Jornal de Pediatria - Vol. 77, Supl.1 , 2001 S71
0021-7557/01/77-Supl.1/S71
Jornal de Pediatria
Copyright © 2001 by Sociedade Brasileira de Pediatria
REVIEW ARTICLE
Treatment of neonatal hyperbilirubinemia
Manoel de Carvalho*
Abstract
Objective: to review the recent medical literature on the treatment of neonatal jaundice, focusing on
practical aspects that are relevant to pediatricians and neonatologists.
Sources: an extensive review of the related literature was performed, also including the author’s
clinical experience in this field of investigation.
Summary of the findings: jaundice is very common among infants during the first days of life. Several
factors such as maternal and neonatal history have to be considered before implementing treatment.
Significant advances have been made in the past few years concerning the treatment of jaundiced newborn
infants. This review focuses on three forms of treatment of neonatal hyperbilirubinemia: phototherapy,
exchange transfusion and the use of drugs to reduce serum bilirubin concentration.
Conclusions: nowadays, the in-depth knowledge about the mechanism of action of phototherapy, the
development of intensified phototherapy units and the use of drugs to reduce bilirubin formation, have
contributed to significantly decrease the need for exchange transfusion.
J Pediatr (Rio J) 2001; 77 (Supl.1): S71-S80: neonatal jaundice, neonatal hyperbilirubinemia,
phototherapy, exchange transfusion.
Introduction
Hyperbilirubinemia is the most frequent pathology in
the neonatal period. It is estimated that around 60% of
newborns develop serum bilirubin levels higher than 5mg%.1
In most cases, the etiology of this disorder is multifactorial.
Treatment depends on the type and intensity of
hyperbilirubinemia.
Several factors must be considered before treatment is
begun in icteric newborns. First, it is important that the
obstetric history of the mother and delivery be analyzed to
allow identification of the factors that may be contributing
to the occurrence of hyperbilirubinemia, such as drugs
taken by the mother (diazepam, ocytocins), type of delivery
(forceps, pelvic, cesarean section), delay in umbilical cord
clamping, blood type, Rh factor, and maternal Coombs’
test.
Neonatal history must be carefully investigated. The
physician must verify whether the newborn has already
eliminated meconium, and if this elimination was early or
late. If the newborn is breastfeeding, the possibility of
problems on the part of the mother must be investigated, as
well as the frequency with which the newborn is sucking.
Usually, mothers submitted to C-sections are kept away
from the newborns, and breastfeeding is not frequent during
the first days after delivery.
* Associate Professor, Department of Neonatology, Universidade Federal
Fluminense - UFF. Head of the Neonatal ICU, Instituto Fernandes
Figueira/ FIOCRUZ.
S71
S72 Jornal de Pediatria - Vol. 77, Supl.1, 2001
The loss of weight since birth should also be considered.
An excessive loss (> 10%) may indicate insufficient water
and calorie intake. The onset and evolution of
hyperbilirubinemia must be analyzed. Was the onset early
or late? Is progression fast or gradual?
The newborn must be submitted to a detailed physical
examination, with determination of weight and gestational
age. The general state should be observed, as well as level
of activity and reflexes. The presence of visceromegaly,
brain hematomas, and petechiae should be investigated.
The hypothesis of infection should be ruled out.
Only after analysis of the history (maternal, newborn,
and breastfeeding) and physical examination will the blood
be collected for analysis. Basically, laboratory tests are as
follows: 1) total and partial serum bilirubin concentration;
2) blood type and Rh factor and direct Coombs’ test; 3)
hematocrit or hemoglobin.
This information will enable determination of
hyperbilirubinemia as physiologic or pathologic. Pathologic
bilirubinemia is characterized by: a) being clinically
detectable during the first 24 hours after birth; b) an increase
in serum bilirubin concentration higher than 5mg% /day; c)
direct fraction higher than 2mg%; d) total serum bilirubin
level higher than 15mg%; e) presence of clinical signs of
hyperbilirubinemia for more than 1 week in term newborns
or 2 weeks in preterm babies. Once the type and intensity of
hyperbilirubinemia are determined, treatment can be defined.
Due to the high incidence of this disorder in the neonatal
period, the present article will only address the treatment of
indirect, or unconjugated hyperbilirubinemia. Possible
treatments include phototherapy, exchange transfusion, and
adjuvant drug therapy (for example, with heme-oxygenase
inhibiting metalloporphyrins, phenobarbital, and
endovenous immunoglobulin).
The objective of the present article is to review the
current literature and offer a critical analysis of these
treatments, focusing on practical aspects that may be useful
for pediatricians and neonatologists.
Phototherapy
Phototherapy is no doubt the most common treatment
for neonatal hyperbilirubinemia worldwide.2 It is estimated
that in the United States alone more than 350,000 newborns
undergo this treatment every year.3 However, despite the
vast amount of research in humans and animals concerning
mechanisms of action, biological effects, complications,
and clinical application, there is a considerable dearth of
information about how phototherapy acts, what is the ideal
dose to ensure clinical efficacy and how it should be
administered.2,4,5
Treatment of neonatal hyperbilirubinemia - De Carvalho M
Mechanisms of action
The success of phototherapy depends on the
photochemical transformation of bilirubin in areas exposed
to light. This reaction alters the molecular structure of
bilirubin and allows photoproducts to be eliminated by the
kidneys and liver without being metabolically transformed.
Therefore, the basic mechanism of action of phototherapy
is the use of photoenergy to transform bilirubin into more
hydrosoluble products.6
Bilirubin absorbs light in the region from 400 to 500nm.
