Maternal diagnoses around pregnancy and risk of autism spectrum disorder - A population-based study

BackgroundThere is growing interest in the potential effects of maternal health in pregnancy on the risk for autism spectrum disorder (ASD) in the offspring. Studies to date have examined only a few maternal diagnoses in pregnancy and did not account for the potential effects of co-occurring conditions. This study systematically investigates the associations between maternal diagnoses in pregnancy and the risk of ASD in the offspring, addressing comorbidity and familial confounding. MethodsThe study sample included all children born in Denmark in 1998-2007 (N=653,580) and their mothers. We fitted Cox proportional hazard regression models to estimate the risk of ASD associated with maternal chronic and non-chronic ICD-10 diagnoses. We further examined the evidence for potential familial confounding using discordant sibling and negative control designs. ResultsThe analytic sample included 7,866 ASD cases (1.2%) and 645,714 controls, born to 425,399 mothers. We tested 241 non-chronic, and 90 chronic maternal conditions for an association with ASD. In a multivariable model, adjusting for maternal comorbidities, 15 of the non-chronic and 5 of the chronic diagnoses were significantly associated with ASD after correcting for multiple testing. Pregnancy complications and injuries accounted for a major portion of the non-chronic maternal diagnoses associated with risk of ASD (e.g., diabetes mellitus in pregnancy: HR=1.27, 95%CI: 1.07-1.51; fracture of skull and facial bones: HR=1.61, 95%CI: 1.09-2.38), and maternal psychiatric diagnoses were most strongly associated with ASD among the chronic conditions (e.g., major depressive disorder: HR=1.89, 95%CI: 1.39, 2.56). Results from negative control (timing of diagnosis, before vs. during pregnancy) and sibling analyses provide limited evidence for the role of familial confounding in the observed associations. ConclusionsOur findings highlight the potential relevance of maternal health around pregnancy for offspring long-term neurodevelopmental outcomes and offer insights into the ASD etiology - necessitating further dissection of the mechanisms underlying the observed associations.