Opioids and benzodiazepines can impact development in extremely premature infants

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By David Douglas

NEW YORK (Reuters Health) - Extremely premature infants exposed to opioids and benzodiazepines for prolonged periods are more likely to have untoward outcomes than infants without such exposure, according to a secondary analysis of data from a large clinical trial.

"Clinically, these results are important," Dr. Mihai Puia-Dumitrescu told Reuters Health by email, "to help the bedside providers choose standardized non-pharmacologic interventions first, such as proper containment, optimizing sensory experiences, and encouraging maximal parental presence."

"As survival for extremely premature (EP) infants and critically ill neonates is improving," he added, "the overall number of children with disability and neurodevelopmental compromise is not falling as one could expect."

To determine what role opioids and benzodiazepines might have during a critical period of brain growth and development Dr. Puia-Dumitrescu of the University of Washington Medical Center, in Seattle, and colleagues examined data from the Preterm Erythropoietin Neuroprotection (PENUT) Trial conducted between 2013 and 2016.

The researchers studied 936 EP infants with a mean gestational age of 181 days, with neurodevelopmental outcome data available for 692. Thirty-two percent received either opioids (morphine or fentanyl) or benzodiazepines and 51% received both; the remaining 17% received neither, the team reports in JAMA Network Open.

"Infants exposed to both classes of medications for more than 7 days were more likely to have increased in-hospital morbidities, prolonged hospitalizations, and lower Bayley Scales of Infant Development-Third Edition (BSID-III) cognitive, motor and language scores at 2 years corrected age when compared to unexposed infants or infants exposed to opioids or benzodiazepines alone," said Dr. Puia-Dumitrescu.

The estimated adjusted mean length of hospital stay was 1.4 days longer for infants receiving either opioids or benzodiazepines than for unexposed infants. Those exposed to both stayed 34.2 days longer in the hospital.

For those receiving both classes of drugs, the adjusted odds ratio for necrotizing enterocolitis was 9.7 and 7.7 for severe bronchopulmonary dysplasia.

However, short exposure to the medications of interest was not associated with lower BSID III scores and, said Dr. Puia-Dumitrescu, "Limiting pharmacologic interventions for painful procedures and intra/postoperative periods may be the safest options for this vulnerable population. Prolonged exposure to the combination of opioids and benzodiazepines should be avoided."

He added, "There are situations where exposure to opioids and/or benzodiazepines is hard to avoid, so they should be used with caution and for limited periods in these cases."

The known direct and indirect adverse effects of such exposure "must always be weighed against the clear adverse effects of untreated pain and agitation on the developing brain. Clinicians must continue to balance the risks and benefits of prolonged opioid and benzodiazepine exposure with painful procedures in this population. Long term follow-up studies are indicated," Dr. Puia-Dumitrescu said.

The study had no commercial funding and the researchers report no conflicts of interest.

SOURCE: https://bit.ly/3B63Eiw JAMA Network Open, online July 7, 2021.

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