PEDIATRICS (ISSN 0031 4005). Copyright © 1989 by the American Academy of Pediatrics.
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PEDIATRICS
Vol. 83 No. 6 June
1989
Bilirubin
and Brain
Damage:
What
Do We Do Now?
In many ways, the study reported by van de Bor
and her colleagues’ has a message akin to the classic
telegram: “Bad news. Start worrying. Details to
follow.” Perhaps we should start worrying about
low levels of bilirubin in very low birth weight
infants, but it is premature to do anything else,
other than wait for the critical details that might
dictate a change in current practice.
Compared with similar previous investigations,
this study has several strengths. First, the sample
of 831 surviving infants includes many more very
low birth weight infants than previous studies.25
Second, follow-up evaluations were performed on
100% of the surviving children-a truly remarkable
achievement. Third, with the exception of the
Na-tional Institute of Child Health and Human
Devel-opment (NICHD) randomized phototherapy trial,6
in which enrollment was completed in 1976, it is
the only evaluation of a large cohort of infants in
the modern era of neonatal intensive care. This is
important because such care includes vigorous
treatment of hyperbilirubinemia with phototherapy
as well as exchange transfusion. Finally, the
con-sideration of possible confounding variables
(in-cluding intracranial hemorrhage) is more complete
and more sophisticated than that found in previous
investigations.
There are some weaknesses, of course. These
infants were tested at a corrected age of 2 years and
many “minor” abnormalities found may be less
obvious or absent by 4 to 7 years of age.4 The
measurement of intracranial hemorrhage was crude
and bilirubin determinations were performed only
when there was clinical indication. Thus, there is
concern that the measured maximal bilirubin
con-centration was not, in fact, the maximal bilirubin
concentration in certain infants. If so, maximal
bilirubin concentration is less likely to be a
predic-tor of long-term outcome and, as the authors point
out, this would only underestimate the full effect of
bilirubin.
The Dutch investigators found a dose-response
relationship between peak total serum bilirubin
levels and the risk of neurologic handicap at 2 years:
the odds of handicap increased by about 30% for
each 50-mol/L (2.9-mg/dL) increase in maximal
bilirubin concentration.
Note that the odds of disease and the probability
(or risk) of disease are related but not the same. If
the probability of disease is P, the odds are P/(1
-P). When P is small, the probability and odds are
almost the same. For example, if P = .01, odds are
0.01/0.99 = 0.0101; if P = .1, odds are 0.1/0.9 =
0.11. However, as P increases, odds get higher
rap-idly. For example, if P = .25, odds =
0.33,
if P = .5,odds = 1, and if P = .99, odds = 99! The logistic
model assumes that increases in the level of each
risk factor multiply the odds of disease by a fixed
amount. If bilirubin and the other risk factors are
related to the odds of handicap in that simple way,
then the odds ratio of 1.3 per 50 mol/L of bilirubin is the estimate that best fits the data. For every
50-mol/L increase in maximal bilirubin
concentra-tion, the predicted odds of handicap are multiplied
by 1.3. Thus, a baby with a maximal bilirubin
concentration of 250 mol/L would be predicted to
have odds of handicap (1.3) =
2.86
times higherthan a baby with a maximal bilirubin concentration
of 50 zmol/L. (This is equivalent to an odds ratio
of 1.57 per 5-mg/dL increase in maximal bilirubin
concentration.)
Given this observed association, we must ask: (1)
is the association real? (2) If so, is it causal?, and
(3) If
causal, what should we do about it?Is the association real? Spurious associations
may be observed either because of random error
(chance) or systematic error (bias).7 The best way
to assess random error is to calculate a confidence
interval around the parameter used to measure the
strength of the association. In general, as sample
size increases, random error becomes smaller and
the confidence interval narrower. In this study,
however, the 95% confidence interval for the
esti-mated odds ratio of 1.3 ranged from 1.03 to 1.62.
Thus, the actual effect of an elevated bilirubin level
may be trivial (or even nonexistent), or it may be
considerably greater than observed. In spite of the
large sample size, the estimate of the odds ratio is
imprecise.
