (HRs), or relative risks (RRs), along with their corresponding 95% confidence intervals (CIs). This information was crucial for the meta-analysis to objectively assess the strength and precision of the association between maternal tobacco smoking and ADHD.
Exclusion criteria.
We excluded studies that did not involve human subjects, those with insufficient data, and articles such as reviews, editorials, and case reports. Additionally, we excluded studies that did not adequately measure the exposure or the outcome variables, as well as those with incomplete or unclear data reporting. Studies that failed to provide sufficient effect estimates or raw data for quantitative analysis were also excluded.
This review focuses specifically on the effects of maternal tobacco smoking during pregnancy. Studies examining other forms of tobacco use (e.g., chewing tobacco, snuff) or the effects of other smoked substances besides tobacco (e.g., cannabis) were excluded.
Study selection process
Initial screening.
The study selection process involved multiple stages to ensure the inclusion of relevant studies. Two independent reviewers initially screened the titles and abstracts of all identified articles. Articles that were clearly irrelevant to the study aims were excluded at this stage.
Full-text review.
The full texts were obtained and reviewed against the predefined inclusion and exclusion criteria for articles that appeared relevant based on their titles and abstracts. Both reviewers independently assessed each article to determine its eligibility.
Consensus and discrepancy resolution.
In cases where discrepancies arose between the reviewers during any stage of the screening process, a third independent reviewer was consulted. The third reviewer objectively examined the full texts in question and facilitated open discussion between all reviewers until a consensus decision was reached on final study selection. This systematic and rigorous screening methodology minimized potential bias or errors and ensured a robust, credible, and reproducible process.
Data extraction
Development of data extraction form.
To maintain the integrity and consistency of the data, a detailed standardized data extraction form was developed prior to conducting the extractions. This form underwent thorough pilot testing by the research team to ensure it effectively captured all essential study details in an organized and reproducible manner.
Data extraction process.
Two independent reviewers utilized this well-defined form to systematically extract relevant information from each included study. The extracted data from each study underwent rigorous cross-checking by both reviewers to ensure accuracy. Any discrepancies were resolved through open discussion and consensus decision-making, involving a third reviewer when necessary.
The comprehensive data extraction form enabled the collection of important bibliographic details, study characteristics, population descriptors, exposure and outcome assessment methods, reported effect estimates, adjusted covariates, and quality assessment ratings. By capturing this information in a standardized manner from each study, consistency and completeness were ensured.
Quality assessment
Newcastle-Ottawa Scale (NOS).
The methodological quality of the included studies was carefully assessed using the widely accepted Newcastle-Ottawa Scale (NOS) [43]. This scale evaluates non-randomized studies based on three key domains: selection of study groups, comparability between groups, and ascertainment of exposure and outcome variables. Each study was assigned a detailed quality rating on a scale ranging from zero to nine points, with higher scores indicating stronger methodological conduct and reporting. Scores below 5 indicated low-quality articles, scores between 5 and 7 indicated moderate quality, and scores of 8 or higher indicated good quality [44,45].
Independent quality assessment.
Two independent reviewers applied the standardized NOS criteria to assess the quality of each study. Any discrepancies in scoring were resolved through open discussion, involving a third reviewer if necessary. Based on the total points achieved, studies were categorized as having good, moderate, or low methodological quality.
The NOS takes into account important criteria specific to case-control and cohort study designs, such as representative case selection, well-defined controls, comparability of cases and controls on key confounding factors, and robust ascertainment of exposure status. This rigorous and standardized approach to quality assessment allowed for objective evaluation of potential biases within and between studies. It also facilitated meaningful subgroup analyses to explore whether the strength of associations varied based on study quality ratings.
Statistical analysis
Meta-analysis.
To ensure the validity and reliability of our systematic review and meta-analysis findings, we employed rigorous statistical and graphical techniques to assess heterogeneity comprehensively. For studies that reported effect estimates separately for different time periods of exposure, we conducted meta-analyses methods to synthesize the stratified estimates into overall effects within each study. This approach maximized the inclusion of data without duplicating participant populations. Similarly, if studies provided results stratified by important covariates, but did not report an overall estimate, we performed meta-analyses to combine the stratified effects. In cases where studies presented raw exposure and outcome group data without a calculated effect size, we used Stata software to generate OR estimates with 95% confidence intervals.
Heterogeneity assessment.
