Periconceptional Exposures and Child Health in the Third Generation

Abstract

In view of the increasing prevalence of neurodevelopmental disorders, the burdens they inflict on affected patients, family and society, as well as their unclear etiology, identifying their risk factors is of tremendous importance. We need to better determine the etiologic window of intervention and identify high-risk populations who would benefit from public health interventions. Given the early onset of neurodevelopmental disorders, scientists have focused on risk factors in early childhood and in utero, based on the Developmental Origins of Health and Disease hypothesis. However, the third generational effects have rarely been explored, although pregnant women’s exposures to internal and external factors can affect not only their offspring but their grandchildren via the germline. This dissertation comprises three studies that investigated the multigenerational associations of grandmothers’ exposures experienced periconceptionally with their grandchildren’s neurodevelopmental deficits and adverse birth outcomes. Neurodevelopmental disorders are a group of heterogeneous conditions that affect the development of the neurological system and brain, leading to a delay or disturbance in the acquisition of motor, social language and cognitive skills. While some neurodevelopmental disorders are highly heritable, most have complex and multiple contributors, including genetic, biological, psychosocial and environmental factors. Adverse birth outcomes, including preterm birth or low birth weight, have also been proposed as risk factors for pervasive developmental disorders as well as many chronic diseases later in life. While previous studies have focused on the relationship between maternal exposure during pregnancy and health outcomes in the offspring, the third generational effect has been neglected, mainly due to a lack of data on three generations in human, particularly for neurodevelopmental deficits. However, with access to a national, longitudinal healthcare professional’s cohort study data (Nurses’ Health Study II), this research possessed a unique setting to investigate associations in a population-based study across three generations. In Chapters 1 and 2, grandchildren’s risk of attention-deficit/hyperactivity disorder (ADHD), one of the most prevalent neurodevelopmental disorders, was assessed according to grandmothers’ smoking during pregnancy, pre-pregnancy obesity status, and gestational weight gain. In Chapter 3, we revisited a previous study that examined the relationship between grandmaternal use of diethylstilbestrol during pregnancy and risk of preterm birth and low birth weight, by further addressing a more comprehensive list of confounding factors as well as indication bias. Overall, the findings from this research demonstrate that grandmothers’ periconceptional health risk behaviors, unhealthy weight status, and exposure to an endocrine disruptor were associated with their grandchildren’s risk of ADHD or preterm birth/low birth weight, independent of maternal factors.