Neonatal jaundice and

Hemolytic Disease of the

Newborn
 Definition
• Neonatal jaundice is the term used when a
newborn has an excessive amount of bilirubin
in the blood.
• Bilirubin is a yellowish-red pigment that is
formed and released into the bloodstream when
red blood cells are broken down.
• Jaundice comes from the French word jaune,
which means yellow; thus a jaundiced baby is
one whose skin color appears yellow due to
bilirubin.
 Description
• Jaundice is the most common condition
requiring medical attention in newborns

• Neonatal jaundice affects 60 percent of full-

term infants and 80 percent of preterm infants
in the first three days after birth.
 Background
• Bilirubin is formed when the body breaks down
old red blood cells. The liver usually processes
and removes the bilirubin from the blood.

• Jaundice in babies usually occurs because their

immature livers are not efficient at removing
bilirubin from the bloodstream.
Neonates,however,may not appear jaundice
until the serum bilirubin concentration exceeds
5.0~7.0mg/dl(119µmol/l)

Infants of East Asian and Native American

descent have higher levels of bilirubin than
white infants, who in turn have higher bilirubin
levels than infants of African descent
 Early peak
RE.system

Catabolism of effete Ineffective Erythropoiesis-Bone Marrow

RBC Tissue Heme-heme protein

Heme oxygenase

75%Heme Biliverdin 25%Heme

Bilirubin + serum Albumin Biliverdin reductase

Acceptor proteins Y,Z

Glucurony 1 tranferase Features of
Enterohepatic
circulation metabolism of
bilirubin in neonate
Bilirubin glucuronide
β-glucuronase
Bilirubin

Fecal bilirubin ,stercobilinogen

 Chacteristic of the bilirubin metabolism in
neonate
Over product in bilirubin –8.8mg/kg/d,but 3.8mg in adult
• RBC life span 80 days
• Shunt bilirubin-from bone marrow ,liver
Transport of bilirubin
• Phintensively relative to the binding of albumin to bilirubin (PH>7.4)
• Relative lower concentration of serum album
Immaturity in metabolism in liver
• Acceptor proteins Y,Z in lower level
• Lower activity of uridine diphosphoglucurony1 transferase
Enterohepatic circulation
• Relative intestinal sterile
• High activity of β-glucuronase
 Typing the Neonatal jaundice into
Physiological and pathological states

Physiological
• Visible at 2~3 day of brith
and most apparent at 4~6 day
after birth
• Absent after 2 and 3~4 weeks
of birth for full-term and
preterm infants
• Total serum bilirubin
<12mg/dl(205
µmol/l),<15mg/dl(257 µmol/l)
• No disorders were found
Pathological
• Clinical jaundice in first 24 h
• Total serum
bilirubin>12~15mg/dl (205
~257 µmol/l) or increase by
5mg/dl (85 µmol/l) a day
• Direct serum bilirubin
>2.0mg/dl
• Prolonged jaundice
• Reocurrence of jaundice
 Unconjugated hyperbilirubinemia related
to patological state
Excessive production of bilirubin (hemolyis)
• Blood group incompability(Rh,ABO )
• RBC enzyme abnormalities
• Glucose-6-phosphate dehydrogenase
• Pyruvate kinase
• Sepsis
• RBC membrane defects
• Extravascular blood
• Polycythemia
Impaired conjugation or excretion
• Hormonal deficience(hypotyroidism)
Disorders of bilirubin metabolism
• Criglers-najjar syndromes type1
• Gribert disease
Enhanced Enterohepatic circulation
• Intestinal obstruction
• Meconium plugs
Conjugated hyperbilirubinemia related to
patological state
Obstruction to biliary flow
Hepatic cell injury
• Infection
• Toxic
• Metabolic errors
• Chromosomal disorders
Chronic bilirubin overload
• Erythroblastosis fetalis
• Spherocytosis
• Congenital erythropoietic porphyria
Newborn Jaundice Symptoms
Zone 1 2 3 4 5
SBR (umol/L) 100 150 200 250 >250
Risk Factors for High Bilirubin Levels
• High bilirubin level prior to hospital discharge
• Jaundice observed in the first 24 hours
• Blood group incompatibility
• Gestational age less than 37 weeks
• Previous sibling received phototherapy/family history
of jaundice
• East Asian ethnicity
• Presence of bruising or cephalhematoma
• Exclusive breastfeeding, particularly if nursing is not
going well and weight loss is excessive (> 10% of birth
weight)
Medical Treatment
•Jaundice is most often treated with
phototherapy. This involves placing the
baby on a warmer beneath special lights.

