Early-life brain injury affects thousands of newborns every year in Canada, often with serious consequences. UBC researchers are changing how we understand and treat these injuries — and giving new hope to patients and their families.

 

When Coulson McRae was born, his parents knew right away that something was wrong.

“He wasn’t breathing. The medical team rushed him out of the delivery room and they had to work on him for a long time,” his mother, Amanda, remembers.

Ten weeks premature, Coulson was moved into the neonatal intensive care unit (NICU) at B.C. Women’s Hospital in Vancouver, where he stayed for several weeks until his condition stabilized. Neurological tests revealed an injury to his brain.

“I remember the doctor pointing out the lesions on the MRI scan,” says Chad, his father.

There were three of them, deep in the right side of Coulson’s brain.

“They assured us that the injury was relatively minor, but they also gave us a long list of issues that could develop as he got older,” Chad says.

The list included cognitive and language delays, as well as problems with motor control and behaviour.

“It was definitely a scary and uncertain time for us,” Amanda says.

In Canada, 30 per cent of babies born preterm show signs of brain injury. Injuries are also common in those born with congenital heart disease (CHD). They range from minor to life-altering.

As recently as a decade ago, early-life brain injury — that is, an injury which happens before, during or after delivery — was thought to be more or less permanent.

“The consensus was that, beyond the most acute period, the first few hours after an injury, there wasn’t much more that we could do. These injuries were understood to have fixed outcomes,” explains Dr. Steven Miller, Head of the UBC Faculty of Medicine’s Department of Pediatrics.

But thanks to recent advances in brain imaging and neuroscience, that thinking is changing. Research has revealed that, in many cases, the consequences of early-life brain injuries aren’t necessarily permanent.

In this, Dr. Miller sees an opportunity to rethink the way we care for children with perinatal brain injury (PBI) — and vastly improve patients’ chances of meaningful recovery.

From intensive care to ‘the importance of the everyday’

“Most people would be surprised to learn that the single highest-risk time in your life to have a stroke is the day you’re born,” Dr. Miller, who is also chief of Pediatric Medicine at B.C. Children’s Hospital, explains.

Coulson McRae in the neonatal intensive care as an infant, and with his family, age five. Photos courtesy of the McRae family.

Babies born pre-term, like Coulson, and those with CHD are at particular risk because of changes in the way blood flows through their bodies to their brains. As a result, the brain’s blood supply is much more easily disrupted, depriving it of oxygen and important nutrients — the fuel for its development.

“The difference is that these injuries don’t typically cause the level of brain cell loss we see in, for example, adults. While there is localized cell loss, these injuries ‘freeze’ key developmental processes more widely,” he says.

In babies born preterm or with congenital heart disease, the injuries typically happen in the white matter, where they disrupt the development and maturation of the brain’s neural circuits — specialized networks of cells that allow us to perform different tasks, from holding a spoon to understanding language. This causes many of the issues we see, such as motor and language delays.

“The good news is that these developmental processes can be encouraged, making recovery a real possibility for many kids,” Dr. Miller explains.

Thanks to advances in brain imaging and neuroscience, we now know that the effects of early-life brain injuries aren’t necessarily permanent.

He and his colleagues at UBC and the B.C. Children’s Hospital Research Institute (BCCHR) in Vancouver and SickKids in Toronto set out to identify and understand the factors that shape the recovery process, for better and worse — beginning in the NICU.

In a series of landmark studies on neonatal intensive care, they have shown that routine clinical factors such as pain management, infection and nutrition can all have a profound impact.

Dr. Ruth Grunau

“Pain management has been a particular focus, because we discovered that the physiological and hormonal effects of pain can interfere with brain development in preterm infants, and these children are much likelier to need surgery and other painful procedures in the first days and weeks of life while the brain is rapidly maturing,” explains Dr. Ruth Grunau, a UBC professor of neonatology and world-renowned expert in pain in preterm infants.

“Using advanced neuroimaging we have shown, additionally, that pain can disrupt brain connectivity — and the effects are more pronounced in girls than boys,” adds Dr. Thiviya Selvanathan, a UBC assistant professor of neurology and investigator at BCCHR whose research focuses on the newborn brain.

