Maternal medication use in pregnancy and offspring ASD risk: A prescription-wide, target-informed study

Background. Certain prescription drugs used during pregnancy are associated with offspring autism spectrum disorder (ASD). Nonetheless, ASD risk following prenatal exposure to most drugs remains unknown. Furthermore, methodological challenges and ethical concerns hinder the scope for causal inference. Methods. We used a case-cohort study design of a nationally representative sample from Israel to examine the associations between maternal prescription drug use during pregnancy and offspring ASD. To scrutinize these associations, the analyses were (a) adjusted for indication proxy (level 2 Anatomical Therapeutic Chemical (ATC) codes), (b) repeated using shared pharmacological targets as exposures, and (c) inspected further through target-enrichment analysis. Results. The sample included 1,400 individuals with and 94,713 without an ASD diagnosis. Among all drugs prescribed during pregnancy, five were statistically significantly associated with increased offspring ASD risk after adjustment for indication proxy (e.g., hazard ratio [95% confidence interval] cyproterone = 2.71 [1.17–6.25] and prednisolone = 2.10 [1.27–3.49]), and two with decreased risk (ferrous sulfate = 0.82 [0.68, 0.99] and lynestrenol = 0.43 [0.2, 0.93]). Further analysis revealed four pharmacological targets shared by these drugs, which were themselves associated with ASD (e.g., neuronal acetylcholine receptor α4β4 = 1.45 [1.05–1.99] and serotonin 2b receptor = 1.31 [1.04–1.61]). Enrichment analysis suggested the association between ASD and medications affecting cholinergic and serotonergic signaling. Conclusions. Increased ASD risk followed prenatal exposure to five prescription drugs, and decreased risk followed exposure to two. Subsequent analyses suggested no confounding by indication in these associations, but further studies are warranted.