Earlier Jaundice Treatment Decreases Brain Injury in Preemies

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."

The NICHD sponsors research on development, before and after birth;
maternal, child, and family health; reproductive biology and population
issues; and medical rehabilitation. For more information, visit the
Institute's Web site at <http://www.nichd.nih.gov/>.

The National Institutes of Health (NIH) -- The Nation's Medical Research
Agency -- includes 27 Institutes and Centers and is a component of the U.S.
Department of Health and Human Services. It is the primary federal agency
for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and its programs,
visit <www.nih.gov>.

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This NIH News Release is available online at: <http://www.nih.gov/news/health/oct2008/nichd-29.htm>.