Pregnant women with
epilepsy (PWWE) require continuous anti-epileptic
drug (AED) treatment to avoid risk to themselves and fetal risks secondary to maternal
seizures, resulting in prolonged AED exposure to the developing embryo and fetus. The objectives of this study were to determine whether high-resolution metabolomics is able to link the metabolite profile of PWWE receiving
lamotrigine or
levetiracetam for seizure control to associated pharmacodynamic (PD)
biological responses. Untargeted metabolomic analysis of plasma obtained from 82 PWWE was completed using high-resolution mass spectrometry.
Biological alterations due to
lamotrigine or
levetiracetam monotherapy were determined by a metabolome-wide association study that compared patients taking either
drug to those who did not require AED treatment. Metabolic changes associated with AED use were then evaluated by testing for
drug-dose associated metabolic variations and pathway enrichment. AED
therapy resulted in
drug-associated metabolic profiles recognizable within maternal plasma. Both the parent compounds and major metabolites were detected, and each AED was correlated with other metabolic features and pathways. Changes in metabolites and metabolic pathways important to maternal health and linked to fetal neurodevelopment were detected for both drugs, including changes in one‑carbon metabolism,
neurotransmitter biosynthesis and
steroid metabolism. In addition, decreased levels of
5-methyltetrahydrofolate and
tetrahydrofolate were detected in women taking
lamotrigine, which is consistent with recent findings showing increased risk of
autism spectrum disorder traits in PWWE using AED. These results represent a first step in development of pharmacometabolomic framework with potential to detect adverse AED-related metabolic changes during pregnancy.