Associations of parental birth characteristics with 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 autism spectrum disorder (ASD) risk. New hypotheses regarding multigenerational risk for ASD have been proposed, but epidemiological evidence is largely lacking. We evaluated whether parental birth characteristics, including preterm birth and low birthweight, were 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 parental preterm (<37 weeks) and low birthweight (<2500 g) status, with or without adjustment for certain grandmaternal sociodemographic factors. Mediation analyses were performed for selected parental and offspring health-related factors.

Results: Offspring of mothers or fathers with adverse birth characteristics had about 31-43% higher risk for ASD (maternal preterm birth, OR = 1.31, 95% CI= 1.12, 1.55; maternal low birthweight, OR = 1.35, 95% CI: 1.17,1.57; paternal preterm birth, OR = 1.43, 95% CI = 1.18, 1.73; paternal low birthweight, 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 that parental social-mental and offspring perinatal factors might explain a small magnitude of the total effect observed, especially for maternal birth characteristic associations.

Conclusions: Offspring of parents born with adverse characteristics had an elevated risk for ASD. Transmission of ASD risk through maternal and paternal factors should be considered in future research on ASD aetiology.

Keywords: Autism spectrum disorder; Denmark; birth cohort.

Figure 1.

The directed acyclic graph (DAG) for the main variables included in the analyses for parental preterm birth or low birthweight and autism spectrum disorder (ASD) risk in children. The directed acyclic graph represents proposed causal relationships between the variables of interest. A crude (unadjusted) model includes all possible pathways between maternal or paternal birth outcomes and autism spectrum disorder (ASD) in children. First, the direct causal effect (indicated by the long dash line) summarizes possible epigenetic reprogramming of the germ cells that leads to multigenerational transmission of ASD risk. Second, several indirect or mediating paths from parental birth characteristics and ASD in children were evaluated (indicated by dash-dot lines). Maternal chronic diseases and pregnancy complications are not expected to mediate paternal exposures (indicated with dotted line). Finally, factors that could influence the intrauterine growth of the parents constitute possible backdoor paths (solid lines). We blocked these backdoor paths by controlling for several measured factors in the adjusted models. Possible influences of other unmeasured genetic and environmental factors shared across generations (denoted with a bracket) could not be directly evaluated in this project and warrant future investigation.