BMJ-Neonatal Jaundice PDF

Neonatal jaundice
Straight to the point of care
Last updated: Apr 28, 2020

Table of Contents
Summary 3
Basics 4
Definition 4
Epidemiology 4
Aetiology 4
Pathophysiology 5
Classification 7
Prevention 8
Primary prevention 8
Screening 8
Secondary prevention 8
Diagnosis 9
Case history 9
Step-by-step diagnostic approach 9
Risk factors 10
History & examination factors 11
Diagnostic tests 14
Differential diagnosis 15
Treatment 16
Recommendations 16
Treatment details overview 18
Treatment options 20
Emerging 32
Follow up 33
Recommendations 33
Complications 34
Prognosis 35
Guidelines 36
Diagnostic guidelines 36
Treatment guidelines 37
Online resources 40
References 41
Images 49
Disclaimer 52
Summary
◊ Usually noted clinically when serum bilirubin is >85.5 micromol/L (5 mg/dL). Occurs in 50% to 70% of
term neonates. Most cases physiological.
◊ Jaundice in the first 24 hours of life is considered pathological.
◊ Treatment for severe hyperbilirubinaemia includes phototherapy and/or exchange transfusion.
◊ The major complication of unconjugated hyperbilirubinaemia is kernicterus.

Neonatal jaundice Basics
Definition
Neonatal jaundice is the yellowing discoloration of the skin and sclera of a neonate, which is caused by
increased levels of bilirubin in the blood. A neonate refers to an infant in the first 28 days of life.
BASICS
This topic focuses on recognising and managing early neonatal jaundice, which is most commonly caused
by unconjugated hyperbilirubinaemia. While prolonged jaundice with conjugated hyperbilirubinaemia may
present during this period, appropriate management depends on the pathological cause and detailed
commentary is beyond the scope of this material.
Epidemiology
Jaundice is the most common condition in newborns that requires medical attention. About 50% to 70% of
term babies and 80% of preterm babies develop jaundice in the first week of life.[2] Jaundice usually appears
2 to 4 days after birth and resolves 1 to 2 weeks later without the need for treatment.
The incidence of hyperbilirubinaemia varies. A study in the UK and Ireland showed an incidence of severe
hyperbilirubinaemia (maximum unconjugated serum bilirubin ≥510 micromol/L [29.8 mg/dL]) of 7.1 in
100,000.[3] A study in Denmark showed an incidence of extreme hyperbilirubinaemia (492 micromol/L [28.8
mg/dL]) of 25 in 100,000.[4] In the US, severe hyperbilirubinaemia (total serum bilirubin >95th percentile)
occurs in 8% to 9% of neonates during the first week; approximately 4% after 72 hours of life.[5] Incidence
data for low and middle income countries vary.[6] The incidence of East Asians in a US Washington state
population-based study was higher than that of white infants.[7] In studies in the US, a predominantly white
and breastfed population in Michigan showed a 95th percentile total serum bilirubin level at 96 hours of life of
224.1 micromol/L (13.1 mg/dL).[8] In studies from Pennsylvania and Northern California, the 95th percentile
was 299.3 (17.5 mg/dL).[1] [9] In a mixed population of neonates from the US, Hong Kong, Japan, and Israel,
the 95th percentile was 265.1 micromol/L (15.5 mg/dL).[10] The risk for neonatal hyperbilirubinaemia is
higher in males and increases progressively with decreasing gestational age.
Aetiology
Physiological jaundice can be a result of:
• Increased bilirubin load secondary to increased red blood cell (RBC) volume, decreased RBC life
span, or increased enterohepatic circulation
• Decreased uptake by the liver because of decreased ligandins or binding of ligandins to other anions
• Decreased conjugation in the liver because of decreased uridine diphosphoglucuronyl transferase
(UDPGT) activity. UGT1A1 gene polymorphisms of Gly71Arg and TATA promoter, which decrease
UDPGT enzymatic activity, have been noted to be significant risk factors associated with neonatal
hyperbilirubinaemia[11]
• Decreased excretion into bile.
Pathological jaundice with unconjugated hyperbilirubinaemia can be a result of:
• Haemolytic anaemias: these result in increased destruction of RBCs, with resultant increased haem,
which is converted to excess unconjugated bilirubin; the immature liver is unable to handle the excess
load. They can be the result of blood group incompatibility (rhesus, ABO), RBC enzyme defects
(glucose-6-phosphate dehydrogenase deficiency; pyruvate kinase deficiency), RBC membrane defects
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(e.g., hereditary spherocytosis, infantile pyknocytosis), thalassaemia, drug-induced (by vitamin K,
sulphonamides, nitrofurantoin, anti-malarials, penicillin), or sepsis
• Extravasation of blood: sequestration of blood in cavities result in increased bilirubin load. Examples
include cephalhaematoma; intracranial, pulmonary, or gastrointestinal haemorrhage; large
BASICS
haemangiomas; excessive ecchymoses; or petechiae
• Polycythaemia: increased number of RBCs leads to increased production of bilirubin
• Increased enterohepatic circulation: delayed gastrointestinal transit increases bilirubin levels.
Examples include intestinal atresia/stenosis, pyloric stenosis, Hirschsprung's disease, meconium ileus/
plug syndrome
• Defective conjugation: congenital deficiencies of UDPGT enzyme include Crigler-Najjar syndrome;
UDPGT enzyme inhibition can be the result of drugs (e.g., novobiocin), or Lucey-Driscoll syndrome
• Metabolic conditions (galactosaemia, hypothyroidism, tyrosinosis, hypermethioninaemia, maternal
diabetes)
• Breastfeeding (including failure to establish lactation)
• Decreased binding of bilirubin to albumin: increased availability of the free (unconjugated) bilirubin to
cross the blood-brain barrier. This can be caused by drugs (sulphonamides, penicillin, gentamicin),
acidosis, asphyxia, hypothermia, increased osmolality, or hypoglycaemia.
Pathological jaundice with conjugated hyperbilirubinaemia (direct bilirubin is >34.2 micromol/L (2.0 mg/dL))
can be a result of:
• Hepatocellular disease:
• Metabolic or genetic defects. Examples include alpha1-antitrypsin deficiency, cystic fibrosis,