The light emitted in this spectrum enters the epidermis and
reaches subcutaneous tissue. Thus, only bilirubin found
close to the skin surface (2 mm) is directly affected by
light7,8.
Two mechanisms have been proposed to explain the
action of phototherapy for reducing serum levels of bilirubin:
photoisomerization and photooxidation.9
Photoisomerization
Once irradiated by light, bilirubin molecules originate
two types of isomers: a geometric or configurational isomer
and a structural isomer, or lumirubin. The geometric isomer
forms quickly and can reverse back to a bilirubin molecule;
its excretion is slow in newborns. The formation of structural
isomers is slower than that of geometric isomers; however,
this is an irreversible reaction. Since it is soluble in water,
lumirubin is quickly eliminated through bile, and especially
through the urine of affected newborns submitted to
phototherapy, with no need for conjugation.
Photooxidation
In aerobic environments, a small part of the active
bilirubin molecule suffers a process of oxidation, leading to
the production of pyrrolic complexes, soluble in water and
eliminated in urine. The quantitative contribution of
photooxidation for the decrease of serum bilirubin levels
has not been completely elucidated. However, it seems that
this contribution is small.
Efficacy of phototherapy
The efficacy of phototherapy depends on several factors,
such as the initial, pretreatment bilirubin concentration, the
body surface exposed to light, the dose and irradiance
emitted, and the type of light used (Figure 1). The main
factors influencing phototherapy are discussed below.
Initial serum concentration of bilirubin
The higher the initial serum bilirubin levels the more
pronounced and faster the decrease. Weise has shown, by
means of mathematical calculation, that the phototherapy
Treatment of neonatal hyperbilirubinemia - De Carvalho M
Jornal de Pediatria - Vol. 77, Supl.1 , 2001 S73
action had been elucidated, it was recommended that the
light source be placed around 50 cm away from the patient.
Currently, it is known that irradiance (dose of photoenergy)
may be significantly increased by placing the lamps as close
as possible to the patient. In relation to conventional
phototherapy using white fluorescent lamps, irradiance,
measured on the skin of the newborn, is about 4µw/cm2/nm
when placed 30cm above the patient. Irradiance increases
to 8 and 12µw/cm2/nm when the light source is placed 20
and 10cm, respectively, away from the patient.12
Figure 1 - Variables that interfere with the effectiveness of
phototherapy
dose required to decrease the serum bilirubin concentration
from 20mg% to 7mg% is the same dose required to decrease
the concentration from 10mg% to 5mg%.10
The efficacy of phototherapy decreases with the decrease
in bilirubin levels. With a serum concentration equal to or
smaller than 5mg%, the efficacy of phototherapy is
minimal.11
Body surface exposed to light
Since phototherapy acts on the patient’s skin, it is fair to
suppose that the amount of body surface exposed to light is
an important determinant of its efficacy. The largest the
irradiated area, the more effective the therapy. 12
The use of diapers in icteric newborns submitted to
phototherapy significantly decreases the surface exposed to
light, and therefore should be avoided. Reflecting surfaces
(parabolic mirrors, reflecting films, aluminum foil, or white
fabric) placed below or laterally in relation to the newborn
have been successfully used to increase the body surface
exposed to light.13 The use of these artifacts increases
exposure to light in up to 35%.14 However, it is important
to keep in mind that the use of these materials decreases
visibility of the patient, in addition to increasing the risk for
overheating. Another way of increasing the exposed surface
is using additional sources of light (double or triple
phototherapy).15-17
Distance between light source and patient
The photoenergy that reaches the newborn varies
inversely with the distance between the source and the
patient.12,16 In early times, before several mechanisms of
The problems related to placing the light source too
close to the patient include blocking the view of the patient,
making the handling of the patient difficult, and excessive
heating. The recommendation is that light sources in
phototherapy be placed 30cm above the patient. However,
it is important to note that only equipment using fluorescent
lamps should be placed close to the patient. Halogen lamps,
discussed below, must be kept about 50 cm away from the
patient, due to the significant risk for burns. 18
Irradiance
The efficacy of phototherapy depends directly on the
amount of energy liberated (irradiance). The higher the
dose administered to the newborn, and the larger the
illuminated surface, the more effective the phototherapy.19
In clinical practice, the irradiance emitted by phototherapy
units is measured using radiometers or dosimeters, which
measure the amount of photoenergy emitted between 400 a
500nm. Currently, phototherapy equipment emits
significantly more energy than the equipment available in
the 1970s. The energy recommended by several authors, as
measured on the newborn’s skin, is significantly higher than
the amounts recommended in the past.19,20
The ideal therapeutic dose for phototherapy has not yet
been defined. However, taking into consideration the wealth
of clinical and laboratory investigations, it is evident that
the objective of phototherapy is to provide icteric newborns
with a therapeutic dose sufficient to reduce serum bilirubin
concentrations as fast as possible. The fact that the
importance of the light dose is often not considered is
doubtless one of the factors behind the wide variation in the
efficacy of phototherapy in nurseries. The administration of
phototherapy without determining irradiance is commonly
ineffective.
Based on experiments conducted at the end the of
1970s, several authors have suggested a minimal
phototherapy dose of 4 µw/cm2/nm.1,12,21 This minimal
effective dose would be the cutoff point below which the
photoreaction of bilirubin is too small to justify phototherapy.
Unfortunately, despite current clinical and laboratory
evidence, numerous newborns are still submitted to
subtherapeutic doses of phototherapy.
