Prenatal maternal stress and risk of neurodevelopmental disorders in the offspring: a systematic review and meta-analysis

Importance: Prenatal stress exposure has been linked to increased risk of autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) in the offspring, although the evidence is inconsistent. Objective: This systematic review and meta-analysis was performed to systematically critically review the existing literature on the association between prenatal stress and the risk of ASD and ADHD. Data sources: Based on a registered protocol, we searched electronic databases PubMed, PsycINFO, Web of Science, Scopus and EMBASE for articles in accordance with a detailed search strategy. Study selection: Two investigators independently searched titles, abstracts and full-text articles. Cohort and case-control studies assessing prenatal exposure to stress and the risk of ASD or ADHD as an outcome measure were included. Study extraction and synthesis: Data extraction and quality assessment were performed independently by two investigators. We performed this study following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). Main Outcomes and Measures: Random-effects meta-analyses were performed to calculate adjusted and unadjusted pooled estimates for prenatal stress and risk of ASD and ADHD, using the generic inverse variance method. Results: Of 1456 studies emerged from the databases, 27 studies in total met the inclusion criteria of the systematic review (15 for ASD, 12 for ADHD). Prenatal stress was significantly associated with an increased risk of both ASD (pooled OR=1.64, [95% CI=1.15 – 2.34]; I2=90%) and ADHD (pooled OR=1.72, [95% CI= 1.27-2.34]; I2=85%). A significant association between prenatal and ASD was observed in the meta-analysis of the cohort but not case-control studies. Significant associations for between prenatal stress and ASD and ADHD were observed in low to moderate quality studies but in high quality studies. Conclusions and relevance: This study suggests that prenatal stress may be associated with an increased risk of ASD and ADHD in the offspring. However, several limitations in the included literature should be noted including significant heterogeneity, potential recall bias and lack of adjustment for key potential confounders. Future research exploring this association should address the limitations in the current literature in order to test whether this association is potentially causal or attributable to methodological limitations.