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

J Pediatr. 2016 May:172:81-87.e2. doi: 10.1016/j.jpeds.2015.12.024. Epub 2016 Jan 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Analgesics, Opioid / adverse effects*
  • Cerebellum / abnormalities*
  • Cerebellum / drug effects*
  • Cerebellum / growth & development
  • Cerebrum / drug effects
  • Cerebrum / growth & development*
  • Developmental Disabilities / chemically induced*
  • Female
  • Humans
  • Infant, Newborn
  • Infant, Premature / growth & development
  • Magnetic Resonance Imaging
  • Male
  • Morphine / adverse effects*
  • Nervous System Malformations / chemically induced*
  • Prospective Studies


  • Analgesics, Opioid
  • Morphine

Supplementary concepts

  • Cerebellar Hypoplasia