Risk of Brain Disorder Rare in Healthy Newborns with Jaundice

UCSF-Kaiser Permanente Study Shows High Bilirubin Alone Rarely Causes Type of Cerebral Palsy

By Suzanne Leigh

A study tracking more than 100,000 infants has shown that newborns with jaundice that are otherwise healthy are highly unlikely to develop a severe and potentially deadly form of cerebral palsy.

Researchers at UCSF Benioff Children’s Hospital San Francisco and the Kaiser Permanente Northern California Division of Research sought to examine the correlation between elevated levels of the liver-produced pigment bilirubin, which causes the yellowing of the skin and eyes associated with jaundice, and cerebral palsy — a range of disorders that impairs control of movement. The team was especially interested in kernicterus, a rare and life-threatening type of cerebral palsy triggered by escalating bilirubin that injures the brain.

Jaundice occurs in most newborns because the immature liver is unable to break down the pigment fast enough. Treatment is not usually required, but in some cases babies undergo phototherapy, in which they are exposed to special lights that change bilirubin into a compound that can be excreted.

In cases when very high bilirubin fails to drop, an infant may have an exchange transfusion, which is the replacement of blood with donor blood.

The study, which evaluated the health records of two groups of babies selected from 525,409 births, was led by Yvonne W. Wu, MD, MPH, professor of clinical neurology and pediatrics at UCSF Benioff Children’s Hospital San Francisco. The babies had been born at 15 hospitals within the Kaiser Permanente Northern California region from 1995 through 2011. One group comprised 1,833 newborns with levels of bilirubin above those at which the American Academy of Pediatrics (AAP) recommends exchange transfusions. The second group was made up of 104,716 randomly sampled newborns, born at least 35 weeks’ gestation with lower levels of the pigment. The two groups were followed for an average of seven and six years respectively.

The researchers, whose work was published on January 5 in the journal JAMA Pediatrics, confirmed three cases of kernicterus based on the brain MRIs of children with cerebral palsy. All three cases had occurred in newborns with the highest levels of bilirubin. But further study revealed that each child had two or more risk factors for brain damage.

 “We found that cerebral palsy consistent with kernicterus did not occur in a single infant with high bilirubin without the presence of additional risk factors for neurotoxicity, such as prematurity, sepsis and the hereditary blood disorder G6PD deficiency. This was the case even in infants with very high bilirubin,” said second author Michael W. Kuzniewicz, MD, MPH, assistant professor of neonatology in the department of pediatrics at UCSF Benioff Children’s Hospital San Francisco, and head of the perinatal research unit of the division of research at Kaiser Permanente Northern California.

In 2004, the AAP published a guideline for treating infants whose bilirubin remained high despite phototherapy. It recommended exchange transfusions based on the level of bilirubin, the age of the infant and other risk factors for brain damage.

“Our study was the first to evaluate how well the exchange transfusion guidelines predicted risk of cerebral palsy and kernicterus in babies with jaundice,” said principal investigator Thomas B. Newman, MD, MPH, of the departments of epidemiology and pediatrics at UCSF Benioff Children’s Hospital San Francisco. "It was reassuring that brain injury due to high bilirubin was rare and that only those infants whose levels were well above exchange transfusion guidelines developed kernicterus.”

An exchange transfusion is an invasive procedure that entails risks to the baby, such as blood clot formation, blood pressure instability, bleeding and changes in blood chemistry, said Wu. “Based on our study, the current guidelines for when to perform exchange transfusions have been quite successful in preventing kernicterus. However, our study also raises the question whether the threshold for exchange transfusion could be higher for infants with high bilirubin levels who are otherwise healthy and who have no other risk factors for brain injury,” she said.  

Co-authors of the study are Andrea C. Wickremasinghe, MD, and Charles E. McCulloch, PhD, of the department of epidemiology and biostatistics at UCSF; and Eileen M. Walsh, RN, MPH, and Soora Wi, MPH, of the Kaiser Permanente Northern California Division of Research.

Funding was provided by a grant from the Agency for Healthcare Research and Quality.

UCSF Benioff Children’s Hospital San Francisco creates an environment where children and their families find compassionate care at the forefront 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 2,000 babies born in the hospital.

The Kaiser Permanente Division of Research conducts, publishes and disseminates epidemiologic and health services research to improve the health and medical care of Kaiser Permanente members and the society at large. It seeks to understand the determinants of illness and well-being, and to improve the quality and cost-effectiveness of health care. Currently, DOR’s 500-plus staff is working on more than 250 epidemiological and health services research projects. For more information, visit the website or follow @KPDOR.