Brain Injury and Development in Preterm Infants Exposed to Fentanyl

Abstract

Background Fentanyl is commonly utilized in preterm infants. Relatively little is known regarding the neurodevelopmental outcomes of preterm infants exposed to fentanyl. Objective To investigate the association between cumulative fentanyl dose and brain injury and diameters in a cohort of preterm infants Methods Data on demographics, perinatal course, and neonatal course, including total fentanyl exposure prior to term equivalent age, were retrospectively evaluated for 103 infants born at ≤ 30 weeks gestational age who underwent magnetic resonance imaging at term equivalent age (mean gestational age 26.9 ± 1.8 weeks). Magnetic resonance images were evaluated for brain injury and regional brain diameters. Developmental testing was conducted at term equivalent and 2 years of age. Results Seventy-eight infants (76%) received fentanyl (median cumulative dose 3 μg/kg, interquartile range 1 – 441 μg/kg). Cumulative fentanyl dose in the first week of life correlated with the incidence of cerebellar hemorrhage after correction for covariates (OR 2.1, 95% confidence interval 1.1 – 4.1). Cumulative fentanyl dose before term equivalent age correlated with reductions in transverse cerebellar diameter after correction for covariates including the presence of cerebellar hemorrhage (r = 0.461, p = 0.002). No correlation was detected between cumulative fentanyl dose and development at 2 years of age. Conclusions Higher cumulative fentanyl dose in preterm infants correlated with a higher incidence of cerebellar injury and lower cerebellar diameter at term equivalent age. Our findings must be taken with caution, but emphasize the need for future prospective trials examining the risks and benefits of commonly utilized analgesic agents in preterm infants.

Smaller Cerebellar Growth and Poorer Neurodevelopmental Outcomes in Very Preterm Infants Exposed to Neonatal Morphine

“…Other opiates have also been shown to affect cerebellar growth in infants prenatally exposed to illicit drugs 25 and in preterm infants exposed to fentanyl. 26 We did not find an association with fentanyl exposure, likely because fentanyl was not frequently used in our cohort (n=30).…”

“…However, our findings are consistent with animal models which show a specific effect of morphine on Purkinje cells of the cerebellum 4,5 as well as the association of other opioid exposure with smaller growth of the human cerebellum. 25,26 Some infants in our sample were exposed to large cumulative doses of morphine due to extended exposure (> 60 days), which may not be generalizable to other neonatal intensive care units. Even though we have detailed data of the neonatal course, we did not take into account factors after hospital discharge that could affect motor outcomes and mitigate potential associations of morphine and motor function.…”

Brain growth in the NICU: critical periods of tissue-specific expansion

“…(37) Of note, we have previously reported in the larger cohort reductions in transverse cerebellar diameter at term equivalent age in association with cumulative fentanyl dose. (22) While a large proportion of subjects in the current study received fentanyl (89%), exposure was very brief, with 6 out of the 9 infants receiving less than 2 days of fentanyl. Nonetheless, given the cerebellum’s developmental vulnerability to opioid exposure, (38, 39) and more recent reports demonstrating associations between increased opioid exposure and impaired cerebellar growth, (40) further investigations into these relationships alongside longitudinal neurodevelopmental follow-up are needed to establish the clinical significance of these findings.…”

“…The details of these cohorts have been previously published. (11, 22). Infants whose data included term equivalent and serial scans were selected for inclusion in this study.…”

Manejo da dor neonatal: influência de fatores psicológicos e organizacionais

“…Estudos da área da Neonatologia têm fornecido dados empíricos, especificamente relacionados aos efeitos em longo prazo da experiência dolorosa no início da vida, mostrando uma importante associação entre presença de dor repetitiva sem medidas analgésicas adequadas e anormalidades na maturação cerebral (Brummelte et al, 2012;McPherson et al, 2015). O Recém-Nascido Prematuro (RNPT), em especial aquele com peso de nascimento menor que 1.000 g, está mais vulnerável aos efeitos nefastos da alteração no processamento cerebral em resposta ao estresse da dor, resultando em sensibilidade dolorosa alterada, deficit de aprendizagem e distúrbios neurocomportamentais na infância e adolescência (Grunau, 2013).…”