Abstract
While exposure to nicotine during developmental periods can significantly affect brain development, studies examining the association between maternal smoking and autism spectrum disorder (ASD) in offspring have produced conflicting findings, and prior meta-analyses have found no significant association. Our meta-analysis used a novel approach of investigating population-level smoking metrics as moderators. The main meta-analysis, with 22 observational studies comprising 795,632 cases and 1,829,256 control participants, used a random-effects model to find no significant association between maternal smoking during pregnancy and ASD in offspring (pooled odds ratio (OR) = 1.16, 95% CI: 0.97–1.40). However, meta-regression analyses with moderators were significant when we matched pooled ORs with adult male smoking prevalence (z = 2.55, p = 0.01) in each country, using World Health Organization data. Our study shows that using population-level smoking metrics uncovers significant relationships between maternal smoking and ASD risk. Correlational analyses show that male smoking prevalence approximates secondhand smoke exposure. While we cannot exclude the possibility that our findings reflect the role of paternal or postnatal nicotine exposure, as opposed to maternal or in utero nicotine exposure, this study underlines the importance of investigating paternal and secondhand smoking in addition to maternal smoking in ASD.
Highlights
Autism is a neurodevelopmental disorder defined by persistent difficulties in reciprocal social interaction and in verbal and nonverbal communication skills
Three previously published meta-analyses have shown no significant association between maternal smoking and autism spectrum disorder (ASD) in offspring, analyzing 5 or 15 individual studies[29,30,31]
Our main analysis, which included 22 studies and is the first to include an observational study in an Asian population, showed no significant association between maternal smoking during pregnancy and ASD (Fig. 3)
Summary
Autism is a neurodevelopmental disorder defined by persistent difficulties in reciprocal social interaction and in verbal and nonverbal communication skills. Rosen et al.[30] included 15 studies and found a summary OR of 1.02 (95% CI: 0.93–1.12), while Tang et al.[31] analyzed a partially different set of 15 studies and found a summary OR of 1.02 (95% CI: 0.93–1.13) These prior meta-analyses failed to account for study-level and population-level factors regarding smoke exposure that may moderate the relationship between maternal smoking and ASD risk. The studies do not systematically account for the possible role of indirect, secondhand smoke exposure; most of the observational studies included in these meta-analyses only reported active maternal smoking. This assessment alone may inadequately reflect total in utero nicotine exposure
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