UNMC Department of Anesthesiology researchers, Melody Nguyen, Gurudutt Pendyala, PhD, and Kunal Sualy, MD, published a new study in Molecular Psychiatry that raises important questions about chronic midazolam use in premature infants.
Dr. Pendyala said studies indicate that each year, about one in 10 babies in the United States is born prematurely, and many of them spend weeks or months in neonatal intensive care units (NICUs), often requiring sedation to manage pain and stress from medical procedures.
The new study sheds light on how one commonly used sedative, midazolam (also known by the brand name Versed), may have long-term effects on brain development, behavior and physical health when used over extended periods during the neonatal period.
Nguyen said midazolam is commonly used in the NICU for sedation and seizure control, especially in critically ill neonates. While it’s effective for acute symptom management, she said, there is a lack of understanding of how prolonged exposure during sensitive developmental windows may impact long-term brain development, metabolism and behavior.
“Given the rapid and dynamic growth of the neonatal brain, even subtle disruptions during this period can have lasting consequences,” Nguyen said. “Our goal was to systematically examine the potential downstream effects of chronic early-life exposure, using a developmental model that closely mirrors key neurodevelopmental milestones in human infants. Understanding these effects is crucial to balancing immediate clinical needs with long-term neurodevelopmental outcomes.”
Published in Molecular Psychiatry, the study used a preclinical model to mimic how premature infants are exposed to midazolam during critical stages of early brain development. While the drug is widely considered safe in the short term, Dr. Pendyala said they found that chronic exposure during early life can lead to lasting changes, including increased anxiety, reduced social interaction, early signs of depression and physical changes such as obesity in adulthood.
“We give this drug to help premature babies feel calm and reduce their anxiety while they’re undergoing painful but necessary procedures,” said Dr. Pendyala. “But our findings suggest that long-term use may come at a cost to their developing brains.”
Dr. Sualy said the long-term effects are not entirely known, especially after prolonged exposure. “As with any medication, it is important to understand the potential long-term effects of midazolam, and provide this information to medical providers and families of patients, to allow for informed decision-making,” he said.
The team used animal models to track midazolam during early development into adulthood, examining behavior, brain chemistry and physical growth. “Early on, the sedated animals showed slower physical development,” said Dr. Pendyala. “But as they matured, they became heavier than their peers, suggesting changes in appetite regulation or stress-related eating.”
Dr. Pendyala added the study also revealed that these animals had lower levels of dopamine, a chemical associated with feelings of reward and motivation. “This drop in dopamine was linked to signs of increased anxiety, social withdrawal, and depressive-like behaviors, particularly during adolescence, a time of heightened social development.”
Dr. Pendyala said they found increased brain inflammation in adulthood, despite no clear signs of inflammation during the neonatal treatment period. This delayed onset suggests that the drug may have subtle, lasting effects that only emerge later in life.
“This is the first study to follow the effects of chronic midazolam exposure across all stages of development—from infancy to adulthood,” said Dr. Pendyala. “Until now, research was mostly limited to short-term effects or cell culture studies that don’t capture the complexity of brain development.”
The project began as the PhD thesis of graduate student Melody Nguyen and included key contributions from Kunal Sualy, MD, associate professor at the UNMC Department of Anesthesiology.
“What surprised me most was how subtle but persistent some of the long-term effects were,” Nguyen said. “Although early changes in growth factor expression were not statistically significant, we later saw a clear and significant increase in these markers in young adulthood, suggesting a delayed or compensatory response.”
Nguyen said this delayed emergence of molecular changes, especially in the absence of major early structural abnormalities, highlighted how early drug exposure may reprogram developmental pathways in ways that only manifest later in life.
“It was also unexpected to see signs of social anxiety and altered neurotransmitter levels appear transiently during adolescence but not persist into adulthood,” she said. “These findings emphasize that early-life exposures don’t always cause immediate or visible harm but may quietly shape neurodevelopmental trajectories over time.”
Dr. Pendyala emphasized while the findings don’t suggest that midazolam should be abandoned altogether, especially when it’s needed to reduce pain, they do raise important questions about dosage and duration, especially for the most vulnerable patients.
The team is now exploring alternative sedatives, including a drug called dexmedetomidine (Precedex), which may have anti-inflammatory properties and could be safer for long-term use. They’re also planning further studies using single-cell spatial transcriptomics to identify which types of brain cells are most affected and why.
“These babies are incredibly resilient, but they’re also incredibly vulnerable,” said Dr. Pendyala. “As we learn more, our hope is to help improve the long-term outcomes for children who start life in the NICU.”
“It truly takes a team to accomplish a high-quality research project and successfully get it published,” said Dr. Sualy. “We were lucky to have Dr. Pendyala guiding us and providing effective support and education.”