Neonatal Jaundice

Physiologic jaundice of the newborn is usually a transient,

benign icterus that occurs during the first week of life in
otherwise healthy full-term infants. Physiologic jaundice is
caused by mild unconjugated (indirect-reacting) hyperbilirubinemia.
Total serum bilirubin greater than 20 mg/dl or an
indirect bilirubin greater than 15 mg/dl is considered pathologic
jaundice. Risk factors include fetal-maternal blood type
incompatibility (ABO and Rh incompatibility), prematurity,
exclusive breast-feeding, maternal age greater than or equal
to 25 years, male sex, delayed meconium passage, and excessive
birth trauma such as bruising or cephalhematomas.154
Hyperbilirubinemia
is a risk with early hospital discharge
(within 48 hours) because hyperbilirubinemia may not be
evident prior to this time.
PATHOPHYSIOLOGY
Physiologic jaundice results
from the complex interaction of factors that cause (1) increased
bilirubin production (e.g., hemolysis), (2) impaired hepatic
uptake or excretion of unconjugated bilirubin, and (3) delayed
maturation of liver conjugating mechanisms. Unconjugated
bilirubin is lipid soluble, bound to albumin in the blood, and in
the free form readily crosses the blood-brain barrier in infants.
Chronic bilirubin encephalopathy (kernicterus) is caused
by the deposition of toxic, unconjugated bilirubin in brain
cells and usually does not occur in healthy full-term infants.
Elevated

conjugated bilirubin in a sign of underlying disease.

A late rising indirect bilirubin level also may be a manifestation
of glucose-6-phosphate dehydrogenase deficiency, a hereditary
X-linked genetic defect.156,157 Elevated unconjugated
bilirubin levels also can cause hemolysis, further increasing
neonatal jaundice.158
CLINICAL MANIFESTATIONS Physiologic jaundice
develops during the second or third day after birth and
usually subsides in 1 to 2 weeks in full-term infants and
2 to 4 weeks in premature infants. After this, increasing
bilirubin values and persistent jaundice indicate pathologic
hyperbilirubinemia. Manifestations include yellowing
skin,
dark urine, light-colored stools, and weight loss. Premature
infants with respiratory distress, acidosis, or sepsis are at
greater risk for encephalopathy. The resulting disabilities
include athetoid cerebral palsy and speech and hearing
impairment.
159,160
EVALUATION AND TREATMENT Total and direct
(conjugated) bilirubin levels are monitored and the bilirubin/
albumin ratio is being evaluated.161, 161a Pathologic jaundice
should be suspected with serum bilirubin values that increase
greater than 5 mg/dl per day, persistent jaundice (greater than
7 to 10 days in the full-term infant), or conjugated bilirubin
greater than 2 mg/dl. Other causes of jaundice must be eliminated
to confirm physiologic jaundice. Treatment depends
on the degree of hyperbilirubinemia.

Physiologic jaundice is
usually treated by phototherapy (
ultraviolet light) with good
eye protection.162 Pathologic jaundice requires an exchange
transfusion and treatment of the underlying cause.
Neonatal Respiratory Distress Syndrome
Respiratory distress syndrome (RDS) of the newborn, also
known as hyaline membrane disease (HMD), is a major
cause of morbidity and mortality in premature newborns.48
The epidemiology, pathophysiology, and clinical presentation
of RDS are outlined in Box 34-2. The major predisposing
factor is prematurity because the immature lung is not
well structured for gas exchange and has not yet developed
adequate surfactant production and secretion. Occasionally
RDS is seen in other situations, most notably infants of
diabetic mothers. An additional factor that increases risk is
cesarean delivery. It is more common in boys than girls and
in whites than nonwhites. The incidence of RDS (in the absence
of preventive treatment) is approximately 50% to 60%
at 29 weeks of gestation and decreases significantly by 36
weeks. Preterm births account for up to 12% of all births49
and approximately 10% of newborns who require some assistance
to begin breathing at birth.50 Antenatal stress on the
fetus may accelerate lung maturation and decrease RDS risk.
In special circumstances, such as elective early delivery (e.g.,
for maternal health reasons), RDS risk is assessed by sampling
amniotic fluid for quantification of secreted surfactant lipids,
the basis of the lecithin/sphingomyelin (L/S) ratio (value of 2

or greater predicts low risk). Another common test looks for

presence of the lipid phosphatidylglycerol, which also reflects
lung maturity.
PATHOPHYSIOLOGY RDS is a state of pulmonary
insufficiency that in its natural course commences at or
shortly after birth. Severity tends to increase over the first
2 days of life.51 It is caused primarily by surfactant deficiency
and, secondarily, by a deficiency in alveolar surface area for
gas exchange. Premature infants are born with many underdeveloped
and small alveoli that are difficult to inflate. Those
that are available for gas exchange do not have adequate surfactant,
which is necessary at the air interface to maintain alveolar
distention at end-expiration. The net effect is atelectasis
(see Figure 34-11), which causes significant hypoxemia, and
is difficult for the neonate to overcome because it requires a
significant negative inspiratory pressure to open the alveoli
with each breath. The chest wall is weak and highly compliant,
making it difficult to overcome this increased work of breathing.
This results in a decrease in tidal volume causing alveolar
hypoventilation and hypercapnia. Hypoxia and hypercapnia
cause pulmonary vasoconstriction, which increases intrapulmonary
resistance and shunting (Figure 34-12). To make
the situation more complex, prolonged hypoxemia activates anaerobic glycolysis,
which produces lactic acid and thus
causes metabolic acidosis. Alveolar hypoventilation makes
it impossible to get rid of excess carbon dioxide (CO2), and
combined metabolic and respiratory acidosis develops. Lowered
pH causes further vasoconstriction. This results in hypoperfusion
of the lung and a decrease in effective pulmonary

