Effect of in utero exposure to antiepileptic drugs on cortical networks and neurophysiological outcomes at 6 years.

Objective: The human brain undergoes an activity-dependent organization during late gestation, making it very sensitive to all effects on the spontaneous neuronal activity. Pregnant mothers with epilepsy are treated with antiepileptic drugs (AEDs) that may reach the fetus and cause altered cortical network activity after birth. However, it is not known whether these functional effects of intrauterine AED exposure persist later in childhood.

Methods: We studied cortical activity networks computed from electroencephalographic recordings during sleep of 25, 6-year-old children with in utero exposure to AEDs and 21 without exposure. The frequency-specific networks were determined for N1 and N2 sleep states, and the study groups were compared for sleep-state-specific changes and dynamic differences between sleep states. Finally, we correlated these difference networks with the children's neurophysiological performance at 6 years.

Results: We found brain-wide changes in the cortical activity networks and their sleep-state dynamics in the children with intrauterine AED exposure. Moreover, the strength of cortical network connectivity was significantly associated with multiple domains of neurocognitive performance, in particular, verbal comprehension, processing speed, and IQ. Our findings together suggest that fetal AED exposure causes very long-lasting changes in the cortical networks with significant links to early school-age cognitive performance.

Significance: AED treatment of pregnant mothers is indicated for maternal health reasons; however, the long-term neurodevelopmental effects on the offspring are poorly understood. Our present study shows that in utero exposure to AEDs causes persisting changes in the cortical activity networks, which can be measured with electroencephalography at 6 years of age. Moreover, these network changes correlate to the child's neurocognitive performance at the same age. These findings together suggest a pathway for how fetal drug exposures may cause persisting and neurocognitively meaningful changes in cortical connectivity patterns.