•These lights are able to penetrate a baby’s

skin and affect the bilirubin within the
child. The light changes bilirubin into
lumirubin, which is easily handled by the
baby's body.
•Two factors help decide whether or not to start
phototherapy: the age of the child and the level of bilirubin.

•Younger children with higher bilirubin levels will more

often require treatment.

•The decision to begin phototherapy depends on the

opinion of your pediatrician and on your comfort level
Hemolytic Disease of the
Newborn
 Hemolytic Disease of the
Newborn
• Hemolytic Disease of the Newborn is also
called erythroblastosis fetalis.

• This condition occurs when there is an

incompatibility between the blood types
of the mother and baby.
•hemolytic" means breaking down
of red blood cells
•"erythroblastosis" refers to
making of immature red blood cells
•"fetalis" refers to fetus
 Causes
• HDN most frequently occurs when an Rh negative mother has a
baby with an Rh positive father.
• When the baby's Rh factor is positive, like the father's, problems
can develop if the baby's red blood cells cross to the Rh negative
mother.
• This usually happens at delivery when the placenta detaches.
• However, it may also happen anytime blood cells of the two
circulations mix, such as during a miscarriage or abortion, with a
fall, or during an invasive prenatal testing procedure (i.e., an
amniocentesis or chorionic villus sampling).
 Causes

• The mother's immune system sees the baby's Rh

positive red blood cells as "foreign." Just as when
bacteria invade the body, the immune system responds
by developing antibodies to fight and destroy these
foreign cells.
• The mother's immune system then keeps the antibodies
in case the foreign cells appear again, even in a future
pregnancy. The mother is now "Rh sensitized."
 Causes

• In a first pregnancy, Rh sensitization is not likely.

Usually it only becomes a problem in a future
pregnancy with another Rh positive baby. During that
pregnancy, the mother's antibodies cross the placenta
to fight the Rh positive cells in the baby's body. As the
antibodies destroy the red blood cells, the baby can
become sick. This is called erythroblastosis fetalis
during pregnancy. In the newborn, the condition is
called hemolytic disease of the newborn.
 Causes

• Although it is not as common, a similar problem of

incompatibility may happen between the blood types
(A, B, O, AB) of the mother and baby in the following
situations:

Mother's Blood O A B
Type

Baby's Blood A or B B A
Type
 Clinical features
Babies affected by HDN are usually in a mother's
second or higher pregnancy, after she has become
sensitized with a first baby.

Hemolysis
Anemia
Liver and spleen get bigger
Erythroblasts
Hyperbilirubinemia -Jaundice within 24or 36h
after birth
During pregnancy:
•mild anemia, hyperbilirubinemia, and jaundice
The placenta helps rid some of the bilirubin, but not all.
•severe anemia with enlargement of the liver and spleen
When these organs and the bone marrow cannot compensate for
the fast destruction of red blood cells, severe anemia results and
other organs are affected.
•hydrops fetalis
This occurs as the baby's organs are unable to handle the
anemia. The heart begins to fail and large amounts of fluid build
up in the baby's tissues and organs. A fetus with hydrops is at
great risk of being stillborn.
After birth:
•severe hyperbilirubinemia and jaundice
The baby's liver is unable to handle the large
amount of bilirubin that results from red blood cell
breakdown. The baby's liver is enlarged and
anemia continues.

