Higher risk of autism spectrum disorder in children whose parents were born preterm or with low birthweight

Jingyuan Xiao, Zeyan Liew and Jiong Li

Autism spectrum disorder (ASD) comprises a heterogeneous group of impaired neurodevelopmental conditions. The aetiology of ASD is complex and largely unclear, with some recent evidence suggesting the possibility of transmission of risk across multiple generations.

Our study, recently published in the International Journal of Epidemiology, evaluated the associations between birth characteristics of parents and the subsequent risk of ASD in their children.

Using population-level data from Denmark, with nearly 40 years of follow-up, we found that children of mothers or fathers who had been born preterm (<37 weeks) or with low birthweight (<2500g) had a 30%–40% higher risk of ASD. The association was particularly marked for parents born very preterm (<32 weeks), with about a twofold increase in their children’s risk of ASD.

We proposed several plausible mechanisms underlying the observed associations using a causal diagram that includes:

• a direct causal path representing epigenetic modifications in the germ cells marked by unfavourable parental birth characteristics that pass down to the next generation
• mediating paths through the overall social status and development of mental and physical health of parents in adulthood
• backdoor pathways due to grandparental factors that affect intrauterine growth of the parent
• other confounding paths from unmeasured genetic and environmental factors tracked across generations.

From medical registers, we were able to extract some information on the lifecourse development, from birth through to reproductive age, of the parents. Our mediation analysis showed that a small magnitude of the estimated total effect of unfavourable birth characteristics of parents on risk of ASD in their children could be explained by parental educational status and mental health in adulthood. Educational attainment was defined as whether the mother or father had completed upper secondary schooling, and mental health as whether either parent had a diagnosis of a mental disorder before the birth of the child.

The fact that individuals with unfavourable birth characteristics who had not had children at the time of the study were left out might of course lead to some selection bias. This potential issue is being investigated by our group, as we hope to bring more insight into bias modelling for future multigenerational studies. We were also unable to assess the effects of other potentially relevant factors, such as maternal body mass index and smoking status, as these data were not available.

Future studies are recommended to investigate genetic and environmental factors that can elucidate the multigenerational disease transmission pathways. In particular, factors influencing parental in utero and lifecourse development before conception should be considered. For instance, birth cohort studies from European countries have suggested that advancing grandparental age at the time of birth of the parent and maternal grandmothers’ smoking might influence the risk of ASD in their grandchildren. Additionally, the Nurses’ Health Study II in the US found an association between exposure to diethylstilbestrol during pregnancy and increased risk of attention-deficit/hyperactivity disorder in offspring, warranting further cross-cohort comparisons of multigenerational exposure effects in a broader context of neurodevelopmental research.

Our findings provide the first evidence that suggests a link between unfavourable birth characteristics in parents and ASD in their children. Although these novel findings should not be used to guide a change of decision for men and women planning parenthood, it is important to understand possible health risks for the offspring and to explore risk mitigation strategies. The findings also suggest that improvements in prenatal care that reduce the occurrence of adverse birth outcomes might be beneficial to the health of subsequent generations.

Read more:

Xiao J, Gao Y, Yu Y, et al. Associations of parental birth characteristics with autism spectrum disorder (ASD) risk in their offspring: a population-based multigenerational cohort study in Denmark. Int J Epidemiol 2021; 7 January. doi: 10.1093/ije/dyaa246.

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Jingyuan Xiao is a PhD student in the Department of Environmental Health Sciences at the Yale School of Public Health. Her research interests centre on early origins of neuropsychiatric disorders.

Zeyan Liew is an assistant professor of epidemiology at the Yale School of Public Health. He is an environmental and perinatal epidemiologist, with a core focus on understanding how exposures that occur during critical and vulnerable periods of development may shape disease risks and influence health outcomes throughout the lifespan.

Jiong Li is an associate professor in the Department of Clinical Epidemiology at Aarhus University, Denmark. He uses data from national registers in Denmark and other Nordic countries to perform population-based epidemiological research. His main research interests are transgenerational health transmissions, particularly the effects of maternal health (disease and medication) during pregnancy on future disease risk in the offspring.