Systematic error (bias) is a more vexing cause of
spurious associations, because it persists in spite of
increases in the sample size. Bias is much more
likely to cause a spurious association when it is
differential (when the systematic error occurs
dif-ferentially according to whether the risk factor is
present). In the study by van de Bor et at, we must
be sure that the (somewhat subjective)
measure-ment of neurodevelopmental outcome was not
in-fluenced by past bilirubin levels. The best way to
prevent this would have been to ensure that those
responsible for evaluating neurodevelopmental
out-come were unaware of (“blinded” to) the degree of
previous bilirubin exposure.
Is the association causal? Given that the
associ-ation does not seem to be (entirely) due to chance
or bias, the next question is whether it represents
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COMMENTARIES 1063
a cause-effect relationship.7 The two rival
expla-nations are effect-cause and effect-effect. The
for-mer is primarily a consideration in cross-sectional
studies and is ruled out in the present study by the
temporal relationship between the variables. (It is
not possible for neurologic handicap to cause
ele-vation of bilirubin levels obtained 2 years
previ-ously.) The latter explanation, also called
“con-founding,” is much more difficult to rule out. The
question is whether bilirubin and neurologic
hand-icap are associated only because both are related to
some third factor, such as intracranial hemorrhage.
We know that severe intracranial hemorrhage is
associated with neurologic handicap; if intracranial
hemorrhage also increases maximal bilirubin
con-centration, then maximal bilirubin concentration
would be associated with handicap simply because
babies with higher maximal bilirubin concentration
would be more likely to have had an intracranial
hemorrhage.
How do we go about determining whether
con-founding is a likely basis for an association? To be
a confounder, a variable must be associated with
both the risk factor (maximal bilirubin
concentra-tion) and the outcome (neurologic handicap). Thus,
a good approach to evaluating the likelihood of
confounding is to consider which determinants of
handicap might also be associated with maximal
bilirubin concentration. Van de Bor et al considered the major known predictors of neurodevelopmental
outcome: gestational age, birth weight, seizures,
intracranial hemorrhage, respiratory distress
syn-drome, ventriculomegaly, and bronchopulmonary
dysplasia. Gestational age, birth weight, and
respi-ratory distress syndrome turned out not to be
as-sociated with handicap in the present study. Of the
remainder, based on our understanding of bilirubin
metabolism, only intracranial hemorrhage might
have been expected to be associated with maximal
bilirubin concentration, and, when examined, that
association has been either weak8 or absent.9 Thus,
even before the multivariate analysis, the suspicion
that confounding by any of the variables measured
could cause the observed association is fairly low.
Confounding by unknown or unmeasured variables
can never be ruled out in an observational study,
but such unknown variables would have to be
strongly (and independently) related to both
out-come and maximal bilirubin concentration,1#{176} and
this does not seem likely.
The logistic regression analysis performed by van
de Bor et al further strengthens the case for
caus-ality. As mentioned before, logistic regression uses
a model in which the different risk factors are
assumed independently to increase the odds of the
disease. This allows the independent effect of the
risk factor (maximal bilirubin concentration) to be
estimated with potential confounding factors (like
intracranial hemorrhage) held constant
statisti-cally. An important limitation of this approach is
that, to control for confounding statistically, the
measurement of the potential confounder must be
valid. In the van de Bor et a! study, the
measure-ment of intracranial hemorrhage was somewhat
crude: intracranial hemorrhage was treated as
pre-sent or absent, and ultrasound evaluations were not
performed in all infants. The investigators assumed
that significant intracranial hemorrhage would
have been apparent and would have led to an
ultra-sound evaluation, but such hemorrhages may not
be clinically obvious.’1 Nevertheless, the fact that
the association is of similar magnitude with and
without the potential confounders included in the
logistic model (our own analysis of table 1 gives an
odds ratio of 1.28 per 5O-mol/L maximal bilirubin
concentration)’2 suggests that significant
con-founding is unlikely.
In addition to seeking evidence to suggest that
an association is not causal, as discussed before, it
is important to consider positive evidence for a
causal relationship. Four important characteristics
to consider are consistency of the association, its
strength, the presence of a dose-response relation-ship, and its biologic plausibility. We will discuss, rather briefly, how these issues relate to the effects
of bilirubin on developmental outcome. (They have
been thoroughly reviewed elsewhere.13”4)
Except for babies with erythroblastosis and
ker-nicterus, the association between serum bilirubin
and neurologic handicap has not been consistent.