•kernicterus
Kernicterus is the most severe form of
hyperbilirubinemia and results from the buildup of
bilirubin in the brain. This can cause seizures,
brain damage, deafness, and death.
 Workup
CBC:
•Anemia
•Increased nucleated RBCs, reticulocytosis:
The reticulocyte count can be as high as 40%
•Neutropenia
•Thrombocytopenia:

Serologic tests
Indirect Coombs test and direct antibody test (DAT)
the following tests:
•testing of the baby's umbilical cord blood for blood group,
Rh factor, red blood cell count, and antibodies

•testing of the baby's blood for bilirubin levels

•Characteristics •Rh •ABO
•Clinical •First born •5% •50%
aspects •Later •More severe •No increased
pregnancies severity

•Stillborn/hydro •Frequent •Rare

ps
•Severe anemia •Frequent •Rare
•Jaundice •Moderate to •Mild
severe, frequent
•Late anemia •Frequent •Rare
•Laboratory •DAT •Positive •Weakly positive
findings
•Indirect •Positive •Usually
Coombs test positive
•Spherocytosis •Rare •Frequent
 Treatment

 Specific treatment for hemolytic disease of the newborn

will be determined by your baby's physician based on:
• your baby's gestational age, overall health, and medical
history
• extent of the disease
• your baby's tolerance for specific medications, procedures,
or therapies
• expectations for the course of the disease
• your opinion or preference
 Treatment
During pregnancy, treatment for HDN may include:
• intrauterine blood transfusion of red blood cells into the baby's circulation
This is done by placing a needle through the mother's uterus and into the
abdominal cavity of the fetus or directly into the vein in the umbilical cord. It
may be necessary to give a sedative medication to keep the baby from moving.
Intrauterine transfusions may need to be repeated.

• early delivery if the fetus develops complications

If the fetus has mature lungs, labor and delivery may be induced to prevent
worsening of HDN.
 Treatment
 After birth, treatment may include:
• blood transfusions (for severe anemia)

• intravenous fluids (for low blood pressure)

• help for respiratory distress using oxygen or a mechanical

breathing machine

• exchange transfusion to replace the baby's damaged blood

with fresh blood
The exchange transfusion helps increase the red blood cell count and lower
the levels of bilirubin. An exchange transfusion is done by alternating giving
and withdrawing blood in small amounts through a vein or artery. Exchange
transfusions may need to be repeated if the bilirubin levels remain high.
Phototherapy

• the blue-green region (425 -490 nm) of visible

light being the most effective;
• Nonpolar bilirubin is converted into 2 types of
water-soluble photoisomers (Lumirubin)
• Decrease in bilirubin is mainly the result of
excretion of these photoproducts in bile and
removal via stool.
•. Indications for Phototherapy in the Term
Infant with Hemolytic Disease of the Newborn

•Age •Total Serum Bilirubin, (TSB)

mg/dL
•Unborn (cord •>3.5
blood)
•<12 h •>10
•<18 h •>12
•<24 h •>14
•2-3 d •>15
Intravenous immunoglobulin

• Intravenous immunoglobulin -- Several studies have

reported success in minimizing the need for exchange
transfusion in severe HDN with IVIG. It is an effective
adjunct to phototherapy.
• The mechanism of action appears to be related to blockage
of Fc receptors in the neonatal reticuloendothelial system.
• Its efficacy, however, depends on timing of administration,
duration of treatment, and severity of hemolysis.
• 0.5-1 g/kg IV in first few h following birth for severe
hemolysis in newborn; start infusion at rate of 0.01
mL/kg/min for 30 min, then increase q15-30min; not to
exceed rate of 0.06 mL/kg/min;
• if adverse reactions occur, reduce rate to a previously
well-tolerated rate
 Exchange transfusion

• Exchange transfusion removes circulating

bilirubin and antibody-coated RBCs, replacing
them with RBCs compatible with maternal
serum and providing albumin with new
bilirubin binding sites.
• This process removes approximately 70-90% of fetal
RBCs
• Because most of the bilirubin is in the extravascular space,
only about 25% of the total bilirubin is removed by an
exchange transfusion.
• Exchange transfusion is not free of risk, with the estimated
morbidity rate at 5% and the mortality rate as high as
0.5% from the procedure. Apnea, bradycardia, cyanosis,
vasospasm, and hypothermia with metabolic
abnormalities (eg, hypoglycemia, hypocalcemia) are the
most common adverse effects.
 •Guidelines for Exchange Transfusion in Neonates
with Hemolytic Disease

