Several observational studies have linked antiepileptic (AED) use during pregnancy to offspring birth defects (BDs) and neurodevelopmental disorders (NDDs), including attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Research in humans and animals suggest the associations might be causal, as there is evidence that AEDs cross the human placenta and animal models show aberrant brain development and behavior following exposure. However, important non-causal explanations for associations need to be ruled out before we can conclude that the association in humans is causal. Specifically, maternal indications for AED use (e.g., epilepsy), genetic factors (e.g., common to BDs, NDDs, and seizures), other environmental factors (e.g., socioeconomic resources), or a combination of these factors may explain the increased risk for BDs and NDDs in offspring after exposure to AED use. Understanding whether associations are causal is important for doctors and patients weighing the potential risks and benefits of AED use during pregnancy. Specifically, although AED exposure may harm the fetus, AED use is the primary treatment for epilepsy, and seizures during pregnancy put fetus and mother at risk. The objective of this proposal is to test the hypothesis that prenatal exposure to AEDs causes these outcomes. I will accomplish the objective of this proposal through the analysis of a large, national dataset from Sweden and pursuing two aims: (1) estimate the risk of BDs following AED use during pregnancy, and (2) estimate the risk of NDDs following AED use during pregnancy independent of confounding.
In aim 1, I will leverage the largest sample to date to examine associations between AEDs and offspring BDs. I will do this by comparing exposed and unexposed offspring of women with epilepsy, while adjusting for many measured covariates that previous research has not accounted for.
In aim 2, I will use marginal models (e.g., propensity score matching) and several comparison groups to help rule out alternative explanations for the associations. This proposal is significant because it will inform basic research investigating mechanisms for BDs and NDDs and best-practice guidelines for treatment during pregnancy. I am uniquely equipped to answer the question in this proposal because I will analyze the largest study to date (n = ~2.1 million), have access to combined Swedish registers with predictors spanning multiple domains and levels of analysis, and will use multiple advanced designs to test causal inferences. This proposal also weaves together my previous work in which I have investigated pre- and perinatal risk factors for NDDs and used pharmaco-epidemiologic approaches to investigate the risks for seizures. This project will facilitate my long-term training goal to develop a career researching risk factors for NDDs, including extensive training in epidemiologic methods, women?s health and neuropsychopharmacology, the etiology and assessment of NDDs, and professional development (e.g., training in ethics and dissemination).

Public Health Relevance

Clinical guidelines currently recommend that pregnant women discontinue use of antiepileptic drugs when possible, in part on the basis of research documenting associations between prenatal exposure to antiepileptic drugs (AEDs) and numerous birth and neurodevelopmental disorders. However, research has failed to adequately test whether AED exposure actually causes these problems. The proposed research seeks to more rigorously test associations between prenatal exposure to several AEDs and offspring birth defects and neurodevelopmental disorders by analyzing Swedish national datasets using multiple approaches rule out alternative explanations for the associations, which will help physicians and pregnant women better weigh the risks and benefits of takin the medications.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Whittemore, Vicky R
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Indiana University Bloomington
Schools of Arts and Sciences
United States
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