S74 Jornal de Pediatria - Vol. 77, Supl.1, 2001
Treatment of neonatal hyperbilirubinemia - De Carvalho M
Facchini et al. carried out 20 assessments of irradiance
in conventional phototherapy equipment in four maternity
wards in the city of Campinas, Brazil, and found levels
below 4 µw/cm2/nm in all the units assessed.22 De Carvalho
and Lopes assessed phototherapy units in 21 public hospitals
in Rio de Janeiro, and found a mean irradiance, measured in
the blue spectrum, of 2,4 µw/cm2/nm (ranging from 0.6 to
4.4µw/cm2/nm). From the 102 units, only one presented
irradiance above 4mw/cm2/nm measured on the newborn’s
skin.23 A recent study carried out in a maternity ward in São
Paulo observed irradiance ranging from 2 to 3.2 µw/cm2/
nm24 in conventional phototherapy equipment.
Type of light used in phototherapyThere are several
reasons why our conventional phototherapy equipment
emits, at the level of the newborn’s skin, irradiance below
minimum recommended levels. Among them are the
insufficient number of lamps per unit; often, the use of
equipment with burnt bulbs; the lower intensity of daylight
fluorescent lamps manufactured in Brazil when compared
to those manufactured in the U.S.; and the positioning of the
light sources far from the patient.24-26,28
irradiance tends to decline with time, it is recommended that
this energy be periodically determined with photodosimeters,
and that the lamps be replaced whenever irradiance falls
below the minimum effective level.12,19,21 However,
photodosimeters were not available in Brazil until 1989.
Currently, these dosimeters are found in very few institutions.
Type of light used in phototherapy
The bilirubin molecule absorbs light in the band between
400nm and 500nm, with a maximal peak at around 460nm.26
In theory, all types of light that emit enough energy within
this range should be efficient to induce photodegradation of
bilirubin. Based on this principle, several types of light
sources have been used in phototherapy. The most common
are white (daylight) and blue fluorescent lamps, blue
monochromatic light (special blue) and halogen quartz
lamps with tungsten filament.
Blue light
Several studies have shown that blue light lamps produce
a faster and more pronounced decrease in serum bilirubin
levels than the light obtained with white fluorescent lamps.30
However, blue fluorescent light is not often used in nurseries
due to the undesirable effects associated with this type of
light. It is common to hear medical professionals complain
of dizziness, nausea, and vomits after prolonged exposure
to blue light. Another inconvenience is that under blue light,
the newborn appears extremely cyanotic, making clinical
assessment more difficult.
White light
This has been the most commonly employed in
phototherapy throughout the years. It is the only type of
light whose safety was tested in a large population of
newborns followed during the first 6 years after birth.27 The
problem with this type of light is that it has a very wide
emission spectrum (380 to 770nm). Since the light absorption
spectrum by the bilirubin molecule is relatively short (350
to 500nm), that means that, in theory, the light emitted
outside this spectrum would not have any role in the
photochemical reaction.
The irradiance emitted in the band corresponding to the
absorption of bilirubin is low - thus the need to equip
phototherapy units with an adequate number of fluorescent
lights (usually 7 to 8). When the phototherapy unit equipped
with white fluorescent lights is positioned 50 cm away from
the patient, the photoenergy reaching the newborn is below
the minimum levels (4µw/cm2/nm) recommended in the
literature.28
A frequent question among pediatricians and
neonatologists that deal with phototherapy equipment using
white fluorescent lamps is when to change them. Since
Blue light (special blue) was introduced in clinical
practice in 1972.31 Since then, several studies have shown
that these lamps produce a faster and more pronounced
decrease in serum bilirubin than white fluorescent light. 32
They emit around 45% more energy in the band between
400 and 490nm than do white fluorescent lamps, and are
considered by some investigators as the most effective light
source for use in phototherapy.32 Unfortunately, these
special blue lamps are not manufactured in Brazil.
So as to find an alternative to this problem, most
pediatric services in Brazil adopt the practice of replacing
phototherapy lamps after a certain time, varying from 200
to 2,000 hours. An extensive literature review has not
provided any elements for inferring the emitted irradiance
(and, consequently, the efficacy of phototherapy) based on
the time of use of white fluorescent lamps. De Carvalho and
Lopes, analyzing phototherapy equipment with different
brands of white fluorescent lamps observed a decrease in
irradiance of about 20% after 2,000 hours of uninterrupted
use.29 Therefore, it seems that irradiance should be measured
periodically, and that lamps should be exchanged whenever
this irradiance, measured at the skin of the newborn, is
below clinically levels.
Green light
Green light seems to be more effective than white
fluorescent light. In a study with 100 icteric newborns,
Vecchi et al. showed a more pronounced decrease in serum
bilirubin concentration after 24 hours in patients submitted
to phototherapy with green light than in those submitted to
white fluorescent light (20% vs. 16%). 33 However, there
seems to be no difference in terms of efficacy between green
light therapy and blue light therapy. Most works show that
both the decrease in the concentration of bilirubin and the
total duration of phototherapy are not different with blue or
green lamps.
Treatment of neonatal hyperbilirubinemia - De Carvalho M
Despite an extensive number of works showing that
green fluorescent light is efficient to reduce serum bilirubin
levels, its exact mechanism of action remains unknown.
Similarly to blue light (although less frequently), green light
may cause erythema in newborns, in addition to nausea and
dizziness in the medical staff.34
Light emitting diodes
Light emitting diode (LED) are sources of light with an
extremely short emission spectrum. Currently, they are
available in the market for a variety of applications (traffic
indicators, commercial signs, etc.). LEDs are extremely
small, with a diameter of 5mm, weighing, on average, 0.3g.
For the treatment of neonatal hyperbilirubinemia, LEDs are
grouped in plates containing 100, 200 or 300 units. These
plates must be placed in direct contact with the patient or at
variable distances.35 When in direct contact with the patient,
irradiance reaches values higher than 200µw/cm2/nm.36
Types of phototherapy
So as to increase treatment efficacy, new types of
equipment have been introduced in the market. Below is a
description of the main types of phototherapy equipment
used in Brazil.
