Elsevier

The Journal of Pediatrics

Volume 172, May 2016, Pages 81-87.e2
The Journal of Pediatrics

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

https://doi.org/10.1016/j.jpeds.2015.12.024Get rights and content

Objective

To examine the relationship between morphine exposure and growth of the cerebellum and cerebrum in very preterm neonates from early in life to term-equivalent age, as well as to examine morphine exposure and brain volumes in relation to neurodevelopmental outcomes at 18 months corrected age (CA).

Study design

A prospective cohort of 136 very preterm neonates (24-32 weeks gestational age) was serially scanned with magnetic resonance imaging near birth and at term-equivalent age for volumetric measurements of the cerebellum and cerebrum. Motor outcomes were assessed with the Peabody Developmental Motor Scales, Second Edition and cognitive outcomes with the Bayley Scales of Infant and Toddler Development, Third Edition at 18 months CA. Generalized least squares models and linear regression models were used to assess relationships between morphine exposure, brain volumes, and neurodevelopmental outcomes.

Results

A 10-fold increase in morphine exposure was associated with a 5.5% decrease in cerebellar volume, after adjustment for multiple clinical confounders and total brain volume (P = .04). When infants exposed to glucocorticoids were excluded, the association of morphine was more pronounced, with an 8.1% decrease in cerebellar volume. Morphine exposure was not associated with cerebral volume (P = .30). Greater morphine exposure also predicted poorer motor (P < .001) and cognitive outcomes (P = .006) at 18 months CA, an association mediated, in part, by slower brain growth.

Conclusions

Morphine exposure in very preterm neonates is independently associated with impaired cerebellar growth in the neonatal period and poorer neurodevelopmental outcomes in early childhood. Alternatives to better manage pain in preterm neonates that optimize brain development and functional outcomes are urgently needed.

Section snippets

Methods

We studied a prospective cohort of 188 infants born very preterm (24-32 weeks gestational age [GA]) admitted to the neonatal intensive care unit at the British Columbia Women's Hospital from April 2006 to September 2010, participating in a study of early brain development. Neonates with adequate quality magnetic resonance imaging (MRI) scans for volumetric analysis and detailed morphine exposure recorded were included in this study (n = 136) (Figure 1; available at www.jpeds.com). Infants

Results

Our cohort of infants was born at a median age of 27.4 weeks postmenstrual age (range 24-32; IQR 25.8-29.8) and had serial imaging at a median age of 32.3 weeks (IQR 30.8-34.0) and at 40.3 weeks (IQR 38.9-42.0). Of the 136 infants, 91 (67%) were exposed to morphine, receiving a median cumulative dose of 1.905 mg/kg. Table I describes the clinical characteristics of our cohort by morphine exposure. Of the 136 infants, 127 (93%) were followed to 18 months CA. Median scores were 96 (IQR 86-98) on

Discussion

Morphine exposure was differentially associated with small cerebellar volumes but not cerebral volumes. Consistent with Steinhorn et al,7 morphine exposure was not related to smaller brain volume; however, higher morphine exposure in very preterm neonates was associated with reduced cerebellar volume at term-equivalent age, even after adjusting for known confounders. This result is consistent with mouse models, suggesting a critical period during development when Purkinje cells of the

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    Funded by Canadian Institutes of Health Research (MOP79262 [to S.M.] and MOP86489 [to R.G.]). J.Z. was supported by the Canadian Child Health Clinician Scientist Program, Child & Family Research Institute (CFRI), Michael Smith Foundation for Health Research (MSFHR), and NeuroDevNet. S.M. is currently the Bloorview Children's Hospital Chair in Pediatric Neuroscience and was supported by a Tier 2 Canada Research Chair in Neonatal Neuroscience and MSFHR Scholar Award. R.G. and R.B. are supported by CFRI (Senior Scientist Awards) and R.G. holds a Eunice Kennedy Shriver Institute of Child Health and Human Development (RO1 HD039783). C.S.'s research program is supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke (R01 NS061957 and R01 NS055064). The authors declare no conflicts of interest.

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