Some investigators have found an association in
low birth weight infants,2’3”5”6 but others have not,4
particularly when bilirubin levels did not exceed 20
mg/dL (342 mol/L).4”2#{176} In two studies, signifi-cantly elevated bilirubin levels appeared to improve
developmental outcome in very low birth weight2
and term infants.2’
The major neurologic deficit was cerebral
palsy-not associated classically with bilirubin
encepha-lopathy in the full-term infant. Nevertheless, this
and other nonspecific neurodevelopmental
abnor-malities have been the predominant findings in
previous studies identifying an association between
bilirubin levels and handicap in preterm and low
birth weight infants.2’3
The strength of an observed association is also
important; stronger relationships are more likely to
be causal. But estimates of the strength of the
association between bilirubin levels and brain
dam-age have varied in direction as well as magnitude,
and the estimate in the present study was
insuffi-ciently precise to provide evidence of a strong
re-lationship.
Van de Bor and co-workers do provide evidence,
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PEDIATRICS
Vol. 83 No. 6 June
1989
however, of a dose-response relationship, and the
association is biologically plausible. Bilirubin is
neurotoxic in a variety of animal models,2225 and
recent studies have demonstrated transient effects
of bilirubin on brainstem-evoked potentials,2m
in-fant behavior, and the characteristics ofthe baby’s
cry.3#{176}
The evidence presented by van de Bor et al is not
overwhelming, but it does suggest a causal
relation-ship between maximal bilirubin concentration and
neurodevelopmental outcome, although the
mag-nitude of the effect may be small.
What do we do now? In brief, nothing much.
First, as noted before, although the association
between maximal bilirubin concentration and
neu-rologic handicap was statistically significant, the
95% confidence interval was wide, the association
(in other studies) has not been consistent, and panic
about bilirubin in the 100- to 2O0-mol/L (6 to 12
mg/dL) range is certainly premature.
Second, even if the observed effect size were true,
we lack a crucial piece of information: would an
intervention that reduced maximal bilirubin
con-centration also reduce the incidence of neurologic
handicap? Randomized clinical trials are necessary
before we can make therapeutic recommendations,
and one such trial has been completed. We have
preliminary data from the NICHD collaborative
phototherapy trial in which approximately 500 of
the infants 2,000 g were followed up for 6 years.6
Phototherapy reduced peak bilirubin levels
signifi-cantly (by about 70 mol/L [4 mg/dL]), but this
did not reduce the incidence of motor deficits or
cerebral palsy, and there was no effect on IQ scores.6
The implications of the study by van de Bor et
al for larger or more mature babies are worth
men-tioning. Even if the relative risk of neurologic
hand-icap for term babies with hyperbilirubinemia were
the same as that found by van de Bor et al for
preterm babies, the absolute risk would be much
smaller. Thus, instead of changing the odds of
handicap from 10% to 13%, a 50-imol/L change in
maximal bilirubin concentration might alter the
odds from 1% to 1.3%. If this were the case, and if
treatment could decrease the maximal bilirubin
concentration by 50 imol/L, about 33 premature
infants would need to be treated to prevent one
case of neurologic handicap. To achieve similar
benefit in term infants, we would have to treat 333
babies. Clearly, the benefits of interventions to
reduce bilirubin levels are much less likely to exceed the risks in larger or more mature infants.
What do we do now? The first step is to confirm
these results with additional observational studies.
We could begin by further analyzing the NICHD
trial results and by assembling data from infants in
intensive care nursery follow-up programs in the
United States. Many neonatal groups have been
systematically following up their surviving infants
with birth weights of <1,500 g. Maximal bilirubin
values are available, as are data concerning
intra-cranial hemorrhage and developmental outcome. If
the data of van de Bor et al are correct, then there
appears to be justification for another randomized
trial of the effect on neurologic outcome of
decreas-ing serum bilirubin concentrations (perhaps by
ad-ministering tin protoporphyrin in the delivery
room) in a group of premature low birth weight
infants.
Meanwhile, start worrying. Details to follow.
REFERENCES
THOMAS
B.
