Long-term effects of routine morphine infusion in mechanically ventilated neonates on children’s functioning: Five-year follow-up of a randomized controlled trial

Abstract

Newborns on ventilatory support often receive morphine to induce analgesia. Animal experiments suggest that this may impair subsequent cognitive and behavioral development. There are sparse human data on long-term effects of neonatal morphine. We aimed to investigate the effects of continuous morphine administered in the neonatal period on the child's functioning. We conducted a follow-up study among 5-year-olds who, as mechanically ventilated neonates, had participated in a placebo-controlled trial on effects of morphine administration on pain and neurologic outcome. They were now tested on intelligence, visual motor integration, behavior, chronic pain, and health-related quality of life. Univariate analyses showed significantly lower overall intelligence quotient (IQ) scores for children who earlier had received morphine, that is, mean 94 (SD 14.5) versus 100 (SD 12.9) for those who received placebo (P = 0.049). Other between-group differences in outcomes were not found. The statistical difference disappeared after correction for treatment condition, open-label morphine consumption over the first 28 days, and a propensity score for clinically relevant co-variables in multiple regression analyses. However, scores on one IQ subtest, "visual analysis," were significantly negatively related to having received morphine and to open-label morphine consumption the first 28 days. The finding of a significant effect of morphine on the "visual analysis" IQ subtest calls for follow-up at a later age focusing on the higher-order neurocognitive functions. Morphine received in the neonatal period has negative effects on the child's cognitive functioning at the age of 5 years which warrants follow-up at a later age.

Prematurity, Opioid Exposure and Neonatal Pain: Do They Affect the Developing Brain?

“…1; for all online suppl. material, see www.karger.com/doi/10.1159/000376566) [15,16]. In the previous follow-up study of this same group of children, IQ, visual motor integration, behavior, and executive functioning were assessed at the age of 8/9 years [16].…”

“…For feasibility reasons we chose to only include children of the original RCT who were recruited in Rotterdam and included in the local follow-up program (n = 44) [16]. Participants were recruited from both arms of the original RCT, as short-term survival and long-term cognition did not essentially differ between the groups [4,15,16]. Reasons for exclusion were as follows: term birth (n = 6), twins or triplets (n = 5), contraindications for an MRI or neuropsychological study (n = 11) such as intellectual disabilities (IQ of 80 or less), and brain abnormalities such as intraventricular hemorrhage (all grades), periventricular leukomalacia and subependymal cysts.…”

“…As previous studies found short- and long-term effects of pain and pain treatment in brain development, cognition and pain sensitivity, our goal was to study all these long-term consequences in a well-defined cohort of children born preterm who participated in an RCT as neonates [4] and whom we have followed up for about 10 years [15,16]. We conducted structural magnetic resonance imaging (MRI) to study brain morphology and assessed neuropsychological functioning and thermal sensitivity.…”

Translational studies identify long-term impact of prior neonatal pain experience

“…routine use for sedation versus titrated dosing for pain), [15] associated hypotension, [76] and confounding illness factors. [193] In addition, time of assessment may influence results as adverse effects on cognitive function (intelligence quotient, IQ scores) were reported 5 years [46] but not at 8-9 years following continuous morphine infusion during NICU. [47] It is not clear if this relates to compensatory recovery, or changes in the sensitivity of testing at different ages.…”

Impact of Common Treatments Given in the Perinatal Period on the Developing Brain

“…Based on the existing evidence, 4 studies have analyzed the relationship between exposure to neonatal analgesic/sedative drugs and outcome at schoolgoing age [92,93,94,95]. None of these trials were designed to assess long-term outcomes.…”