Conventional phototherapy
Conventional phototherapy equipment usually
employs six to seven daylight-type 20 W fluorescent
lamps. With the light source placed 50 cm away from the
patient, irradiance with this conventional equipment is
about 3 to 4µw/cm2/nm. The total illuminated body
surface is large, since the entire body of the newborn
(front or back) is irradiated. The irradiance emitted is very
low and this is not compensated by the large surface area
exposed to light. The final efficacy is lower than that
expected for phototherapy equipment. In fact, several clinical
studies have shown the low efficacy of conventional
phototherapy equipment employing national fluorescent
lamps.23,26,37
With the aim of improving the efficacy of this type of
phototherapy, the following is recommended: a) position
the unit about 30cm away from the patient; b) keep the
acrylic surface of the incubator and the protection of the
phototherapy unit clean; c) verify that all lamps are on; d)
use equipment with seven or eight lamps; e) replace two
white fluorescent lamps with two blue lamps (position them
in the center of the unit); f) periodically check the irradiance
emitted (measured on the patient’s skin); g) the newborn
must be exposed to phototherapy without clothes, to ensure
that maximal exposure of the body to light; h) whenever
possible, maintain enteral feeding.
Since there are no reports of gonadal alterations
associated with phototherapy, we do not recommend routine
Jornal de Pediatria - Vol. 77, Supl.1 , 2001 S75
protection of the gonads. The usual wavelength used in
phototherapy penetrates only 2-3mm into the skin of the
newborn, and therefore does not reach the gonads. Eye
protection, however, should be observed.
Biliblanket phototherapy
This is a contact phototherapy, in which the newborn is
placed on a fiber optic pad. The light source uses a special
halogen lamp. Light travels from the source in the light pad
through a fiber optic cable. The pad is a small rectangle
measuring 13 cm x 10cm. This skin of the newborn is in
direct contact with the pad. The biliblanket has a system of
filters that enable only the passage of light in the band
between 400-500nm.37
The irradiance emitted by the biliblanket is between 35
and 60 µw/cm2/nm. Despite the high irradiance, efficacy is
compromised by the small surface of the body exposed to
light, and mainly by the mobility of the newborn. In clinical
practice, the newborn often falls off the luminous pad and,
as a result, the contact with light is decreased. In premature
newborns, the biliblanket is more effective, since more
body surface is exposed to light, and these patients are not
very active. Currently, the biliblanket is used mainly as an
adjuvant in double phototherapy, i.e., the newborn lies on
the biliblanket while receiving conventional
phototherapy.15,39-41
High intensity phototherapy
In the 1990s, new phototherapy devices began to appear.
These emitted high radiance distributed along a large body
surface. Initially, these units employed 16 special blue
fluorescent lamps disposed along a cylinder. The patient
was, then, placed inside this cylinder in such a way that the
lamps would be around the patient’s body, at a distance of
about 15 cm (360° phototherapy). Under these
circumstances, the irradiance reaching the newborn is higher
than 100µw/cm2/nm, reducing serum bilirubin levels in
about 70% in the first 6 hours of treatment.16,42
Recently, De Carvalho et al.43 created a high intensity
phototherapy unit using white fluorescent lamps.43 This
consists in a set of seven daylight white lamps distributed on
an acrylic crib (60 cm length x 35 cm width), so that the
acrylic basin remains around 5 cm away from the lamps. It
is commonly used in nurseries and collective wards. This
set of lamps emits light from the bottom up, crossing the
inferior wall of the acrylic crib and reaching the newborn
lying there. For increased comfort, a small silicone pad
made of clear material (to avoid blocking the light) is placed
inside the acrylic crib.
To profit from the peripheral light that would normally
be lost, the crib’s walls are covered with semitransparent
reflecting film. The upper opening features an arched acrylic
lamp, also covered with reflecting film, so as to direct the
light that would normally be lost back to the patient’s body.
S76 Jornal de Pediatria - Vol. 77, Supl.1, 2001
Thus, the newborn will receive direct light from the bottom,
and reflected (indirect) light from the lateral walls and
upper dome of the crib (total integral phototherapy). The
heat generated by this set of lamps is dissipated through a
system of ventilation and exhaustion. The direct irradiance
emitted by the unit is about 19µw/cm2/nm. The indirect
irradiance, coming from the walls and reflecting dome, is 23µw/cm2/nm.
A controlled, randomized, prospective clinical study
has shown that, after 24 hours, the decrease in serum
bilirubin levels is about six times higher in newborns treated
with this high-intensity phototherapy than in those exposed
to conventional phototherapy (29% x 4%).44
Currently, in our service, newborns with severe jaundice
(TB >20mg%) are treated with high intensity phototherapy
associated with two bilispots projecting light over the
patient (the dome of the acrylic crib is removed). This type
of triple phototherapy enables the baby to receive high
intensity light over the entire body. Invariably, serum
bilirubin levels decrease significantly a few hours after the
start of treatment (we have observed a reduction of about
40% in basal serum levels of bilirubin in the first six hours
of treatment). As a result, we observed an extraordinary
reduction in the incidence of exchange transfusion in our
service.
High intensity phototherapy using LEDs (described
above), introduced experimentally in 2000, have been
showing good results, but is not available in the market.45
What serum bilirubin levels indicate the need for
phototherapy in icteric newborns?