•Total Serum Bilirubin (TSB), •Weight, g

mg/dL
•>20 •Healthy,
>2500
•>18 •Septic, >2500
•>17 •2000-2499
•>15 •1500-1999
•>13 •1250-1499
•>9-12 •<1250
•The following are requirements for exchange
transfusion
1.Severe anemia (Hb <10 g/dL)
2.Rate of bilirubin rises more than 0.5 mg/dL despite
optimal phototherapy
3.Hyperbilirubinemia
4.Serum bilirubin/albumin ratio exceeding levels that
are considered safe
•Bilirubin/Albumin Ratio Above Which Exchange
transfusion Should Be Considered

•Gestational Age •TSB (mg/dL) / Alb (g/dl)

•>38 weeks •7.2
•35 wk to 37 wk and 6 d •6.8
 Complications
 Bilirubin encephalopathy
• Before the advent of exchange transfusion, kernicterus
affected 15% of infants born with erythroblastosis.
• Approximately 75% of these neonates died within 1
week of life, and a small remainder died during the
first year of life.
• Survivors had permanent neurologic sequelae and were
thought to have accounted for 10% of all patients with
cerebral palsy (CP).
• The mechanism by which unconjugated
bilirubin enters the brain and damages it is
unclear.

• low pH

• A damaged blood-brain barrier

• Bilirubin has been postulated to cause neurotoxicity
via 4 distinct mechanisms:
• (1) interruption of normal neurotransmission (inhibits
phosphorylation of enzymes critical in release of
neurotransmitters),
• (2) mitochondrial dysfunction,
• (3) cellular and intracellular membrane impairment (bilirubin
acid affects membrane ion channels and precipitates on
phospholipid membranes of mitochondria), and
• (4) interference with enzyme activity (binds to specific
bilirubin receptor sites on enzymes
• The pathologic findings include characteristic
staining and neuronal necrosis in basal ganglia,
hippocampal cortex, brainstem nuclei (especially the
auditory, vestibular, and oculomotor), and
cerebellum (especially Purkinje cells).
• The cerebral cortex is generally spared. About half
of these neonates also have extraneuronal lesions,
such as necrosis of renal tubular, intestinal mucosal,
and pancreatic cells.
• Clinical signs of bilirubin encephalopathy typically evolve in 3
phases.
• Phase 1 is marked by poor suck, hypotonia, and depressed sensorium. Fever and
hypertonia are observed in phase 2, and at times, the condition progresses to opisthotonus.
• Phase 3 is characterized by high-pitched cry, hearing and visual abnormalities, poor
feeding, and athetosis. The long-term sequelae include choreoathetoid CP, upward gaze
palsy, sensorineural hearing loss, dental enamel hypoplasia of the deciduous teeth, and, less
often, mental retardation. The abnormal or reduced auditory brainstem response (ABR) of
wave I (auditory nerve) and wave II and V (auditory brainstem nuclei), depicted as
decreased amplitudes, and increased interval I-III and I-V characterize phase I of early,
but reversible, encephalopathy. Subtle bilirubin encephalopathy that consists of either
cognitive dysfunction, isolated hearing loss, or movement disorder has been described in
absence of kernicterus and better correlates with free bilirubin levels.
 Complications
 Late anemia of infancy
• Infants with significant hemolytic disease often develop
anemia in the first month of life and frequently (50%)
require packed RBC transfusion.
• The anemia appears to be due to suppression of fetal
erythropoiesis from transfusion of adult Hb during
intrauterine or exchange transfusion, resulting in low
erythropoietin levels and reticulocyte count.
• Administration of recombinant human erythropoietin (rh-
EPO) has been shown to minimize the need for transfusion
in these newborns.
 Prevention
• Fortunately, HDN is a very preventable disease.
• Because of the advances in prenatal care, nearly all women
with Rh negative blood are identified in early pregnancy by
blood testing. If a mother is Rh negative and has not been
sensitized, she is usually given a drug called Rh
immunoglobulin (RhIg), also known as RhoGAM. This is a
specially developed blood product that can prevent an Rh
negative mother's antibodies from being able to react to Rh
positive cells. Many women are given RhoGAM around the
28th week of pregnancy. After the baby is born, a woman
should receive a second dose of the drug within 72 hours.