 

 

These and other findings point to the importance of careful pain management. In separate studies, the team found that certain medications used for neonatal pain management and sedation can have their own adverse developmental effects on infants born preterm. The same is true for common neonatal infections.

“By identifying preterm infants and those with CHD who are at risk for brain injury as early as possible, and by carefully managing their critical care, we can promote better brain development from the day they’re born,” Dr. Miller says.

This focus on what he calls ‘the importance of everyday’ amounts to a paradigm shift in neonatal intensive care. Indeed, the research has helped to change how many NICUs across Canada support brain development through everyday interventions such as pain prevention and nutrition.

But, just as the effects of early-life brain injuries continue beyond the NICU, so does the importance of the everyday.

Early-life brain injuries can cause language and motor delays, as well as other cognitive and behavioural issues.

Long-term recovery and the social determinants of health

In one of the first longitudinal studies of its kind, launched in 2006, Dr. Miller, Dr. Grunau and their colleagues have been following multiple cohorts of preterm infants, evaluating them during the first weeks of life, at their due date, and then at intervals throughout childhood.

The results so far are striking. They discovered that by the time participants reached preschool age, the trajectory of their brain development correlated strongly with the socioeconomic status of their birth parents. Children born to a birth parent with higher status showed, on average, normal development despite early life brain injury.

“At four-and-a-half years old, these kids had substantially normal trajectories, comparable to those of children without brain injuries,” Dr. Miller says. “Whereas the participants whose birth parents had lower status tended to experience some of the developmental issues you would expect from the size of their injury.”

And the effects were proportional: the higher the birth parent’s socioeconomic status, the better the outcome.

“This drives home that point that the everyday experiences of these kids, from their earliest days in hospital to their day-to-day family life, have a profound effect on recovery,” says Dr. Selvanathan.

“Our research team is now working to identify and understand what’s happening in these homes that promotes this recovery. And not just in these homes. There are almost certainly other day-to-day exposures and experiences that are highly beneficial outside the home in the lives of these children,” Dr. Miller says. “Our ultimate goal is to inform both day-to-day strategies for families as well as policy interventions for government that will help all patients, regardless of socioeconomic level.”

For children with congenital heart disease, there are even more factors to consider.

Dr. Thalia Field

“Because congenital heart disease is a condition that evolves over time, a child with CHD might go on to develop additional cardiac issues such as heart rhythm or heart function problems, which can potentially further impact brain health as they age,” explains Dr. Thalia Field, a UBC professor of neurology and co-director of research with the Vancouver Stroke Program at Vancouver General Hospital (VGH).

This year, Dr. Field and her team received a major grant from the Heart and Stroke Foundation to investigate how CHD affects brain health across the lifespan, from childhood through adulthood. Part of the work includes following the brain health and development of older children and teenagers with congenital heart disease who were part of Dr. Miller’s studies when they were infants.

 

 

“What’s exciting about our study is that, like Dr. Miller’s, we are working in partnership with patients and their families. They bring lived experience and unique perspectives that will inform the way we do the research and the way we feed those results back to healthcare providers and communities,” she says.

 

Dr. Miller and Dr. Selvanathan outside B.C. Children’s Hospital

A brighter future for patients and their families

Now five, Coulson McRae is a bright kid with energy to burn. He and his parents are enthusiastic research partners in several different studies.

“We just received the results of Coulson’s latest MRI scan and they were very reassuring. The neurologist told us there were no concerns,” Amanda says.

Apart from an ADHD diagnosis, which sometimes makes it hard for him to sit still in class, he’s adapting well to his first year of elementary school.

“The reports we get from the researchers are really useful; they’ve helped us process what’s happening with Coulson’s development. And if, by taking part in these studies, we can provide insights that will help other families, that’s great,” Amanda says.

Such insights may indeed hold the secret to better brain outcomes for children born preterm or with congenital heart disease. Dr. Miller and his team plan to continue to follow their study cohort to age 15 and beyond, tracking their development and mapping the pathway to better recovery, piece by piece.

“With the help of our parent and patient research partners, our collaborators, and the incredible brain imaging tools at our disposal, I’m optimistic that we’ll succeed,” he says.

A version of this story was originally posted in UBC Medicine’s Pathways magazine.