Maternal Prenatal Smoking and Autism Spectrum Disorder in Offspring

A California Statewide Cohort and Sibling Study

Ondine S. von Ehrenstein; Xin Cui; Qi Yan; Hilary Aralis; Beate Ritz


Am J Epidemiol. 2021;190(5):728-737. 

In This Article

Abstract and Introduction


We examined associations between maternal smoking and autism spectrum disorder (ASD) in children in a statewide population-based cohort and sibling-comparison design using California birth records (n = 2,015,104) with information on maternal smoking, demographic factors, and pregnancy (2007–2010). ASD cases (n = 11,722) were identified through California Department of Developmental Services records with diagnoses based on the Diagnostic and Statistical Manual of Mental Disorders–IV-TR. We estimated odds ratios for ASD with and without intellectual disability in the full cohort using logistic regression and in a sibling comparison using conditional logistic regression. In the full cohort, the adjusted odds ratio for ASD and maternal smoking 3 months before/during pregnancy compared with nonsmoking was 1.15 (95% confidence interval (CI): 1.04, 1.26), and it was similar in cases with (odds ratio = 1.12, 95% CI: 0.84, 1.49) and without intellectual disability (odds ratio = 1.15, 95% CI: 1.04, 1.27). Heavy prenatal smoking (≥20 cigarettes/day in any trimester) was related to an odds ratio of 1.55 (95% CI: 1.21, 1.98). In the sibling comparison, the odds ratio for heavy smoking was similarly elevated but the confidence interval was wide. Our findings are consistent with an increased risk for ASD in offspring of mothers who smoked ≥20 cigarettes/day during pregnancy; associations with lighter smoking were weaker.


Autism spectrum disorder (ASD) is a severe and heterogeneous developmental disorder characterized by atypical socialization, restricted interests, and repetitive behavior. Prenatal maternal smoking has been suspected to be a risk factor for ASD but previous studies have resulted in equivocal findings. Several studies found no associations,[1] while others suggested small to moderate increases in risk for ASD[2–4] related to maternal smoking. A recent meta-analysis reported a pooled odds ratio of 1.02 (95% confidence interval (CI): 0.93, 1.12); however, there was large heterogeneity in study designs, covariate adjustments, classification of exposure, case definitions, and effect estimate sizes.[5] A number of studies reported associations between ASD and prenatal air pollution exposures that contain many combustion-derived toxics also found in cigarette smoke.[6–8] Biological mechanisms relating maternal smoking to ASD include mitochondrial dysfunction, epigenetic changes,[9,10] gene expression,[11] and fetal testosterone concentrations.[12] Additionally, maternal smoking has been related to impaired fetal brain development,[13,14] adverse behavioral outcomes,[15] attention deficit hyperactivity disorder,[16] and neuropsychological function related to inhibitory control.[17]

Research has established adverse impacts of maternal smoking on fetal brain development, including impairments in cognitive function.[18] Several biological mechanisms that are thought to affect brain function and morphology,[13,19] including inflammatory and epigenetic mechanisms,[20,21] might also be involved in the pathology of ASD.[22] However, previous studies have not considered whether ASD phenotypes with intellectual disability (which is considered a marker of severity of impairment in ASD) are differentially affected or particularly susceptible to maternal prenatal smoking. There is ongoing debate as to whether associations between maternal smoking and child neurobehavioral outcomes might be confounded by shared familial and genetic factors. Women who smoke in pregnancy might be affected by neuropsychological conditions affecting smoking behavior and might carry genetic traits potentially associated with neuropsychiatric outcomes in offspring, including autism.[23–27] Therefore, to examine associations between maternal smoking in pregnancy and child's diagnosis of ASD, we conducted a California-statewide population-based cohort study of all births, and we embedded a sibling comparison aiming to assess the role of shared familial confounding factors. We consider comorbid intellectual disability diagnosis, which is a marker of ASD severity and developmental impairment.