Morphine exposure and neurodevelopmental outcome in extremely preterm infants

Abstract

Background: Opioids are the most common drugs used to treat pain and stress in infants receiving mechanical ventilation in the NICU. However, controversial data regarding their effects on long-term neurological outcome have been reported. Methods: We conducted a retrospective study in extremely preterm infants (gestational age (GA) <28 weeks), admitted to the Wilhelmina Children’s Hospital NICU, Utrecht, between 2008 and 2011 with the aim to investigate the association between morphine exposure up to term age and neurodevelopmental outcome at 2 and 5 years. Morphine administration was expressed as cumulative dose (mg/kg) until term-equivalent age (TEA). Neurodevelopmental outcome was assessed at 2 years with the Bayley Scales of Infant and Toddler Development (BSID-III-NL) and at 5 years with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III-NL). Multivariable linear regression analysis was used to assess the association between morphine exposure and outcome. Analyses were adjusted for confounders: GA, patent ductus arteriosus, long-term mechanical ventilation (>7 days), postnatal corticosteroids, number of painful procedures, intraventricular hemorrhage (IVH), white matter injury (WMI), cerebellar hemorrhage and maternal education. Results: 106 extremely preterm infants were included in the study, 64 received morphine (60.4%) at a mean dose 2.03 ± 2.09 mg/kg during their NICU admission. Infants exposed to morphine were more frequently male, had a lower GA and birth weight, longer mechanical ventilation, a higher incidence of IVH, bronchopulmonary dysplasia and WMI at TEA compared to not-exposed infants. Moreover, exposed subjects revealed a significantly worse motor performance at 2 years (p < 0.005), whereas no differences were observed in cognitive and language of Bayley-III-NL and in WPSSI-III-NL score, respectively. At regression analysis morphine exposure did not represent a risk factor for a worse Bayley-III-NL scores at 2 years. Nevertheless, morphine-exposure resulted a risk factor for a lower Fullscale-IQ scores (p = 0.008, B = −9.3, CI −15.6 −3.1) and Performance-IQ scores (p = 0.005, B = −17.5, CI −27.9 −7) at 5 years of age. Conclusion: Morphine exposure in extremely preterm infants is not associated with neurological outcome at 2 years. However, an association is found with poorer Fullscale -IQ and Performance IQ at 5 years. Future, prospective studies with larger sample sizes are needed to confirm these findings.