Tag Archive for: premature infants

baby in the NICU

Painful NICU procedures change neurological development in preterm babies

baby in the NICU

Premature infants exposed to pain while in the Neonatal Intensive Care Unit (NICU) are at greater risk for motor delays, language deficits and autism, even in the absence of structural brain injuries, according to findings from the new Center for Prenatal, Neonatal & Maternal Health Research at Children’s National Hospital.

Premature infants exposed to pain while in the Neonatal Intensive Care Unit (NICU) are at greater risk for motor delays, language deficits and autism, even in the absence of structural brain injuries, according to findings from the new Center for Prenatal, Neonatal & Maternal Health Research at Children’s National Hospital.

The research sheds light on the potential outcomes of routine medical interventions – such as heel pricks, venipunctures and IV placements – and correlates these skin breaks to changes in neurological connectivity in the preterm infants’ brains. Published in BMC Medicine, the work provides valuable insights about the far-reaching impact of early medical care.

“We know that premature babies are often exposed to repeated medical interventions, light, sound and other stimuli that they would not experience in utero, and we wanted to better understand the long-term effect,” said Kevin Cook, Ph.D., research faculty at the new center and an expert in fetal and neonatal neurology. “Through this study, we can see that early and repeated exposure to pain appears to alter brain development and put children at risk for poor neurodevelopmental outcomes.”

The big picture

Globally, nearly 1 in 10 babies is born preterm, and the Children’s National team was particularly interested in the experience of those born “very” and “extremely” preterm, which is considered any delivery earlier than 32 and 28 weeks of gestation, respectively. While rates of prematurity have been relatively stable, survival rates of these babies have increased remarkably in recent decades, thanks to improved interventions and therapies for preterm infants. Yet neurodevelopmental challenges among these children persist, with noteworthy risks of autism and other neurological deficits.

At Children’s National, researchers are working to understand the mechanism behind those challenges. Given that the late second trimester and the third trimester are critical periods for brain development, the team wanted to study the effects of exposing babies to the world outside the womb early.

The fine print

Dr. Cook and his colleagues collected resting-state functional MRI (fMRI) scans from 148 infants born at least four weeks prematurely, along with 99 infants born full term. The fMRI scans, uniquely suited for studying the resting state of the brain in non-responsive infants, revealed significant hyperconnectivity within the cerebellum, which coordinates muscle activity, and the limbic and paralimbic regions, which govern emotions, motivation and cognitive functions.

Notably, the hyperconnectivity correlated with the number of skin break procedures, including heel pricks, venipunctures and IV placements. When the children returned for developmental evaluations at 18 months, the skin breaks were strongly associated with an increased risk of autism and lower motor and language scores. The toddlers identified at risk for autism had an average of 118 skin breaks, which is significantly more than the average of 65 skin breaks in those who were not at risk.

What’s ahead

Catherine Limperopoulos, Ph.D., director of the Center for Prenatal, Neonatal & Maternal Health Research, said the findings have important implications for understanding how painful NICU procedures can impact long-term outcomes and how physicians conceptualize the risks of care given to preterm babies. She and her team at the center recommend further research into managing pain in premature babies, especially given the limits of current options and the known risk of opioids.

“With this foundational study, we should consider ways to improve pain management for preterm infants and methods to better weigh the interventions used on these incredibly vulnerable patients,” Dr. Limperopoulos said. “Saving their lives is certainly the priority, and the quality of that life should also be forefront of our minds.”

the cerebral blood flow (CBF) maps, corresponding anatomical image aligned to the CBF map, and the regions of interest examined

Tracking preemies’ blood flow to monitor brain maturation

Blood is the conduit through which our cells receive much of what they need to grow and thrive. The nutrients and oxygen that cells require are transported by this liquid messenger. Getting adequate blood flow is especially important during the rapid growth of gestation and early childhood – particularly for the brain, the weight of which roughly triples during the last 13 weeks of a typical pregnancy. Any disruption to blood flow during this time could dramatically affect the development of this critical organ.

