Pain management in premature infants linked to impaired brain development

Morphine, a drug commonly used to manage pain in premature babies, is linked to decreased growth in the cerebellum, resulting in both physical and cognitive impairments, a new study by The Hospital for Sick Children (SickKids) and the University of British Columbia (UBC) has found.

The problem is, the alternatives — using another drug like fentanyl, or not providing any pain relief medication — may pose similar risks to neonatal brain development.

“In our study of 136 babies born very preterm, higher morphine exposure was shown to be associated with impairments in brain growth, particularly in the cerebellum,” says Senior Author Dr. Emily Tam, a paediatric neurologist and associate scientist at SickKids, of research published earlier this month in the Journal of Pediatrics.

During the first weeks of life in a neonatal intensive care unit (NICU), newborns experience multiple procedures a day, including insertion of a tube to help them breathe, as well as injections, heel pricks and tape removal; surgical procedures are also common. Morphine is usually the drug provided to blunt their pain.

It’s during this time when premature babies are most at risk for impairments in brain growth, particularly in the cerebellum. Previously thought to be involved only in motor functions, such as balance and coordination, the cerebellum is now known to play a major role in attention, executive functions, and language. Impairment in the cerebellum is linked to neurodevelopmental conditions including ADHD, autism, learning disabilities and developmental coordination disorder.

In the study, the research team observed babies born at 24 to 32 weeks who were given morphine for sedation and pain control. They found that the greater the morphine exposure among the infants, the smaller the volume of the cerebellum in neuroimaging conducted during the neonatal period, even after considering other risk factors such as number of painful procedures, other brain injuries, and exposure to steroids. A 10-fold increase in morphine predicted a 5.5 per cent decrease in cerebellar volume. Higher levels of morphine exposure also produced poorer results on motor skills and cognitive tests given at 18 months.

The study was conceived by Jill Zwicker, an Assistant Professor in UBC’s Department of Occupational Science and Occupational Therapy, a when she was a postdoctoral fellow with NeuroDevNet, a national Network of Centres of Excellence focused on brain development. Dr. Zwicker noticed that animal models showed an effect of morphine on specific cells of the cerebellum, and wondered if the same would be the case for preterm newborns who receive morphine in NICU.

The latest findings present a dilemma for physicians and parents when caring for infants who are born prematurely and require medical interventions. Previous research by co-author Ruth Grunau, a neonatologist and professor in UBC’s Department of Paediatrics, showed that not alleviating the pain in pre-term newborns carries risks for brain development as well. An alternative drug, fentanyl, has also been shown to affect growth of the cerebellum when given to premature infants.

“Being aware of the association of morphine with smaller cerebellar growth and neurodevelopmental outcomes may alter clinical decision making, but there may be times when morphine may be the best drug of choice for the baby’s care in the NICU,” said Dr. Zwicker.

At this point, there isn’t clear evidence pointing to which methods of pain control are better or worse, added Dr. Tam. “Our finding points to the need for research to optimize pain control in newborns while being mindful to minimize risks for brain development,” she said.

“It is imperative that we find how to treat pain in the neonate in ways that promote optimal brain development,” said co-author Steven Miller, Head of Neurology and the Centre for Brain and Mental Health at SickKids and  Professor of Paediatrics at the University of Toronto.

This study was supported by Canadian Institutes of Health Research, the Canadian Child Health Clinician Scientist Program, Child and Family Research Institute, Michael Smith Foundation for Health Research and NeuroDevNet Network of Centres of Excellence, and SickKids Foundation.