|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
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
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
"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
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.