Now, a new study by Children’s National Health System researchers finds that blood flow to key regions of very premature infants’ brains is altered, providing an early warning sign of disturbed brain maturation well before such injury is visible on conventional imaging. The prospective, observational study was published online Dec. 4, 2017 by The Journal of Pediatrics.

“During the third trimester of pregnancy, the fetal brain undergoes an unprecedented growth spurt. To power that growth, cerebral blood flow increases and delivers the extra oxygen and nutrients needed to nurture normal brain development,” says Catherine Limperopoulos, Ph.D., director of the Developing Brain Research Laboratory at Children’s National and senior author of the study. “In full-term pregnancies, these critical brain structures mature inside the protective womb where the fetus can hear the mother and her heartbeat, which stimulates additional brain maturation. For infants born preterm, however, this essential maturation process happens in settings often stripped of such stimuli.”

The challenge: How to capture what goes right or wrong in the developing brains of these very fragile newborns? The researchers relied on arterial spin labeling (ASL) magnetic resonance (MR) imaging, a noninvasive technique that labels the water portion of blood to map how blood flows through infants’ brains in order to describe which regions do or do not receive adequate blood supply. The imaging work can be done without a contrast agent since water from arterial blood itself illuminates the path traveled by cerebral blood.

“In our study, very preterm infants had greater absolute cortical cerebral blood flow compared with full-term infants. Within regions, however, the insula (a region critical to experiencing emotion), anterior cingulate cortex (a region involved in cognitive processes) and auditory cortex (a region involved in processing sound) for preterm infants received a significantly decreased volume of blood, compared with full-term infants. For preterm infants, parenchymal brain injury and the need for cardiac vasopressor support both were correlated with decreased regional CBF,” Limperopoulos adds.

The team studied 98 preterm infants who were born June 2012 to December 2015, were younger than 32 gestational weeks at birth and who weighed less than 1,500 grams. They matched those preemies by gestational age with 104 infants who had been carried to term. The brain MRIs were performed as the infants slept.

Blood flows where it is needed most with areas of the brain that are used more heavily commandeering more oxygen and nutrients. Thus, during brain development, CBF is a good indicator of functional brain maturation since brain areas that are the most metabolically active need more blood.

the cerebral blood flow (CBF) maps, corresponding anatomical image aligned to the CBF map, and the regions of interest examined

This figure represents the cerebral blood flow (CBF) maps, corresponding anatomical image aligned to the CBF map, and the regions of interest examined. The scale indicates the quantitative value of the CBF map and is expressed in mL/100g/min. The data are from a preterm infant scanned at term age without evidence of brain injury. The insula (see black arrows in panel ‘D’) may be particularly vulnerable to the added stresses of the preterm infant’s life outside the womb.
Credit: M. Bouyssi-Kobar, et al., The Journal of Pediatrics.

“The ongoing maturation of the newborn’s brain can be seen in the distribution pattern of cerebral blood flow, with the greatest volume of blood traveling to the brainstem and deep grey matter,” says Marine Bouyssi-Kobar, M.S., the study’s lead author. “Because of the sharp resolution provided by ASL-MR images, our study finds that in addition to the brainstem and deep grey matter, the insula and the areas of the brain responsible for sensory and motor functions are also among the most oxygenated regions. This underscores the critical importance of these brain regions in early brain development. In preterm infants, the insula may be particularly vulnerable to the added stresses of life outside the womb.”

Of note, compromised regional brain structures in adults are implicated in multiple neurodevelopmental disorders. “Altered development of the insula and anterior cingulate cortex in newborns may represent early warning signs of preterm infants at greater risk for long-term neurodevelopmental impairments,” Limperopoulos says.

Research reported in this post was supported by the Canadian Institutes of Health Research, MOP-81116; the SickKids Foundation, XG 06-069; and the National Institutes of Health under award number R01 HL116585-01.