Abstracts

Rationale: Over one million women with epilepsy (WWE) are of childbearing age in the USA. However, predicting which WWE are at higher risk of having children who will suffer adverse cognitive outcomes after fetal exposure to antiseizure medications (ASMs) is challenging. The ABCB1 gene, an adenosine-triphosphate (ATP)-binding cassette sub-family B member 1, plays a critical role in drug transport and disposition, including commonly used ASMs such as levetiracetam and lamotrigine. We hypothesize that genetic variations in the ABCB1 gene may contribute to the interindividual variability in cognitive outcomes observed in the offspring of WWE.


Methods: WWE in this study were part of the prospective Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study. Participants were exposed to either levetiracetam (LEV, n=50) or lamotrigine (LTG, n=63) during pregnancies. The primary outcome was the cognitive performance of their children at 3 yo, assessed using the Verbal Index score (VIS). Additional clinical features assessed included the age, IQ, and education level of the women with epilepsy (WWE), and the maximum observed ASM% of the defined daily dose (DDD) in the 3rd trimester as a measure for ASM dose exposure. A polygenic score for general cognitive ability (c-PGS) was generated based on published data extracted from the UK Biobank and used as a controlling variable. Samples underwent whole exome sequencing on the Illumina HiSeq X platform, and several quality control procedures were implemented. Both common and rare genetic variants of the ABCB1 gene were evaluated. Rare variants were identified with an occurrence of < 1% in European populations in gnomAD v2, and the rare variant burden was defined as the sum of rare variant counts in the ABCB1 gene.


Results: A total of 14 common variants in the ABCB1 gene were evaluated in both LEV and LTG sub-cohorts. Previously reported common variants in the ABCB1 gene (ABCB1 G2677T/A and C3435T), related to LEV maternal plasma concentrations, were not significantly associated with the children's VIS for those exposed to LEV in utero. However, the ABCB1_rs2214102 T >C variant was significantly associated with these children's VIS after Bonferroni correction. In an adjusted multivariable regression analysis including WWE’s age, IQ, educational background, ASM DDD in the 3rd trimester, and c-PGS, the rs2214102 variant status remained an independent predictor of the children’s VIS for those with in utero exposure to LEV (p < 0.001, 95% CI = 5.70 – 20.54), but not for those with in utero exposure to LTG. The ABCB1 rare variant burden was not significantly associated with the children’s VIS in either the LEV or LTG group.


Conclusions: The ABCB1_rs2214102 variant status in WWE is independently associated with neurodevelopmental outcomes of their children at 3 yo who had in utero exposure to levetiracetam. These findings should be replicated again at older age, where neurodevelopmental assessments are more sensitive. Additionally, future studies should include analyses of the children's genes and replication in other cohorts.


Funding: NIH, NINDS, and NICHD #U01-NS038455, Stanford MCHRI, and AES Junior Investigator funding.