Project Summary
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).