Early life pain exposure alters brain development in preterm infants, particularly female infants, according to a new study. 

The observational cohort study collected and analyzed data from 150 infants born at less than 32 weeks’ gestation. Its findings demonstrated that early life exposure to pain affects brain development in very preterm infants. Additionally, the investigators found sex-specific associations between pain exposure and brain development, with female infants experiencing a greater impact on brain connectivity. 

photo of Selvanathan Thiviya
Thiviya Selvanathan, MD, PhD

“Painful exposures are part of lifesaving care for these babies in the neonatal intensive care unit [NICU]. Our work emphasizes that you need to discover new ways to treat pain in preterm babies that promote brain development,” study author Thiviya Selvanathan, MD, PhD, a pediatric neurologist at BC Children’s Hospital and assistant professor of pediatrics at the University of British Columbia in Vancouver, told Medscape Medical News

The study was published March 15 in JAMA Network Open.

Sex-Specific Difference

With novel imaging technology, researchers can look at the brain in a new way, said Selvanathan. Specifically, “we have the tools to now look at the brain connectome,” which maps how connections in the brain are formed, she said. “Instead of looking at individual brain regions, we can now look at how they interact and work together.” 

The study collected MRI data from 80 male and 70 female infants treated at two NICUs in Toronto between 2015 and 2019. All infants were delivered before term, with a median gestational age at birth of 27.1 weeks. Pain was quantified as the total number of invasive procedures in the initial weeks after birth. 

In the full cohort, the investigators found that greater early life pain was associated with decreased regional connectivity in the neonatal brain, which in turn was associated with worsened neurodevelopmental outcomes at 18 months. The brain’s ability to perform both specialized processing and integrating information from various brain regions was hindered. 

When the researchers stratified the results by sex, they found that greater pain exposure was associated with slower maturation of structural connectivity among female infants only. The finding suggests that these infants may be more vulnerable to the effects of early life pain. However, Selvanathan noted that more research is needed to understand why this sex-specific difference may exist. 

Treating Pain

Families often ask Selvanathan how to support the brain development of their children. “The way we care for babies in the NICU matters for brain development. We need to focus our efforts on minimizing and adequately treating pain,” she said. For example, researchers and clinicians may need to think about pain differently in male and female infants. 

Pain management in preterm infants varies considerably. One way the findings could affect care in the NICU is by encouraging the development and revision of pain monitoring and management protocols, said Selvanathan. The findings also highlight the need for further clinical trials that consider sex-specific effects to better understand methods for treating pain in preterm infants, she added. 

Because the research was an observational cohort study, the investigators cannot draw conclusions about causation. Although the investigators accounted for the severity of illness, it is also possible that the results may reflect the fact that infants who are sicker tend to be exposed to more painful, invasive procedures. Previous animal studies, meanwhile, have independently shown that early life exposure to pain affects brain development.

Understanding Brain Development 

Commenting on the study for Medscape Medical News, Rebecca Pillai Riddell, PhD, professor of psychology at York University in Toronto, said the research provides an important step toward improving our understanding of early brain development. Owing to its large sample size, the study was also able to contribute information on the implications of biological sex effects, she added. 

photo of Rebecca Pillai Riddell
Rebecca Pillai Riddell, PhD

“The brain develops the most during this fetal and early infant stage. Instead of being in a protected uterine environment, now [infants are] basically in a traumatic, painful environment,” said Pillai Riddell, noting the importance of this area of research. 

It’s particularly important to understand preterm development as the age of viability decreases, according to Pillai Riddell. Last year, for example, physicians at Mount Sinai Hospital in Toronto (one of the study locations) successfully delivered a pair of twins at a record 22 weeks’ gestation. In the future, more infants may be delivered at this very early gestational age. 

The study was supported by the Canadian Institutes of Health Research, the CP Alliance, Ontario Brain Institute, and Brain Canada. Selvanathan received financial support from the Canadian Institutes of Health Research Canada Graduate Scholarships–Master’s and Doctoral Awards, Ontario Ministry of Health–University of Toronto Clinician Investigator Program, and SickKids Research Institute Clinician Scientist Training Program. Pillai Riddell reported no relevant financial relationships.

Gwendolyn Rak is a health reporter for Medscape based in Brooklyn, New York.

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