AbstractBackground and aimsSeveral 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.MethodsWe 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.ResultsWe 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.ConclusionsThere 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.