Intergenerational programming of neurodevelopmental disorders - neurodevelopmental disorders (NDD) are highly debilitating for individuals and costly to society

The National Institute of Child Health and Human Development awarded $990,342 to the Regents of the University of Michigan on August 13, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to conduct research on intergenerational programming of neurodevelopmental disorders.

The research constructs a multigenerational cohort of more than 1.4 million grandmaternal-parental-offspring triads using linked nationwide Swedish registries to examine associations between grandmaternal pregnancy characteristics (body mass index, smoking, age, parity, stress, pregnancy-induced disease) and parental pre- and perinatal characteristics (gestational age, birth weight, neonatal disease) with grandoffspring risks of neurodevelopmental disorders including autism spectrum disorder, attention-deficit/hyperactivity disorder, intellectual disability, cerebral palsy, and epilepsy. The study implements causal analytic frameworks and mediation analyses to assess whether grandmaternal pregnancy and parental pre- and perinatal exposures operate on grandoffspring neurodevelopmental disorder risk independent of parental postnatal effects and to evaluate confounding by unmeasured genetic and environmental factors shared within families.

Work is performed at Ann Arbor, Michigan, with performance period through July 31, 2030.

While their etiology is incompletely understood, a growing body of evidence indicates that many potential causes, some of them modifiable, may start operating during the pre- and prenatal periods, at highly sensitive stages of brain development. Non-human animal research further suggests that the etiology of NDD may also concern exposures of distal ancestors whose influence may be transmitted intergenerationally through epigenetic mechanisms. Nevertheless, evidence in humans is almost inexistent. Using linkage of nationwide swedish registries, we propose to construct a whole-country multigenerational cohort of >1.4 million grandmaternal- parental-offspring triads to examine the associations of grandmaternal (both maternal and paternal) pregnancy (body mass index, smoking, age, parity, stress, pregnancy-induced disease) and parental pre- and perinatal characteristics (gestational age, birth weight, neonatal disease) with grandoffspring risks of NDD including autism spectrum disorder, attention-deficit/hyperactivity disorder, intellectual disability, cerebral palsy, and epilepsy. We will implement a causal analytic frame (negative exposure and family controls) to assess the influence of confounding by unmeasured factors (genetic and environmental) shared within families. Using causal mediation analyses, we will determine whether grandmaternal pregnancy and parental pre- and perinatal exposures operate on grandoffspring NDD risk independent of their parental postnatal effects; as this could contribute to differentiate potential mechanisms. This unprecedented study promises to document for the first time the intergenerational role of common exposures on the risk of highly debilitating NDD from a population perspective.