To assess between-study heterogeneity, we utilized both statistical tests and visual inspection of forest plots. The Chi-square test helped determine if observed differences were due to chance alone, with a significance level of P < 0.10 indicating statistically significant heterogeneity. Additionally, we calculated the I² statistic to quantify the percentage of total variation attributed to heterogeneity rather than sampling error. If significant heterogeneity was detected, we selected random-effects models for meta-analyses [46,47]. We carefully examined forest plots to visually assess the overlap and distribution of confidence intervals across studies. Any potential outliers were further investigated through meta-regression model, subgroup analyses, and sensitivity analyses to identify potential sources of heterogeneity.
Exploration of heterogeneity
Meta-regression.
To explore the impact of covariates on heterogeneity, we conducted univariate and multivariate meta-regression using Stata software. Covariates such as study design, study year, sample size, study quality assessment score, methods of ascertaining tobacco smoking, methods of ascertaining ADHD, and geographical area were examined [48].
Sensitivity analysis.
To evaluate the robustness of our findings, we conducted sensitivity analyses by systematically excluding each study one at a time and re-running the meta-analysis. This process helped to determine if any particular study had a disproportionate influence on the overall results [49].
Subgroup analysis.
Subgroup analyses were performed to investigate potential sources of heterogeneity and to explore whether the association between maternal tobacco smoking during pregnancy and ADHD varied across different study characteristics. Subgroups were defined based on study design, study year, sample size, study quality assessment score, methods of ascertaining tobacco smoking, methods of ascertaining ADHD, and geographical area. These analyses provided deeper insights into the relationship and allowed for more nuanced interpretations of the findings [50].
Assessment of publication bias.
We assessed publication bias using both graphical and statistical methods. Funnel plots were visually inspected for asymmetry, which can indicate the presence of publication bias. Additionally, Egger’s regression test and Begg’s adjusted rank correlation test were conducted to statistically evaluate the likelihood of publication bias. To address the potential bias from missing unpublished studies, we used the trim and fill method. These methods provided a comprehensive assessment of the potential impact of publication bias on our meta-analysis findings [47,51].
Missing data.
In the course of our analyses, we encountered several variables that had missing data. To maintain the integrity and accuracy of our findings, we made the decision to exclude these variables from specific analyses that necessitated complete datasets. This exclusion was particularly relevant for more complex statistical techniques, such as meta-regression and subgroup analyses, which require fully populated datasets to yield reliable and interpretable results.
Software.
All data analyses were performed using Stata 17 software, ensuring rigorous and reliable synthesis of the evidence [52].
Results
Characteristics of included studies
An extensive electronic search using specific keywords identified 2,981 articles. After removing 1,203 duplicates, 1,778 articles remained for further evaluation. These articles were screened based on predefined criteria, leading to the exclusion of 1,697 articles. Consequently, 81 relevant articles were identified, of which 13 were excluded for not reporting effect sizes or the inability to calculate them, 5 study focused on the relationship between parental smoking and ADHD in offspring, 6 studies evaluated exposure to second-hand smoke, and 3 articles were duplicates based on the same dataset. This rigorous selection process resulted in 54 articles for the study. An additional study was identified through reference checking, bringing the total to 55 articles for the systematic review and meta-analysis [25–38,53–93] (Fig 1).
A total of 55 studies, conducted between 1998 and 2024 across various countries including the United States, Finland, Sweden, Brazil, the Netherlands, Japan, the UK, Spain, China, Australia, New Zealand, Norway, Canada, France, Sweden, South Korea, Turkey, Romania, Bulgaria, Lithuania, Germany, Denmark, Egypt, and India, were analyzed to examine the association between maternal tobacco smoking during pregnancy and the risk of ADHD in offspring. These studies collectively included 4,016,522 participants [25–38,53–93] (Tables 1–3).
Maternal tobacco smoking during pregnancy and the risk of ADHD in offspring
The systematic review comprised 13 cross-sectional, 11 case-control, and 31 cohort studies. To address potential heterogeneity, a random-effects model was used for the meta-analysis. The meta-analysis results indicated a significantly higher odds of ADHD in children whose mothers smoked during pregnancy compared to those who did not. The pooled estimate showed an OR of 1.71 (95% CI: 1.55-1.88; P < 0.001), suggesting a considerable increase in the likelihood of ADHD in children exposed to maternal tobacco smoking during pregnancy (Fig 2).
Evaluation of publication bias
Egger’s test (p = 0.204) showed no evidence of publication bias for the association between maternal tobacco smoking during pregnancy and ADHD in children. However, Begg’s test (p = 0.042) indicated some publication bias (Fig 3).
