Earlier jaundice treatment decreases brain injury in preterm infants

A study from a National Institutes of Health research network found that an early treatment to prevent severe newborn jaundice in extremely early preterm infants reduced the infants' rate of brain injury, a serious complication of severe jaundice.

The study also found that the smallest, most frail infants in the study were more likely to die than were the larger infants, regardless of whether they received the early or the conventional treatment. Moreover, the study found a trend toward a higher proportion of deaths among the smaller infants in the early treatment group, when compared to the smaller infants receiving the conventional treatment. However, this trend was within the statistical margin of error.

The study, appearing in the Oct. 30 New England Journal of Medicine, was conducted by researchers in the Neonatal Research Network of NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The study's first author was Brenda H. Morris, M.D., a researcher at the University of Texas Medical School at Houston when the study was conducted.

Based on the results, the authors concluded that the early treatment should be considered for the larger infants - those at birth weighing from 751 to 1000 grams (about 1.65 pounds to about 2.2 pounds).

The researchers did not rule out the treatment for the smaller infants - those weighing from 501 to 750 grams (about 1.10 pounds to about 1.65 pounds). However, they said the study findings merited caution before offering the early treatment to this group of infants.

"The study results provide important information for treatment options for extremely low birth weight infants with neonatal jaundice," said NICHD Director Duane Alexander, M.D.

Infants weighing 1000 grams or less, like those in the NIH Neonatal Research Network study, are classified as being of extremely low birth weight. The smallest, most frail category of preterm infants, extremely low birth weight infants are usually born between the 5th and 6th month of pregnancy, far in advance of the 9 months required for a pregnancy to reach term. Compared to infants born later, extremely low birth weight infants are at increased risk for infant death and for profound, life long disability.

Jaundice, or yellowing of the skin, is common in newborns. The condition results from an accumulation of bilirubin, a yellowish substance produced when red blood cells are broken down. Ordinarily, bilirubin is removed from the body by the liver.

For most infants with jaundice, the yellow skin color will fade after a few days and the infant won't suffer any ill effects. In some infants, however, the liver fails to remove bilirubin rapidly enough, and potentially toxic levels accumulate. The condition is known as hyperbilirubinemia. Untreated, hyperbilirubinemia may cause severe brain injury, which could result in cerebral palsy, profound intellectual and developmental disability, blindness, and severe hearing loss.

The first line of treatment for newborn hyperbilirubinemia is phototherapy - exposure to high intensity light. The light penetrates the skin and converts bilirubin to a less toxic substance, which is eliminated through the urine.

For infants born at or near term, clinical practice guidelines exist for the evaluation and treatment of high bilirubin levels. Until the current study, however, little information was available on treating high bilirubin levels in preterm infants.

Previous studies of bilirubin levels in extremely low birth weight infants produced conflicting results. The authors wrote that some studies suggested that bilirubin levels as low as 5 milligrams per deciliter could result in permanent damage to the brain. Other studies suggested that somewhat higher bilirubin levels might not pose any threat to the developing brain, or might even be protective against brain injury.

The 1,974 infants in the study were randomly assigned to one of two groups. Infants in the early, or aggressive, treatment group received phototherapy if their bilirubin levels reached 5 milligrams per deciliter. Infants in the conservative treatment group received phototherapy after their bilirubin levels reached 8 milligrams per deciliter. The infants were evaluated for a range of neurological conditions when they were between 18 and 22 months of age. Classified as "neurodevelopmental impairment" by the researchers, these conditions included blindness, severe hearing loss, moderate or severe cerebral palsy, and a low score on a test of infant cognitive development.

In their statistical analysis of the study results, the researchers combined the death rate and the rate of neurodevelopmental impairment into a single figure, the primary outcome. The primary outcome measured the proportion of infants who had either died or had neurodevelopmental impairment at 18-22 months of age. The two measures were calculated together to account for the fact that the degree of neurodevelopmental impairment at 18 to 22 months would not be known for infants who died before they reached that age. The proportion of infants who had either died or had neurodevelopmental impairment did not differ significantly between the aggressive treatment group (52 percent) and the conservative treatment group (55 percent).

The researchers also calculated a number of secondary outcomes, to determine the study results for various subgroups of infants in the study. The secondary outcomes each encompass a smaller number of cases than does the primary outcome. In general, the larger the number in the sample, the more accurate a statistical calculation will be. Because the secondary outcomes each involve a smaller number of cases than the primary outcome, results from the secondary outcomes may not be as statistically precise or reliable as results from the primary outcome.

The article also presented the death rate and the rate of neurodevelopmental impairment separately. Infants in the aggressive treatment group were less likely to have neurodevelopmental impairment (26 percent) than were infants in the conservative treatment group (30 percent). The difference in death rates between the two groups was not statistically meaningful: 24 percent for those in the aggressive treatment group, and 23 percent in the conservative treatment group.

The researchers also found differences when they calculated rates of neurodevelopmental impairment and death according to the infants' weight. For infants weighing from 751 to 1000 grams, 25 percent in the aggressive treatment group experienced neurodevelopmental impairment, versus 29 percent in the conservative treatment group. For infants in this weight category, the death rate for the aggressive treatment group was 13 percent, not different in statistical terms from the 14 percent rate observed for the conservative treatment group.

For infants weighing 501 to 750 grams, those in the aggressive treatment group were less likely to have the most severe neurodevelopmental impairments, termed profound impairment, at 10 percent, than were infants in the conservative treatment group, who had a 14 percent rate of profound impairment. The death rate and the rate of neurodevelopmental impairment (not profound) for this group fell within the statistical margin of error.

Though not statistically meaningful, the aggressive treatment group showed a trend toward a slightly higher death rate (39 percent) than did the infants in the conservative treatment group (34 percent). Infants in this weight category were less likely to develop a neurodevelopmental impairment if they were in the aggressive treatment group (27 percent) than in the conservative treatment group (32 percent), but this difference also was not statistically meaningful.

The study authors could not account for the trend toward a slightly higher death rate among smaller infants in the aggressive treatment group. They noted that, although bilirubin can be toxic, it is also an antioxidant, and possibly could protect against the oxygen damage that can occur from chemical reactions that take place in the body. They also hypothesized that because the smaller infants had thinner, more translucent skin than did the larger infants, the intense light used to reduce bilirubin levels might have potential negative effects on the infant's health.

The study authors concluded that, based on the study results, infants from 751 to 1,000 grams birth weight should be considered for aggressive treatment of bilirubinemia, as the aggressive treatment did not appear to increase the chances of death, but did appear to reduce the rate of neurodevelopmental impairment. They added that, for smaller infants weighing from 501 to 750 grams at birth, the potential to reduce the chances of neurodevelopmental impairment must be carefully weighed against the possibility of increased risk of death.

When evaluated in combination with other issues affecting an extremely low birth weight infant, the study results may offer guidance for physicians and family members considering treatment options, said Rosemary Higgins, M.D., the NICHD co-author of the study.

"These are extremely frail infants who may have a number of health problems," Dr. Higgins said. "The bilirubin level shouldn't be considered in isolation. It's just one aspect of an infant's overall health status that needs to be carefully evaluated so that the best treatment decisions possible can be made for that individual."

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