The indication for phototherapy will depend on the type
of jaundice (hemolytic or not) and on specific characteristics
of the newborn (term or preterm, presence of asphyxia,
ecchymosis, etc.). The determination of serum bilirubin
concentration is highly imprecise when conventional
methods are used.46 Therefore, such a level does not exist
in and of itself. It must be analyzed within a global context
that includes several factors related to the newborn and to
the newborn’s perinatal history (Figure 2).
In healthy term newborns presenting non-hemolytic
jaundice (physiologic), the current trend is to delay the use
of photoherapy until serum bilirubin reaches values
considerably higher than those used in the past. The reason
for this conduct is that several scientific publications show
a lack of correlation between the serum levels of bilirubin
and neurologic damage in terms newborns with nonhemolytic jaundice.47,48
The serum levels of bilirubin that are indicative of the
need for phototherapy (non-hemolytic jaundice) used in our
service, according to the weight range, appear in Table 1. In
healthy term newborns with non-hemolytic jaundice, the
Treatment of neonatal hyperbilirubinemia - De Carvalho M
recommendation of the American Academy of Pediatrics
(AAP) appears in Table 2. According to the AAP,
phototherapy must be started in term newborns with nonhemolytic jaundice presenting serum bilirubin levels of
15mg%. After more than 48 hours after birth, these levels
would be between 18 and 20mg%. However, despite the
recommendations of the AAP, most pediatricians and
neonatologists still recommend phototherapy for patients
with lower serum bilirubin levels.49
Exchange transfusion
The main objective of exchange transfusion is to remove
the excess of bilirubin, thus preventing its toxic effects.
With this technique, about 85% of the circulating red cells
are replaced when the volume of blood replaced is equivalent
to twice the newborn’s volume (80ml/kg). Usually, the
serum bilirubin concentration is reduced in 50%. Despite
being a relatively safe procedure when performed by
experienced professionals, the mortality associated with
exchange transfusion is about 1%. The complications of
exchange transfusion include, among others,
thromboembolism, necrotizing enteritis, vascular
perforation, hemorrhage, infection, and electrolyte,
metabolic, and acid-base disturbances.50
The indications for exchange transfusion must be
individualized and based on an overall clinical assessment
of patients with jaundice. In general, there are two types of
exchange transfusion: early and late.
Early exchange transfusion
The criteria for indication of early exchange transfusion
include less than 12mg% hemoglobin and more than 4mg%
bilirubin in the umbilical cord and serum bilirubin levels at
a rate of increase higher than 0.5mg%/hour.50
Often, these newborns are hydropic and anemic. In
addition, they may be hemodynamically unstable, and present
heart failure. It is important to stress that, despite the
anemia, these patients are not hypovolemic. Therefore, the
performance of exchange transfusion with two blood
volumes may worsen their cardiocirculatory instability.
In our service, we have chosen to treat hydropic and
anemic newborns with an aggressive anticongestive therapy
(diurectic, cardiotonic amines, and, if required,
digitalization) before performing exchange transfusion.
Once the patient is stable, we carry out exchange transfusion
with one volume using high hematocrit blood (usually
around 65%). Eight to 12 hours later, with the patient in a
more stable condition and less anemic, we perform a second
exchange transfusion (now with two volumes of total blood).
The administration of albumin before exchange
transfusion, with the aim of increasing the removal of
Treatment of neonatal hyperbilirubinemia - De Carvalho M
circulating bilirubin is controversial and we do not use this
routine in our service.
Jornal de Pediatria - Vol. 77, Supl.1 , 2001 S77
Table 1 -
Indicative levels for phototherapy in preterm
newborns
Birthweight (kg)
Late exchange transfusion
This is usually based on serum levels of bilirubin.
However, the preestablished level of bilirubin should not be
analyzed in isolation. Watchko and Oski describe a
phenomenon they name as vigintifobia (twenty scare). In a
magisterial article published in 1983, those authors show
that there is no scientific basis to recommend exchange
transfusion in term newborns without evidence of hemolysis
only on the basis of a serum bilirubin level of 20mg%.51
bt (mg%)
< 1.0
1.0 through 1.2
1.2 through 1.4
1.4 through 1.6
1.6 through 1.8
1.8 through 2.2
2.2 through 2.5
> 2.5
5
6
7
8
10
12
12–15
> 15
The indication for exchange transfusion in newborns
with 20mg% bilirubin and without hemolytic disease has
become an everyday practice for pediatricians. It is extremely
hard to change this hospital routine. We all seem to suffer
from vigintifobia!
Figure 2 - Determinant factors for the recommendation of
phototherapy in newborns with jaundice
The notion that a 20mg% serum bilirubin concentration
was an indicator for exchange transfusion was established
in the beginning of the 1950s, following studies in newborns
with hemolytic disease due to Rh incompatibility.52 Since
then, this criterion was extrapolated to newborns without
hemolytic disease.
Generally, it is a consensus in the literature that term
newborns with hemolytic disease due to Rh incompatibility
or any other form of hemolytic anemia are at risk for
developing kernicterus when the concentration of bilirubin
is higher than 20mg%.50 However, despite the lack of
scientific evidence, term newborns with jaundice but without
hemolytic disease (Rh or ABO) are also submitted to
exchange transfusion when serum bilirubin levels reach
20mg%.
Drug therapy for hyperbilirubinemia
Phenobarbital
Studies with Rhesus monkeys have shown that
phenobarbital increases the activity of glucuronyltransferase
and, consequently, bilirubin conjugation. Based on that
observation, phenobarbital is being used in pregnant women
and newborns with the aim of preventing or minimizing
neonatal hyperbilirubinemia. The use of phenobarbital in
pregnant women considerably reduces the levels of bilirubin
in newborns. However, according to Valaes et al., for this
effect to be achieved, it is necessary that the pregnant
woman take at least one 100mg tablet for at least 10 days.