Revised effect size
We estimated the effect size for potentially missing studies using the trim and fill method. Fig 4 illustrates this method, which estimated results for 12 missing studies. Considering these missing studies, the revised OR was 1.54 (95% CI: 1.40–1.70; P < 0.001), reinforcing the significant relationship between maternal tobacco smoking during pregnancy and ADHD in children (Fig 4).
Meta-regression
Meta-regression analysis examined variables such as sample size, study design, study location, time period, methods of ascertaining tobacco smoking, methods of ascertaining ADHD, and study quality assessed using the Newcastle-Ottawa scale. Only study design (cross-sectional, case-control, and cohort) and study location (USA and Canada, Europe, Asia, South America, Australia, Africa) showed a significant association with heterogeneity (P < 0.10) (Table 4).
Sensitivity analysis
Sensitivity analysis involved sequentially removing each study to assess the robustness of the meta-analysis results. The estimated OR remained stable, indicating the robustness of the findings (Fig 5 and Table 5).
Subgroup analysis
Subgroup analyses were performed to explore potential sources of heterogeneity, considering sample size, study design, geographic location, publication year, methods of ascertaining tobacco smoking, methods of ascertaining ADHD, and study quality assessed using the Newcastle-Ottawa Scale. Results remained relatively consistent across different study designs: cross-sectional studies (OR = 2.37, 95% CI: 1.72–3.28), case-control studies (OR = 1.72, 95% CI: 1.49–2.00), and cohort studies (OR = 1.53, 95% CI: 1.34–1.74). Geographic variation was observed, with ORs of 1.54 (95% CI: 1.25–1.91) in the US and Canada, 1.63 (95% CI: 1.42–1.88) in Europe, 2.32 (95% CI: 1.60–3.35) in Asia, 1.29 (95% CI: 1.14–1.46) in South America, 1.89 (95% CI: 1.82–1.96) in Australia, and 4.81 (95% CI: 2.80–8.27) in Africa. Studies published in 2010 or earlier showed an OR of 1.58 (95% CI: 1.36–1.83), compared to 1.77 (95% CI: 1.56–2.01) for studies published from 2011 onwards. Sample size also appeared to influence the results: studies with fewer than 2,000 participants had an OR of 1.47 (95% CI: 1.32–1.62), while those with 2,000 or more participants had an OR of 1.70 (95% CI: 1.56–1.86).
Subgroup analysis based on tobacco smoking ascertainment method revealed ORs of 1.65 (95% CI: 1.40–1.95) for self-report, 1.75 (95% CI: 1.51–2.04) for interview, 1.76 (95% CI: 1.47–2.10) for medical records, and 1.28 (95% CI: 1.11–1.49) for biological measurement. Similarly, ADHD ascertainment method yielded ORs of 1.92 (95% CI: 1.59–2.31) for clinical interview/diagnosis, 1.58 (95% CI: 1.42–1.75) for self-report by child/parent or teacher report, and 1.66 (95% CI: 1.41–1.97) for medical records/databases. Finally, studies of good quality had an OR of 1.76(95% CI: 1.63–1.91), moderate quality studies had an OR of 1.49(95% CI: 1.34–1.65), and low-quality studies had an OR of 2.70(95% CI: 1.42–5.14) (Table 6).
Discussion
This systematic review and meta-analysis of 55 studies, encompassing over four million participants, provides compelling evidence that maternal tobacco smoking during pregnancy significantly increases the odds of ADHD in children (OR = 1.71, 95% CI: 1.55–1.88). This finding, indicating a 71% increased likelihood of ADHD in children exposed to prenatal tobacco smoke, remained consistent across various study designs, geographic regions, and time periods. Our results align with those of Huang et al. [21], who reported a 60% increased risk of ADHD in children of mothers who smoked during pregnancy based on their meta-analysis of 20 studies. These findings underscore the critical need for public health interventions aimed at reducing tobacco smoking during pregnancy.
Several physiological mechanisms could explain the link between maternal tobacco smoking during pregnancy and a heightened risk of ADHD in offspring [100,101]. Nicotine, the primary psychoactive substance in tobacco, can readily cross the placental barrier, impacting fetal brain development directly [19]. Exposure to nicotine during critical periods of brain development can disrupt neurotransmitter systems, particularly the dopaminergic system, which is vital for regulating attention and behavior [4,19].
Smoking during pregnancy can also lead to chronic fetal hypoxia due to carbon monoxide and other harmful substances in tobacco smoke [102]. Hypoxia can impair oxygen delivery to the fetal brain, resulting in neurodevelopmental deficits. Prolonged hypoxia can cause structural changes in the brain, such as reduced cortical thickness and altered connectivity, which are associated with ADHD symptoms [103,104].
