Midazolam Exposure May Impair Hippocampal Growth in Preemies

Higher exposure resulted in poorer cognitive outcomes at 18 months.

Higher exposure to midazolam in very preterm babies is linked to impaired hippocampal growth and lower cognitive scores, according to data published in the Annals of Neurology.

“No one wants to see a baby in pain. That said, some very preterm babies require many painful procedures during their neonatal intensive care,” Emma Duerden, PhD, of the Department of Pediatrics at the Hospital for Sick Children in Toronto, Ontario, told Neurology Advisor. “Midazolam is used in some neonatal intensive care units for sedation of very preterm born babies. However, animal experiments suggest that midazolam adversely impacts the developing hippocampus, a brain region important for memory.”

Dr Duerden and colleagues examined preterm neonates (24-32 weeks gestation) with MRI and DTI scans and conducted developmental assessments at approximately 18 months to understand any link between exposure to sedatives or analgesics and hippocampal growth and neurodevelopment.

Of the 138 preterm neonates, 51% were male with a median gestation of 27.7 weeks and 101 invasive procedures. Those with the most invasive procedures were more likely to be born earlier, intubated longer, have more doses of morphine and midazolam, and have more infections and surgical procedures (P<0.05 for all). Those with more invasive procedures had smaller hippocampal volumes measured early on and at term-equivalent age (P<0.0001, both).    

After adjustment for surgery and mechanical ventilation and controlling for cerebral volume, midazolam was significantly associated with decreased hippocampal growth (β= -1.96, P<0.001). Likewise, the total midazolam dose was associated with an increased MD value (β=0.002, P=0.02).

“… the reduction in hippocampal volumetric growth coupled with an increase in MD values may indicate that midazolam exposure results in lower cellular density and/or alterations in cellular/synaptic structure, neuronal size, and organization in the hippocampus in preterm born neonates,” the authors wrote.

Most of the participants (85%) returned for neurodevelopmental assessment and were found to have median language and cognitive scores in the normal ranges. The researchers found cognitive scores to be associated with hippocampal volume growth (β=-0.31, P=0.003) with a negative association to total midazolam dose (β=-0.27, P=0.03) in linear regression.

“Slower growth of the hippocampus was associated with poorer cognitive outcome at 18 months of age,” Steven Miller, MD, CM, of the Department of Pediatrics at the Hospital for Sick Children in Toronto, told Neurology Advisor. “Our findings suggest the need for caution in the use of midazolam in the very preterm neonate.”

“It is critical that we identify how to treat pain in preterm neonates in ways that enable optimal brain development and cognitive outcomes,” Dr Miller said.


Duerden EG, Guo T, Dodbiba L, et al. Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants. Ann Neurol. 2016; doi:10.1002/ana.24601.