blood flow. Increased pulmonary vascular resistance causes

a partial return to fetal circulation, with right-to-left shunting
of blood through the ductus arteriosus and foramen ovale
(see Figures 34-11 and 34-12). With inadequate pulmonary
circulation
and alveolar perfusion, the oxygen content of
the blood continues to decrease, pH decreases, and materials
needed for surfactant production are not circulated to the
alveoli. Capillary permeability increases, resulting in the leakage
of plasma proteins. Fibrin deposits in the air spaces create
the appearance of hyaline
membranes for which the disorder
is named. The plasma proteins leaked into the air space have
the additional adverse effect of interfering with the function
of surfactant that may be present. The pathogenesis of RDS is
summarized in Figure 34-12.
CLINICAL MANIFESTATIONS Signs of RDS appear
within minutes of birth. Some neonates require immediate
resuscitation because of asphyxia or initial severe respiratory
distress. Tachypnea (respiratory rate more than 60 breaths per
minute), expiratory grunting or whining, intercostal and subcostal
retractions, nasal flaring, and poor color are the most
striking clinical manifestations of RDS. The natural course is
characterized by progressive hypoxemia and dyspnea. Apnea
and irregular respirations occur as the infant tires. The severity
of the hypoxemia and the difficulty in providing adequate
supplemental oxygenation give rise to the Vermont Oxford
Neonatal Network definition of RDS as a Pao2 less than 50

mmHg in room air, central cyanosis in room air, or a need

for supplemental oxygen to maintain Pao2 greater than 50
mmHg, as well as the classic chest film appearance.51 Within
the first 6 hours of life, a chest radiograph will reveal air-filled
bronchi (air bronchograms) silhouetted against lung fields
that have a ground glass appearance associated with alveolar
consolidation. RDS can progress to death in severe cases,
but in most cases the clinical manifestations reach a peak
within 3 days, after which there is gradual improvement with
appropriate treatment.
EVALUATION AND TREATMENT Diagnosis is
made on the basis of clinical manifestations, chest radiographs,
and, occasionally, confirmatory analysis (e.g., L/S
ratio)
of amniotic fluid or tracheal aspirates. The ultimate
treatment for RDS would be prevention of premature birth,
but in the meantime other significant advances in treatment
have been made.
The first is antenatal treatment with glucocorticoids for
women in preterm labor. Glucocorticoids induce a significant
and rapid acceleration of lung maturation and stimulation
of surfactant production in the fetus, and there is extensive
evidence that maternal steroid therapy significantly reduces
the incidence of RDS, central nervous system hemorrhage,
and neonatal mortality.49,52 This treatment is currently recommended
in the setting of preterm labor at 24 to 34 weeks
of gestation unless delivery is imminent; ideally, dosing continues
for 48 hours while attempts are made to halt labor. It

remains unclear whether repeated courses of steroids are safe

in this setting.51
The second major advance in RDS treatment has been
exogenous surfactant, either synthetic or purified from animal
sources and instilled down an endotracheal tube (ETT).
This may be administered in prophylactic or rescue protocol.
Unfortunately, liquid dosing down the ETT may result
in peridosing
adverse events like hypoxia, hypercapnia, and
changes in cerebral blood flow. There has been recent progress
in administering surfactant by less invasive methods such
as through nebulization or nasal CPAP. These modalities result
in more uniform distribution of the drug than through
the ETT.53 Current protocols recommend prophylactic administration
of surfactant to infants weighing less than 1000 g
beginning within 15 to 30 minutes of birth, after the infant is
stabilized. Repeat dosing is usually given every 12 hours during
the first few days. There is usually a dramatic improvement
in oxygenation. For infants weighing more than 1000 g, surfactant
replacement is based on clinical need. Because of concerns
about intervention-induced lung injury, guidelines for
surfactant administration are being reconsidered (see Whats
New? Pulmonary Resuscitation of the NewbornSetting the
Stage for Injury?).
Systematic reviews of randomized, controlled trials have
confirmed that surfactant replacement improves oxygenation
as well as reduces the incidence of RDS, death, pneumothorax,
and pulmonary interstitial emphysema.54 Therapy with

surfactant should be considered complementary to antenatal

glucocorticoids, which promote not only accelerated surfactant
synthesis but also enhanced structural development of the
lung and beneficial effects on mechanisms of fluid clearance
from the lung. These two therapies together appear to have
an additive effect on improving lung function. Supplemental
inositol also may promote maturation of surfactant and prevent
adverse neonatal outcomes in preterm infants.55
Figure 34-11 Patchy atelectasis of neonatal lungs with respiratory
distress syndrome (RDS). (From Damjanov I, Linder J, editors: Andersons
pathology, ed 10, St Louis, 1996, Mosby.)