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Published on: August 25, 2014
Association of Neonatal Midazolam Exposure With Hippocampal Growth and Working Memory Performance in Children Born
Emma G Duerden1, Ting Guo2, Cecil Chau2
1From the Western University (E.G.D.), London; Hospital for Sick Children (T.G.), Toronto, Ontario; University of British Columbia (C.C., A.S., R.E.G., S.P.M.), Vancouver; and The Hospital for Sick Children and University of Toronto (V.C.), Ontario, Canada. eduerden@uwo.ca.
Insights
Neonatal midazolam exposure, a sedative, is linked to reduced hippocampal growth in preterm children, particularly boys. This early exposure may impact long-term memory development through alterations in the subiculum region.
Area of Science:
- Neuroscience
- Developmental Pediatrics
- Pharmacology
Background:
- Early exposure to sedatives and analgesics raises concerns for later learning disorders in children.
- The hippocampus, crucial for learning and memory, may be vulnerable to benzodiazepines like midazolam, especially during neonatal sedation.
Purpose of the Study:
- To investigate the long-term association between neonatal midazolam exposure and school-age hippocampal growth in preterm children.
- To assess higher-order cognitive function in relation to hippocampal volumes in this cohort.
Main Methods:
- Prospective cohort study involving very preterm born children.
- MRI to characterize hippocampal volumes and subfields.
- Neuropsychological testing using Wechsler scales (WISC-V) at 8 years of age.
Main Results:
- Reduced hippocampal volumes at age 8 were associated with neonatal midazolam exposure (p=0.04).
- Boys exposed to higher midazolam doses showed smaller hippocampal volumes (p=0.002).
- Higher midazolam doses correlated with smaller subiculum volumes (p=0.008), which predicted lower working memory scores (p=0.017).
Conclusions:
- Neonatal midazolam exposure has a lasting association with impaired hippocampal growth, most pronounced in boys.
- Alterations in subiculum volume may explain memory deficits in preterm children exposed to midazolam.
Background And Objectives:
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 affected 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 examined. 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 neuropsychological testing. Generalized linear models were used to determine the predictors of 8-year hippocampal volumes. Children were assessed on the Wechsler Abbreviated Scales of Intelligence, Second Edition, and the Wechsler Intelligence Scales for Children, Fifth Edition (WISC-V).
Results:
A total of 140 preterm children who were 8 years of age participated, and 25 (18%) were exposed to midazolam as neonates. Reduced hippocampal volumes at age 8 years were associated with neonatal midazolam exposure (B = -400.2, 95% CI -14.37 to -786.03, p = 0.04), adjusting for neonatal clinical care factors. Boys exposed to higher doses of midazolam as neonates had smaller hippocampal volumes (χ2 = 14.4, p = 0.002) compared with nonexposed 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. Furthermore, 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 seem long-lasting and are most apparent in boys. Alterations in subiculum volumes may underlie hippocampus-dependent memory formation processes in preterm born children exposed to midazolam as neonates.