Table 2 -
Age
Treatment of hyperbilirubin in healthy, full-term
newborns, without hemolysis
Consider
phototherapy
Start
phototherapy
Exchange
transfusion
–
–
–
25 - 48 h
12 mg%
15 mg%
> 20 mg%
49 - 72 h
15 mg%
18 mg%
> 25 mg%
> 72 h
17 mg%
20 mg%
> 25 mg%
< 24 h
American Academy of Pediatrics, 1994
S78 Jornal de Pediatria - Vol. 77, Supl.1, 2001
The administration of smaller doses did not show to be
effective in reducing the degree of jaundice in newborns. 53
Therefore, it seems that both the dose of phenobarbital
administered and the duration of the treatment play an
important role in the process of stimulating enzyme activity.
In practice, this has limited the prophylactic use of prenatal
phenobarbital, since the beginning of delivery cannot be
predicted. In addition, the drug can cause dependence in the
mother and excessive sedation of the newborn. It could be
that the prenatal administration of phenobarbital should be
used only in risk groups.54
The administration of phenobarbital to newborns after
delivery or when jaundice is clinically visible is not effective
to reduce serum bilirubin levels.55 The combination of
phenobarbital and phototherapy in newborns does not reduce
serum bilirubin levels faster than isolated phototherapy.56
Heme-oxygenase inhibitors
Several studies have shown that metalloporphyrin, a
potent heme-oxygenase inhibitor, reduces the conversion
of the heme radical into bilirubin, and thus could have a role
in the treatment of neonatal jaundice.50,57
Recently, in a randomized and controlled study of 517
newborns, Valaes et al. showed that an intramuscular dose
of 6mmol/kg administered during the first 24 hours of life
significantly reduced the maximal serum levels of bilirubin
and the need for phototherapy.58
Other studies have suggested that porphyrin is efficient
to prevent or minimize neonatal jaundice resulting from
G6PD deficiency, and also in cases of ABO incompatibility
and positive Coombs’ test.59,60 However, additional
controlled studies are required to evaluate the efficacy and
side effects of porphyrin before this drug can be incorporated
as part of the arsenal available to pediatricians.
Endovenous gammaglobulin
Recent research has suggested the administration of
endovenous gammaglobulin in newborns with hemolytic
disease whose serum bilirubin concentration continues to
increase despite the use of intensive phototherapy.61-63
The rationale behind this indication is that in isoimmune
hemolytic disease, hyperbilirubinemia results primarily from
erythrocyte phagocytosis in the reticuloendothelial system.64
The administration of endovenous gammaglobulin would
block Fc receptors from the reticuloendothelial system,
decreasing the speed of hemolysis.62
Since immunoglobulin does not remove serum bilirubin,
its use should be associated with efficient phototherapy.
However, not all icteric newborns respond well to the
administration of endovenous immunoglobulin. According
Treatment of neonatal hyperbilirubinemia - De Carvalho M
to Hammerman and Kaplan, isoimmune newborns with
increased serum bilirubin levels in the first 24 hours of life
(in whom the rate of increase is higher than 1mg/hour) and
who present less than 13mg% hemoglobin in the umbilical
cord do not benefit from the administration of endovenous
immunoglobulin. In these patients, since the speed of
hemolysis is very high, the administration of endovenous
gammaglobulin does not have any impact on the need for
exchange transfusion or on the time of exposure to
phototherapy.62
The dose and interval of immunoglobulin administration
varies from 0.5g to 1g.61-65 Alpay et al. treated 116 newborns
with ABO and/or Rh hemolytic disease with 1g endovenous
immunoglobulin (single dose). These patients required less
phototherapy and fewer exchange transfusions, and spent
less time in the hospital.63
Although the use of endovenous gammaglobulin has
become more common in the past years, a larger number of
controlled studies are required before its routine use can be
recommended for the treatment of hyperbilirubinemia caused
by hemolytic disease (ABO or Rh) of the newborn.
References
1. Bland HE. Jaundice in the healthy term neonate: when is treatment
indicated? Curr Probl Pediatr 1996;26:355-63.
2. Maisels MJ. Phototherapy 25 years later. In: Fanaroff AA, Klaus,
MH, eds. Year book of neonatal and perinatal medicine. Chicago:
Mosby; 1996. p.XXIX-XXXIV.
3. Polin RA. What’s new about newborns? Curr Probl Pediatr
1991;21:334-44.
4. Hansen TWR. Therapeutic approaches to neonatal jaundice: an
international survey. Clin Pediatr 1996;35:309-16.
5. De Carvalho M, Lopes JMA. Indicações de fototerapia em
recém-nascidos a termo com icterícia não hemolítica: uma
análise crítica. J Pediatr (Rio J) 1995;71:189-94.
6. Dennery PA, Seidman DS, Stevenson DK. Neonatal
hyperbilirubinemia. N Engl J Med 2001;344:581-90.
7. Ennever JF. Phototherapy for neonatal jaundice. In: Polin RA,
Fox WW, eds. Fetal and neonatal physiology. USA: WB Saunders;
1992. p.1165-73.
8. Agati G, Fusi F. Recent advances in bilirubin photophysics. J
Photochem Photobiol 1990;7:1-14.
9. McDonagh AF, Palma LA, Trull FR. Phototherapy for neonatal
jaundice: configurational isomers of bilirubin. J Am Chem Soc
1982;104:6865-69.
10. Weise G, Ballowitz L. A mathematical description of the temporal
changes in serum bilirubin concentration during phototherapy in
newborn infants. Biol Neonate 1982;42:222-5.