Additionally, maternal tobacco smoking can trigger an inflammatory response, resulting in the release of pro-inflammatory cytokines [105]. These cytokines can cross the placental barrier and affect fetal brain development, potentially leading to neuroinflammation [106]. Neuroinflammation is linked to various neuropsychiatric disorders, including ADHD, suggesting that prenatal exposure to inflammatory agents could contribute to ADHD development [107,108].
Epigenetic modifications may partially explain the observed association between maternal smoking and ADHD in this meta-analysis. Prenatal exposure to tobacco smoke has been shown to disrupt DNA methylation patterns, impacting gene expression crucial for neurodevelopment [109]. Such alterations could have cascading effects on brain development, potentially increasing the susceptibility to ADHD and other neuropsychiatric disorders [24]. While this study does not directly investigate epigenetic mechanisms, the findings align with the growing body of literature suggesting that epigenetic dysregulation plays a significant role in the etiology of ADHD following in-utero tobacco exposure. Further research exploring specific epigenetic markers and their functional consequences in the context of maternal smoking and ADHD is warranted to elucidate the precise biological pathways involved [110].
The meta-regression and subgroup analyses shed light on the factors that contribute to the observed heterogeneity in the results of included studies [21,48,50]. The study design was identified as a significant source of heterogeneity, with cross-sectional, case-control, and cohort studies exhibiting varying effect sizes. This variation could be attributed to differences in study methodologies, sample sizes, and the timing of exposure assessment. Furthermore, there were geographical differences in the odds ratio across regions, with studies from Asia, Australia, and Africa showing the highest odds. These regional disparities may be influenced by variations in smoking prevalence, genetic susceptibility, cultural factors, and healthcare systems. These findings are consistent with the meta-analysis conducted by Huang et al. In their analysis, they also observed variations in the odds of ADHD among children in subgroup analyses based on certain study variables [21].
Although Egger’s test did not indicate significant publication bias, Begg’s test suggested some bias, which was addressed using the trim and fill method. This method estimated the effect size for potentially missing studies, resulting in a revised OR of 1.54 (1.40-1.70). This adjusted estimate reinforces the significant association between maternal tobacco smoking during pregnancy and ADHD in children, indicating that the observed effect is not solely due to publication bias. The sensitivity analysis further confirmed the robustness of the findings. This consistency underscores the reliability of the meta-analytic findings [49].
The findings of this meta-analysis have significant implications for public health and clinical practice. Given the association between maternal tobacco smoking during pregnancy and ADHD in children, there is a critical need for targeted tobacco smoking cessation programs for pregnant women [111,112]. Healthcare providers should emphasize the risks of tobacco smoking during prenatal visits and provide resources and support for smoking cessation [111]. Public health campaigns should also raise awareness about the potential long-term neurodevelopmental consequences of prenatal tobacco smoking. Policies aimed at reducing tobacco smoking prevalence among women of childbearing age could have a substantial impact on reducing the incidence of ADHD and other neurodevelopmental disorders.
Limitations
This meta-analysis, while strengthened by a large sample size and rigorous methodology, has limitations. The observational design of the included studies precludes causal inferences. Potential recall bias and underreporting may be present due to the reliance on self-reported maternal tobacco smoking during pregnancy. Further, the analysis did not differentiate between ADHD subtypes (predominantly inattentive, predominantly hyperactive-impulsive, and combined type), limiting the ability to identify subtype-specific risks associated with maternal tobacco smoking.
Future research
Future research should prioritize several key areas. Investigating the potential moderating roles of genetic and environmental factors on the relationship between prenatal tobacco exposure and ADHD is crucial. Additionally, exploring potential interactions between maternal smoking and other prenatal exposures (e.g., alcohol and drug use) would enhance our understanding of ADHD risk factors. Critically, examining whether the association between prenatal tobacco exposure and ADHD risk varies across ADHD subtypes is essential for a more nuanced understanding of the neurodevelopmental impact and could inform targeted interventions. Finally, further investigation into the underlying epigenetic mechanisms, such as DNA methylation alterations, is warranted. This could identify potential biomarkers and therapeutic targets for ADHD prevention and treatment.
Conclusion
This systematic review and meta-analysis demonstrate a significant association between maternal tobacco smoking during pregnancy and increased odds of ADHD in offspring. These findings underscore the importance of smoking cessation programs for pregnant women and broader public health interventions to reduce prenatal tobacco exposure. Future research should prioritize investigating causal mechanisms and potential interactions with other prenatal exposures. Reducing maternal smoking during pregnancy could substantially improve neurodevelopmental outcomes in children.
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