Associations between preterm birth and low birth weight in parents and autism spectrum disorder (ASD) risk in their offspring: A population-based multigenerational cohort study in Denmark

Abstract

Background: Fetal exposure risk factors are associated with increased ASD risk. New hypotheses regarding transgenerational risk for ASD have been proposed, but epidemiological evidence is still lacking. We evaluated whether parental preterm birth or low birth weight was associated with ASD risk in offspring.Methods: We conducted a nationwide register-based cohort study that included 230,174 mother-child and 157,926 father-child pairs in Denmark. Logistic regression models were used to estimate Odds Ratios (OR) and 95% confidence intervals (CI) for offspring ASD according to the parental preterm (<37 weeks) and low birth weight (<2500 grams) status, with or without adjustment for grandmaternal sociodemographic factors. Mediation analyses were performed for selected parental and offspring health-related factors.Results: Offspring of mothers or fathers with adverse birth outcomes had about 31-43% higher risk for ASD (maternal preterm birth, OR=1.31, 95% CI= 1.12,1.55; maternal low birth weight, OR=1.35, 95% CI: 1.17,1.57; paternal preterm birth, OR=1.43, 95% CI=1.18, 1.73; paternal low birth weight, OR=1.38, 95% CI= 1.13, 1.70). Parents born very preterm (<32 weeks) marked a nearly 2-fold increase in ASD risk in their children. These associations were slightly attenuated upon adjustment for grandmaternal sociodemographic factors. Mediation analyses suggested a small magnitude of indirect effect of parental social-mental and offspring perinatal risk factors on the child, especially for maternal birth outcome associations.Conclusions: Offspring of parents born with adverse outcomes had an elevated risk for ASD. Transgenerational risk for ASD through maternal and paternal factors should be considered in future research on ASD etiology.