11. Tan KL. The pattern of bilirubin response to phototherapy for
neonatal hyperbilirubinemia. Pediatr Res 1982;16:670-2.
12. Maisels MJ. Why use homeopathic doses of phototherapy?
Pediatrics 1996;98:283-7.
Treatment of neonatal hyperbilirubinemia - De Carvalho M
13. De Carvalho M. Aspectos práticos no uso da fototerapia em
recém-nascidos ictéricos. Pediatria Moderna 1998; XXXIV:
167-74.
14. Eggert P, Stick C, Swalve S. On the efficacy of various irradiating
regimens in phototherapy of neonatal jaundice. Eur J Pediatr
1988;147:525-8.
15. Tan KL. Efficacy of bidirectional fiberoptic phototherapy for
neonatal hyperbilirubinemia. Pediatrics 1997;99:5-13.
16. Garg AK, Prasad RS, Hifzi I. A controlled trial or high-intensity
double surface phototherapy on a fluid bed versus conventional
phototherapy in neonatal jaundice. Pediatrics 1995;95:914-6.
17. De Carvalho M, Lopes JMA. Fototerapia simples versus dupla
no tratamento da hiperbilirrubinemia em recém-nascidos de
risco. J Pediatr (Rio J) 1996;72:151-4.
18. De Carvalho M, Lopes JMA. Fototerapia com lâmpada halógena:
avaliação da eficácia. J Pediatr (Rio J) 1993;69:186-92.
19. Mimms L, Estrada M, Goden, D. Phototherapy for neonatal
hyperbilirubinemia - a dose response relationship. J Pediatr
1973;83:658-62.
20. Hansen TWR. Acute management of extreme neonatal jaundice
– the potential benefits of intensified phototherapy and interruption
of enterohepatic bilirubin circulation. Acta Pediatr 1997;
86:843-6.
21. Modi, N, Keay J. Phototherapy for neonatal hyperbilirubinemia:
the importance of dose. Arch Dis Child 1983;58:406-09.
22. Fachini FP, Calil SJ, Hermini AH. Eficácia dos aparelhos de
fototerapia em uso na cidade de Campinas e sugestões para
melhorar seu rendimento. Resumos do XII Congresso Brasileiro,
VI Congresso Latino-Americano, IX Reunião Brasileira de
Enfermagem Perinatal .1990 novembro 24-29; Rio de Janeiro.
p.13.
23. De Carvalho M, Lopes JMA. Fototerapia nos hospitais públicos
do Rio de Janeiro. J Pediatr (Rio J) 1991; 67:157-62.
24. Arcas RM, Wagner NHCV, Reis ME. Avaliação da eficácia da
fototerapia convencional versus alta irradiância. Resumos do
XV Congresso Brasileiro de Perinatologia, XII Reunião de
Enfermagem Perinatal.1996 novembro, Belo Horizonte, p.112.
25. De Carvalho M, Lopes, JMA. Lâmpadas fluorescentes para
fototerapia. J Pediatr (Rio J) 1992; 68:203-05.
26. De Carvalho M, Lopes JMA. Phototherapy units in Brazil: Are
they effective? J Perinat Med 1995;23:315-9.
27. Scheidt PC, Bryla DA, Nelson KB. Phototherapy for neonatal
hyperbilirubinemia: six years follow up of the NICHD clinical
trial. Pediatr 1990;85:455-63.
28. De Carvalho M, Lins MF, Lopes JMA. Lâmpadas fluorescentes
para fototerapia: mudanças no mercado alteram eficácia
terapêutica. J Pediatr (Rio J) 1992;68:203-5.
29. De Carvalho M, Lopes JMA. Qual o tempo de vida útil de
lâmpadas fluorescentes para fototerapia? J Pediatr (Rio J)
1991;67:151-6.
30. Tan KL. Efficacy of “high intensity” blue light and “standard”
daylight phototherapy for non-hemolytic hyperbilirubinemia.
Acta Paediatr 1992;81:870-4.
31. Sisson TRC, Kendal N, Shaw E. Phototherapy of jaundice in the
newborn infant. II - effect of various light intensities. J Pediatr
1972;81:35-8.
32. Romagnoli C, Marroco G, De Carolis MP. Phototherapy for
hyperbilirubinemia in preterm infants: green versus blue lamps
or white light. J Pediatr 1988;112:476-8.
33. Vecchi C, Donzelli GP, Migliorini MG. Green light in
phototherapy. Pediatr Res 1983;17:461-3.
34. Tan KL. Efficacy of fluorescent daylight, blue and green lamps
in the management of non-hemolytic hyperbilirubinemia. J Pediatr
1989;114:132-4.
Jornal de Pediatria - Vol. 77, Supl.1 , 2001 S79
35. Vreman HJ, Stevenson DK, Reader SD. A light emitting diode
(LED) device for phototherapy of jaundice newborns: in vitro
efficacy. Pediatr Res 1997;41:185A.
36. Seidman DS, Moise J, Ergaz Z, Vreman HJ, Stevenson DK, Gale
R. A new blue light emitting phototherapy device versus
conventional phototherapy. A prospective randomized controlled
application in term newborns. Pediatr Res 1998;43:193A.
37. De Carvalho M, Lopes JMA. Comparação entre fototerapia
convencional e de fibra ótica. J Pediatr (Rio J) 1992;68:285-92.
38. De Carvalho M, Lopes JMA, Rossi O. Fototerapia halógena para
o tratamento da icterícia neonatal. Rev Bras Eng 1994;10:25-9.
39. De Carvalho M, Lopes JMA. Fiber optic versus conventional
phototherapy for neonatal hyperbilirubinemia. J Pediatr
1995;127:337-8.
