Association of Neonatal Midazolam Exposure With Hippocampal Growth and Working Memory Performance in Children Born Preterm.

Early exposure to analgesics and sedatives is a key concern for later learning disorders in children. The hippocampus, a key region for learning and memory, may be selectively impacted by exposure to benzodiazepines that are commonly used for sedation, particularly in the neonatal period. In this prospective cohort study, the long-term association of neonatal midazolam exposure, a widely used benzodiazepine in neonatal intensive care, with school-age hippocampal growth was assessed. Higher-order cognitive function in preterm-born children was assessed in relation to hippocampal volumes. METHODS;: Very preterm-born children underwent MRI to characterize the hippocampus and its subfields and neuro- psychological testing. Generalized linear models were used to determine predictors of 8-year hippocampal volumes. Children were assessed on the Wechsler Abbreviated Scales of Intelligence, 2nd edition (WASI-II), and the Wechsler Intelligence Scales for Children, 5th edition (WISC-V). RESULTS;: One hundred and forty preterm children, who were 8 years of age participated, and 25 (18%) were exposed to midazolam as neonates. Reduced hippocampal volumes at 8 years of age were associated with neonatal midazolam exposure (B=-400.2, 95% Confidence Intervals[CI] -14.37- -786.03, p=0.04), adjusting for neonatal clinical care factors. Boys exposed to higher doses of midazolam as neonates had smaller hippocampal volumes (X2=14.4, p=0.002) compared to non-exposed boys and girls (both, p<0.03). Analysis of the hippocampal subfields in relation to neonatal midazolam dose revealed that higher doses were associated with smaller volumes of the subiculum (p=0.008), a hippocampal-cortical relay region implicated in memory processes. Further, smaller school-age subiculum volumes predicted significantly lower working memory scores on the WISC-V (B=0.04, 95%CI 0.01-0.07, p=0.017). DISCUSSION;: Early midazolam exposure and the association with impaired hippocampal growth appears long-lasting and is most apparent in boys. Alterations in subiculum volumes may underlie hippocampus-dependent memory formation processes in preterm born children exposed to midazolam as neonates.