NEWMAN, MD, MPH Department of PediatricsUniversity of California San Francisco
M. JEFFREY MAISELS, MB, BCH Department of Pediatrics
William Beaumont Hospital
Royal Oak, MI
1. van de Bor M, van Zeben to Van der Aa TM, Verloove-Vanhorick SP et a!: Hyperbilirubinemia in very preterm infants and neurodevelopmental outcome at 2 years of age:
Results of a national collaborative survey. Pediatrics
1989;83:915-920
2. Scheidt PC, Mellit ED, Hardy JB: Toxicity to biirubin in neonates: Infant development during first year in relation to maximum neonatal serum bilirubin concentration. J Pe-diatr 1977;91:292-297
3. Naeye RL: Amniotic fluid infections, neonatal hyperbilirubi-nemia, and psychomotor impairment. Pediatrics 1978;62:
497-503
4. Rubin RA, Bellow B, Fisch RO: Neonatal serum bilirubin levels related to cognitive development at ages four through seven years. J Pediatr 1979;4:601-604
5. Johnson L, Boggs TR: Bilirubin-dependent brain damage: Incidence and indications for treatment, in Odell GB, Schaf-fer R, Siinopoulous AB (eds): Phototherapy in the Newborn: An Overview. Washington, DC, National Academy of
Sci-ences,1974, pp 122-149
6. Scheidt PC, Bryla DA, Nelson HB: NICHD phototherapy clinical trial: Six year follow-up results, abstracted. Pediatr Res 1988;23:455A
7. Newman TB, Browner WS, Hulley SB: Enhancing causal inference in observational studies, in Huiley SB, Cummings SR (eda): Designing Clinical Research. Baltimore, Williams &Wilkins, 1988, pp 98-109
8. Epstein MF, Leviton A, Kuban KCK, et al: Bilirubin, intra-ventricular hemorrhage, and phenobarbital in very low birth weight babies. Pediatrics 1988;82:350-354
9. Amato M, FauchereJC, von Muralt G: Relationship between periintraventricular hemorrhage and neonatal hyperbiliru-binemia in very low birth weight infants. Am J Perinatol
l987;4:275-278
10. Winkelstein W Jr, Shiffitoe EJ, Brand R, et a!: Further comments on cancer of the uterine cervix, smoking, and herpes virus infection. Am J Epidemiol 1984;119:1-7 11. Lazzara A, Ahmann P, Dykes F, et al: Clinical predictability
of intraventricular hemorrhage in preterm infants. Pediat-rics 1980;65:30-34
12. McGee DL: A program for logistic regression on the IBM
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PEDIATRICS (ISSN 0031 4005). Copyright © 1989 by the American Academy of Pediatrics.
PEDIATRICS Vol. 83 No. 6 June 1989 1065
PC. Am J Epidemiol 1986;124:702-705
13. Maisels MJ: Neonatal jaundice, in Avery GB (ed): Neona-tology, Pathophysiology and Management of the Newborn, ed
3.Philadelphia, JB Lippincott, 1987, pp 583-585 14. Maisels MJ: Clinical studies of the sequelae of
hyperbiliru-binemia, in Levine RL, Maisels MJ (eds): Hyperbilirubine-mia in the Newborn, Report of the 85th Ross Conference on Pediatric Research. Columbus, OH, ROSS Laboratories, 1983,
pp 26-38
15. Crichton JU, Dunn HG, McBurney AK, et al: Long term
effects of neonatal jaundice on brain function in children of low birth weight. Pediatrics 1972;48:656-670
16. Koch CA, Jones DV, Dine MS. et a!: Hyperbilirubinemia in preterm infants: A follow-up study. J Pediatr 1959;55:23-29
17. Hugh-Jones K, Slack J, Simpson K, et al: Clinical course of hyperbilirubinemia in premature infants. N Engi J Med 1960;263:1223-1229
18. Odell GB, Storey GNB, Rosenberg LA: Studies in kernic-terus: III. The saturation of serum proteins with bilirubin during neonatal life and its relationship to brain damage at
5years.J Pediatr 1970;76:12-21
19. Shiller JG, Silverman WA: Uncomplicated hyperbilirubi-nemia of prematurity. Am J Dis Child 1961;101:587-592 20. Wishingrad L, Cornblath M, Takakuwa P, et al: Studies of
nonhemolytic hyperbilirubinemia in premature infante: Pro-spective randomized selection for exchange transfusion with observations on the levels of serum bilirubin with or without exchange transfusion and neurologic evaluations one year after birth. Pediatrics 1965;36:162
21. Holmes GE, Miller JB, Smith EE: Neonatal bilirubinemia in production of long term neurological deficits. Am J Dis Child 1968;116:37-43
