Prenatal Exposure to Lithium and Autism Spectrum Disorder

About This Grant

Project Summary/Abstract: Autism spectrum disorder (ASD) is a growing public health concern, with rising prevalence and substantial economic and societal costs. Epidemiologic evidence links abnormal maternal thyroid function during pregnancy to increased risk of child ASD and other neurodevelopmental disorders. Lithium, widely used as a psychiatric medication for bipolar disorder and depression due to its mood-stabilizing effects, also presents concerns as an environmental exposure during pregnancy. Lithium inhibits thyroidal iodine uptake, is concentrated in the thyroid, and has known neurotoxic effects. Additionally, more than 56% of U.S. groundwater samples exceed the EPA’s health advisory level for lithium, and conventional water treatment processes do not remove it. Findings from prior case-control studies on the relationship between prenatal lithium exposure and ASD risk are limited by retrospective exposure assessment, emphasizing the need for direct measures of lithium exposure during pregnancy. Our central hypothesis is that higher prenatal lithium exposure increases the risk of maternal thyroid dysfunction, which in turn elevates the risk of child ASD. To our knowledge, no prior study has explored a pathway linking prenatal lithium exposure to ASD through thyroid dysfunction as a potential mechanism. To test our hypothesis, we plan to take advantage of two established ASD studies: (1) MARBLES (Markers of Autism Risk in Babies – Learning Early Signs), a prospective cohort of over 550 pregnant women who have a child with ASD and CHARGE (CHildhood Autism Risk from Genetics and Environment), a population-based, case-control study with over 2000 children and families enrolled. In this project, after selecting MARBLES pregnant women who provided urine samples during pregnancy and subsequently delivered a child with a final diagnosis, we will analyze their urine samples for lithium. Then, we will examine whether prenatal exposure to lithium is associated with child ASD. We will also examine the impact of prenatal lithium exposure on thyroid dysfunction. For CHARGE, we will reconstruct prenatal residential lithium exposure for 500 cases and 500 controls by integrating lithium levels of national databases with geocoded residential histories and drinking water source data, applying the same hypothesis tests as MARBLES. To explore the broader impact of exposure mixtures, we will apply state-of-the-art modeling strategies, and mediation analyses will be conducted to evaluate thyroid dysfunction as a potential mediator in the pathway from lithium exposure to ASD. This study is expected to (1) provide robust evidence of a causal pathway linking prenatal lithium exposure, thyroid dysfunction, and ASD etiology; (2) identify critical windows of exposure to lithium that contribute to thyroid dysfunction and/or ASD; and (3) elucidate the impact of exposure mixtures on thyroid dysfunction and ASD risk. By focusing on modifiable environmental factors, this research will inform intervention and prevention strategies to reduce lithium exposure and mitigate ASD risk, offering actionable insights for public health.