40. Holtrop P, Maddison K, Maisels JM. A randomized trial of
fiberoptic phototherapy versus conventional phototherapy. Pediatr
Res 1991;27:209A.
41. Donzeli GP, Moroni M, Rapisardi G, Agati G, Fusi F. Fiberoptic
phototherapy in the management of jaundice in low birth weight
neonates. Acta Paediatr 1996;85:366-70.
42. Myara A, Sender A, Valete V. Early changes in cutaneous and
serum bilirubin isomers during intense phototherapy of jaundiced
neonates with blue and green light. Biol Neonate 1997;71:75-82.
43. De Carvalho M, Lopes JMA, Netto DB. Fototerapia de alta
intensidade para o tratamento da icterícia do recém-nascido. Rev
Bras Eng Biom 1999;15:109-13.
44. De Carvalho M, De Carvalho D, Trzmielina S, Lopes JMA,
Hansen TWR. Intensified phototherapy using daylight fluorescent
lamps. Acta Pediatr 1999;88:768-71.
45. Seidman DS, Moise J, Ergaz Z, Laor A, Vreman HJ, Stevenson
DK, Gale R. A new blue light emitting phototherapy device: a
prospective randomized controlled study. J Pediatr 2000;136:
771-4.
46. Vreman HJ, Verter J, OH W, Fanaroff AA, Wright LL, Lemos
JA, et al. Interlaboratory variability of bilirubin measurements.
Clin Chem 1996;42:869-73.
47. American Academy of Pediatrics. Practice parameter:
management of hyperbilirubinemia in the healthy term newborn.
Pediatrics 1994;94:558-65.
48. Newman TB, Maisels JM. Less aggressive treatment of neonatal
jaundice and reports of kernicterus: lessons about practice
guidelines. Pediatrics 2000;105:242-5.
49. Gartner LM, Herrarias CT, Sebring RH. Practice patterns in
neonatal hyperbilirubinemia. Pediatrics 1998;101:25-31.
50. Peterec SM. Management of neonatal Rh disease. Clin Perinatol
1995;22:561-92.
51. Watchko JF, Oski FA. Bilirubin 20mg/dl = Vigintiphobia.
Pediatrics 1983; 71:660-63.
52. Hsia DY, Allen FH, Gellis SS. Erithroblastosis fetalis. VIII.
Studies of serum bilirubin in relation to Kernicterus. NEJM
1952; 247:668-71.
53. Valaes T, Kipouros K, Petmezakis M. Effectiveness and safety
of prenatal Phenobarbital for the prevention of neonatal jaundice.
Pediatr Res 1980;14:947-52.
54. Rayburn W, Donn S, Piehl E. Antenatal phenobarbital and
bilirubin metabolism in the very low birth weight infant. Am J
Obstet Gynecol 1988;159:1491-3.
55. Barreto SMV, Gonçalvez AL, Martinez FE. Efeito do fenobarbital
sobre os níveis de bilirrubina em recém-nascidos a termo. J
Pediatr (Rio J) 1985;58:25-8.
56. McDonagh AF, Lightner DA. Like a shriveled blood orange –
bilirubin, jaundice and phototherapy. Pediatrics 1985;75:443-5.
57. Vreman HJ, Stevenson DK. Selection of metalloporphyrin heme
oxygenase inhibitors based on potency and photoreactivity.
Pediatr Res 1993;33:195-9.
S80 Jornal de Pediatria - Vol. 77, Supl.1, 2001
58. Valaes T, Petemezaki S, Henschke C, Drumond GS, Kapas A.
Control of jaundice in preterm newborns by an inhibitor of
bilirubin production: studies with tin-mesoporphyrin. Pediatrics
1994;93:1-11.
59. Martinez JC, Garcia Ho, Otheguy LE, Drumond GS, Kapas A.
Control of severe hyperbilirubinemia in full-term newborns with
the inhibitor of bilirubin production sn-mesoporphyrin. Pediatrics
1999;103:1-5.
60. Valaes T, Drumond GS, Kapas A. Control of hyperbilirubinemia
in glucose – 6-phosphate dehydrogenase deficient newborns
using na inhibitor of bilirubin production sn-mesoporphyrin.
Pediatrics 1998;101:e1-e7.
61. Sato K, Hara T, Kondo T, Iwao H, Honda S, Veda K. High dose
intravenous gamaglobulin therapy for neonatal haemolytic
jaundice due to blood group incompatibility. Acta Paediatr
1991;80:163-6.
62. Hammerman C, Kaplan M. Recent developments in the
management of neonatal hyperbilirubinemia. NeoReviews
2000;1: e19-e23.
63. Alpay F, Sarici SU, Ocutan V, Erdem G, Ozcan O, Gokcay E.
High dose intravenous immunoglobulin therapy in neonatal
immune haemolytic jaundice. Acta Pediatr 1999;88:216-9.
Treatment of neonatal hyperbilirubinemia - De Carvalho M
64. Jones WR, Need JA. Maternal fetal cell surface antigen
incompatibilities. Bailliers Clin Immunol Allergy 1988;2:577605.
65. Mitchell CA, Van Der Weyden MB, Firkin BG. High dose
intravenous gamaglobulin in Coombs positive hemolytic anemia.
Aust NZ J Med 1987;17:290-4.
Correspondence:
Dr. Manoel de Carvalho
Clínica Perinatal Laranjeiras
Rua das Laranjeiras, 445 - Laranjeiras
CEP 22240-002 – Rio de Janeiro, RJ, Brazil
Phone: + 55 21 2556.0022 – Fax: + 55 21 2558.1780
E-mail: [email protected]