22. Chen H-C, Lien IN, Lu T-C: Kernicterus in newborn rab-bits. Am J Pathol 1965;46:331
23. Jirka JH, Duckrow B, Kendig JW, et al: Effect of bilirubin on brain stem auditory evoked potentials in the asphyxiated rat. Pediatr Res 1985;19:556-560
24. Lucey JF, Hibbard E, Behrman RE, et a!: Kernicterus in asphyxiated newborn rhesus monkeys. Exp Neurol
1964;9:43-58
25. Wennberg RP, Hance AJ: Experimental bilirubin encepha-lopathy: Importance of total bilirubin, protein binding, and blood-brain barrier. Pediatr Res 1986;20:789-792
26. Perlman M, Fainmesser P, Sohmer H, et al: Auditory nerve-brainstem evoked responses in hyperbilirubinemic neonates. Pediatrics 1983;72:658-664
27. Nakamura H, Takada S, Shimabuku R, et a!: Auditory nerve and brainstem responses in newborn infants with hyperbil-irubinemia. Pediatrics 1985;75:703-708
28. Wennberg RP, Ahifors CE, Bickers R, et al: Abnormal auditory brain stem response in a newborn infant with hyperbilirubinemia: Improvement with exchange transfu-sion. J Pediatr 1982;100:624-626
29. Escher-Graub DC, Fricker HS: Jaundice and behavioral organization in the full-term neonate. Helu Paediatr Acta 1986;41:425-435
30. Golub HL, Corwin MJ: Infant cry: A clue to diagnosis. Pediatrics 1982;69:197-201
It’s Time
for Pediatricians
to
‘Rally
‘Round
the Pool Fence’
Pediatrics has distinguished itself as one of the
medical disciplines most concerned with preventive
medicine and strategies to prevent accidents and
illness. Immunizations and accident prevention
ed-ucation are a routine part of pediatric practice and
well-child care.
Poison prevention is one of the significant
ac-complishments of the 20th century in which
pedia-tricians played a major role and can feel justly
proud. Pediatricians played a decisive role in the
establishment of the Poison Control Center
net-work and in the development of child-proof safety
caps that ultimately led to the Poison Prevention
Packaging Act of 1970.’ The results have been
gratifying, with the death rate from poisonings in
children declining from 2.2 per 100,000 children in
1960 to 0.5 per 100,000 children in 1980.2 An
esti-mated #{189}to 1 million accidental ingestions have
been prevented by child-resistant closures.3
Poison-ings have been reduced from the second leading
cause of accidental death in children to fourth place
(Table). Deaths from unintentional ingestion of
potentially poisonous substances among children
less than 5 years of age decreased from a peak of
456 in 1959 to 57 in 1981.
Pediatricians and legislators now have the
op-portunity to make another significant impact on
accident prevention. The second leading cause of
accidental death in children and young adults has
become drowning, and swimming pools are a major
risk site. Various studies have shown that 40% to
80% of drowning and near-drowning accidents
oc-cur in swimming pools.’#{176} Using the new
epidemi-ologic designation, drowning is the second leading
cause of years of potential life lost from premature
mortality due to unintentional injury” (Table). Not
only is drowning a major cause of pediatric
mortal-ity, but near-drowning accidents are an important
cause of anoxic encephalopathy with permanent
neurologic dysfunction and morbidity. It is
esti-mated that one third of all survivors are moderately to severely neurologically damaged.’2
TABLE. Leading Causes of Prematu Unintentional Injury
re Mortality Due to
Accident Potential
Life Lost (yr)
Motor vehicle
Traffic accidents 1.4 x 106
Nontraffic accidents 3.4 x i0
Drownings 2 x 10
Fire and flames 1.4 x 10
Poisonings 1.3 x iO
Falls 8 x i0
Firearms 5.5 x i0
Choking on food or object 4.5 x i0
Transport
Water 3.5 x i0
Air 3.4 x iO
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1989;83;1062
Pediatrics
THOMAS B. NEWMAN and M. JEFFREY MAISELS
Bilirubin and Brain Damage: What Do We Do Now?
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Bilirubin and Brain Damage: What Do We Do Now?
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