Opioids, benzodiazepines impact neurodevelopmental outcomes of extremely preterm infants

Extremely preterm infants with prolonged exposure to opioids and benzodiazepines experienced an increased risk for worse neurodevelopmental outcomes at 2 years’ corrected age, according to results from a cohort study.

Researchers published the findings in JAMA Network Open.

“The long-term neurodevelopmental implications of prolonged therapy with opioids, benzodiazepines and/or a combination of the drugs in [extremely preterm] infants are poorly understood,” the researchers wrote. “Given the lack of data regarding the outcomes of these infants, using data from a large multicenter cohort of [extremely preterm] infants, we performed an analysis to describe the use of these drugs in the [neonatal] ICU and then to characterize their association with 2-year neurodevelopmental outcomes.”

Mihai Puia-Dumitrescu, MD, MPH, a pediatrician at the University of Washington Medical Center and Seattle Children’s Hospital and an assistant professor of neurology and pediatrics at the University of Washington, and colleagues performed a cohort study that was a secondary analysis of data from the Preterm Erythropoietin Neuroprotection (PENUT) Trial, which examined infants born between the gestational ages of 24 weeks, 0 days, and 27 weeks, 6 days. The infants were treated at 19 centers in the United States and the researchers gathered data between December 2013 and September 2016. They analyzed data from March to December of 2020, according to the study .

Exposures included short ( 7 days) and prolonged (> 7 days) treatment with opioids and/or benzodiazepines during the neonatal ICU stay. Cognitive, language and motor development scores served as the main outcome measures and were assessed with the Bayley Scales of Infant Development, Third Edition (BSID-III).

The study included 936 extremely preterm infants (48% female infants; 65% white; mean gestational age, 181 days). Data on neurodevelopmental outcomes was available for 692 of those infants (74%).

More than half of all infants (51%) included in the study (n = 481) received both opioids and benzodiazepines, while 32% were treated with either opioids or benzodiazepines (n = 297) and the remaining 17% of infants (n = 158) received neither drug. Infants who received both opioids and benzodiazepines had adjusted ORs of 9.7 (95% CI, 2.9-32.2) for necrotizing enterocolitis and 1.7 (95% CI, 1.1-2.7) for severe bronchopulmonary dysplasia. They also had a longer estimated adjusted mean difference in length of stay of 34.2 (95% CI, 26.2-42.2) days compared with those infants who received neither drug.

After adjustments for site and propensity scores derived for each exposure category, Puia-Dumitrescu found that infants exposed to opioids and benzodiazepines had reduced BSID-III cognitive, motor and language scores compared with infants with no exposure to these agents (eg, estimated difference in mean scores on cognitive scale: 5.72; 95% CI, –8.88 to –2.57). Prolonged exposure to morphine, fentanyl, midazolam or lorazepam correlated with lower BSID-III scores compared with infants who had no exposure to these agents (median motor score, 85 [IQR, 73-97] vs. 97 [91-107]). The researchers observed no difference in BSID-III scores for infants with brief exposures to both opioids and benzodiazepines compared with those of infants with no exposure.

The researchers acknowledged several limitations of the study, including the fact that the PENUT trial was not designed to “definitively evaluate” the effect of opioids and benzodiazepines on neurodevelopmental outcomes at 2 years. While Puia-Dumitrescu and colleagues adjusted their analysis for known potential confounders, they noted that residual confounding by indication may have still occurred. They also emphasized the “critical” need, as more extremely preterm infants survive, for studies that evaluate the risks and benefits of prolonged exposure to opioids and benzodiazepines balanced with painful procedures.

“The known direct and indirect adverse effects of opioid and benzodiazepine exposure on neuronal injury and neurodevelopment must be weighed against the clear adverse effects of untreated pain and agitation on the developing brain,” the researchers wrote. “Standardized nonpharmacologic interventions, such as proper containment, optimizing sensory experiences and encouraging maximal parental presence with limited pharmacologic interventions for painful procedures and intraoperative and postoperative periods may be the safest options for this population.”