Prenatal and Perinatal Risk Factors Associated with Autism Spectrum Disorder: A National Cohort Study

Background Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a multifactorial etiology involving both genetic and environmental factors. While genetic risks are well-characterized, the contribution of specific prenatal and perinatal environmental exposures remains less understood. This study aimed to comprehensively investigate pregnancy-related and birth complications associated with ASD in a large, population-based national cohort. Methods We conducted a retrospective cohort study of all singleton pregnancies delivered in Slovenia between 2005 and 2017 (N = 302,476). We identified 117 children with a confirmed clinical diagnosis of ASD and compared them to the remaining 302,322 pregnancies. Data were obtained from the National Perinatal Information System. We analyzed maternal demographics, medication exposures, obstetric complications, and neonatal outcomes using logistic regression to calculate odds ratios (OR) with 95% confidence intervals (CI). Results ASD cases showed a profound male predominance (83.7% vs. 51.4%; OR 4.88, 95% CI: 2.98–7.97). Early preterm birth (< 31 weeks) was significantly more frequent in the ASD group (4.2% vs. 1.4%; OR 3.14, 95% CI: 1.28–7.70). Postpartum hemorrhage risk was nearly tripled in mothers of children with ASD (6.0% vs. 2.3%; OR 2.70, 95% CI: 1.26–5.81). Neonatal respiratory morbidity was strongly associated with ASD, including Respiratory Distress Syndrome (RDS) (OR 3.42, 95% CI: 1.67–7.02), transient tachypnea of the newborn (OR 3.90, 95% CI: 1.44–10.57), and surfactant administration (OR 6.55, 95% CI: 2.08–20.65). Antenatal dexamethasone exposure was also elevated (OR 3.67), likely reflecting confounding by indication for threatened preterm labor. Conclusions In this national cohort, male sex, extreme prematurity, placental hemorrhage, and neonatal respiratory complications were robust risk factors for ASD. These findings implicate placental dysfunction and perinatal hypoxia-ischemia as key mechanistic pathways in neurodevelopmental vulnerability. While observational data cannot prove causality, the strong associations with markers of hypoxia suggest that optimizing perinatal respiratory management and placental health may be relevant for ASD prevention. Trial registration: 0120–201/2016-2 KME 78/03/16; 3 February 2021