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Ann Pharmacother. 2014 Mar;48(3):335-42. doi: 10.1177/1060028013514026. Epub 2013 Dec 5.

Association of fentanyl with neurodevelopmental outcomes in very-low-birth-weight infants.

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  • 1University of Missouri Health Care, Columbia, MO, USA.



Opioids are commonly used in the neonatal intensive care unit (NICU). Negative neurodevelopmental effects in the short-term setting have been associated with opioids ; however, long-term studies have been limited.


The primary objective was to determine if there is a dose relationship between fentanyl and neurodevelopmental outcomes, as measured by Bayley Scales of Infant and Toddler Development (Bayley-III) composite scores for language, cognition, and motor skills. Secondary objectives included comparison of Bayley-III scores and neurodevelopmental impairment classification based on fentanyl exposure.


A retrospective evaluation of 147 very-low-birth-weight infants with Bayley-III scores obtained at a chronological age of 6 months to 2 years at clinic follow-up was conducted. Univariate and multivariable linear regression analyses were used to determine if there was a dose-related association between fentanyl and neurodevelopmental outcomes. To evaluate secondary outcomes, patients were divided based on cumulative fentanyl dose ("high-dose" versus "low/no-dose").


The univariate analysis found a statistically significant decrease in cognition (P = .034) and motor skills scores (P = .006). No association was found in the multi-variable regression between fentanyl cumulative dose and Bayley-III scores. There was a significant decrease in the motor skills score between the high-dose versus low/no-dose group, 94 ± 20 versus 102 ± 15, respectively (P = .026); however, no statistical differences were noted for language or cognition scores or neurological impairment classification.


When controlling for other variables, the cumulative fentanyl dose did not correlate with neurodevelopmental outcomes. Further evaluation of benefits and risks of opioids in premature infants are needed.


fentanyl; midazolam; neonate; neurodevelopment; opioid; premature

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