Brains of term infants with heart disease resemble those of preemies

November 07, 2007

The brains of full-term infants with congenital heart disease appear more similar to those of premature newborns than to the brains of normal term infants, a study conducted by researchers at UCSF has found. The study suggests that the mental and physical impairments in children with congenital heart disease may also have their origins in utero in addition to injuries resulting from surgery.

As many as half of all infants born with congenital heart disease who survive heart surgery are known to suffer widespread deficits in cognition, including memory, attention, and higher-order language skills, as well as deficits in fine motor skills. Despite the significance of these impairments, the underlying reasons for them have not been well understood.

The researchers postulate that impaired brain development in term infants with congenital heart disease may be related to abnormal fetal circulation and lower levels of oxygen-saturated blood reaching the brain in utero.

"Congenital heart disease already has affected brain development before birth," said study co-author Patrick McQuillen, MD, a pediatric intensivist and assistant professor of pediatrics at UCSF Children's Hospital. "At a metabolic and a micro-structural level, these infants' brains look at least one month less developed at term, even before they have heart surgery," he said.

The study, conducted between September 2001 and July 2005, compared the brains of 41 term infants with congenital heart disease with those of 16 normal newborns. Published in the November 8 issue of the "New England Journal of Medicine," the study is the first to use a highly sensitive neonatal incubator that was developed at UCSF to compare brain development in the two infant groups. The incubator includes a magnetic resonance imaging (MRI) coil that allows it to create much more detailed images than regular MRI.

The device gives researchers studying the brains of infants born with heart deformities "an exciting new window on infant brain development that is amazingly powerful," according to study lead author Steven Miller, MDCM, MAS, a pediatric neurologist and an assistant professor of pediatrics at the University of British Columbia, Child & Family Research Institute. "This is the first suggestion that there are brain abnormalities that we can measure in both the structure and the function of the brain that you cannot detect with regular MRI," Miller said.

The infants with congenital heart disease who were included in the study primarily suffered from two heart defects: transposition of the great arteries, a condition in which the aorta and pulmonary artery are in the wrong position, and hypoplastic left heart syndrome (HLHS) and its variants, a rare condition in which the left heart chamber is severely underdeveloped.

The left side of a healthy heart receives oxygenated blood from the lungs and then pumps it through the left heart chamber to the rest of the body. In infants with congenital heart disease, the volume of blood and the amount of oxygen and other nutrients flowing to the brain and body are compromised by the abnormal circulation. Transposition of the great arteries and HLHS require cardiac surgery shortly after birth. Complete repair of HLHS may require as many as three corrective surgeries.

"If you look at something basic, like head circumference at birth, these babies' heads tend to be smaller than those of normal term babies," McQuillen said. "So, clearly, the brains are not growing normally. But I think our data shows that not only are they not growing, they're not developing as expected."

The advanced MRI techniques used in the study allowed examination of regional brain micro-structural development and of brain biochemistry and found tiny areas of cell injury that are unusual in full-term infants, McQuillen said. "The most common type of injury that we saw was an injury to the white matter (of the brain) that is very unusual in full-term babies but looked identical to that seen in babies that were born prematurely."

Miller said the injuries appear as multiple small areas, usually one to five millimeters each. This pattern is markedly different from the brain injuries in normal term infants, such as perinatal asphyxia, in which the damage is typically located in the brain's gray matter.

The gray matter is where the bodies of the neurons reside, while the white matter contains axons that are the nerve cell fibers connecting gray matter areas of the brain to one another. The location of the injuries is significant because different types of injuries appear at different stages of development, owing to periods of selective vulnerability of cell types that are developmentally regulated and occur at different points during gestation, according to Miller.

Miller and McQuillen emphasize that the ultimate goal of their research is to understand the point at which brain injury occurs in children with congenital heart disease in order to better understand when and how to intervene to protect the baby's brain.

"Traditionally, the focus has always been on the surgery. It would be great to be able to say that you do the surgery and fix their hearts and their blood oxygen and then brain development catches up. We need to look more broadly at what occurs before surgery. For example, there has been interest in doing heart repairs earlier, even in utero," McQuillen said. "Our data has implications for the timing of surgery."

Miller and McQuillen hope their research will help improve outcomes for children with congenital heart disease, who may be moderately to severely delayed on standard developmental measures and be enrolled in special education programs after they enter school.

"The goal for this study is to look at brain injury and development and really connect it to what's happening with these kids once they reach school age," said McQuillen, who added that the research team is grateful to the families who generously donated their time to participate in the studies during periods of extreme family stress.
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Other study investigators include Shannon Hamrick, MD, of Emory University; and Duan Xu, PhD; David V. Glidden, PhD; Natalie Charlton, BS; Tom Karl, MD; Anthony Azakie, MD; Donna M. Ferriero, MD; A James Barkovich, MD; and Daniel B. Vigneron, PhD, all of UCSF.

Funding for the research was provided by grants from the March of Dimes Foundation, American Heart Association, Larry L. Hillblom Foundation, National Institutes of Health, and National Center for Research Resources, and awards to Miller from the Canadian Institutes of Health Research and the Michael Smith Foundation for Health Research.

One of the nation's top children's hospitals, UCSF Children's Hospital creates an environment where children and their families find compassionate care at the healing edge of scientific discovery, with more than 150 experts in 50 medical specialties serving patients throughout Northern California and beyond. The hospital admits about 5,000 children each year, including 1,600 babies born there.

UCSF is a leading university dedicated to defining health worldwide through advanced biomedical research, graduate level education in the life sciences and health professions, and excellence in patient care.

University of California - San Francisco

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