Zellweger's syndrome, Dubin-Johnson syndrome (absence of multidrug resistance-associated
protein 2 from the canalicular membrane of hepatocytes), Rotor's syndrome (organic-anion-
transporting polypeptide [OATP]1B1 and OATP1B3 are absent at the sinusoidal membrane of
hepatocytes), and galactosaemia
• Infections. Examples include rubella, cytomegalovirus, herpes, syphilis, hepatitis A and B,
toxoplasmosis, and urinary tract infection with Escherichia coli
• Total parenteral nutrition[12]
• Neonatal haemochromatosis
• Idiopathic neonatal hepatitis
• Shock.
• Intrahepatic biliary disease due to Alagille syndrome (arteriohepatic dysplasia), or inspissated bile
syndrome
• Extrahepatic biliary disease due to biliary atresia, choledochal cyst, bile duct stenosis, cholelithiasis.
Pathophysiology
Bilirubin is the final product of haem catabolism, which is mostly derived from haemoglobin. Breakdown
of red blood cell haemoglobin results in haem production (75% of source of bilirubin). Haem can also be
derived (25% of source of bilirubin) from breakdown of other proteins such as myoglobin, cytochromes, and
nitric oxide synthases. In the reticulo-endothelial system, haem is further catabolised by haem oxygenase
(rate-limiting step for bilirubin production) to biliverdin. This is acted upon by biliverdin reductase to form
bilirubin. Bilirubin is then bound to serum albumin in the plasma and is transported to the liver. Bilirubin
dissociates from albumin, and with the help of carrier proteins such as ligandins, is taken up into the
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 28, 2020.
5
hepatocytes. Bilirubin is then conjugated by the uridine diphosphoglucuronyl transferase enzyme in the
hepatocytes. Bilirubin glucuronide reaches the intestines via the gallbladder and common bile duct. In
the intestines of the newborn, most of the bilirubin glucuronide is unconjugated by beta glucuronidase.
Some of this unconjugated bilirubin is reabsorbed and gets into the enterohepatic circulation. The rest of
BASICS
the conjugated bilirubin reaches the colon, where the bacteria break it down to urobilinogen, which is then
excreted. When this normal process of bilirubin formation and excretion is disrupted, hyperbilirubinaemia
results.[13]
Metabolic pathway of bilirubin with pathologies relating to unconjugated hyperbilirubinaemia. 1. ABO

incompatibility, Rhesus incompatibility, shorter RBC lifespan in neonates, bruising during delivery; 2.
induced by inflammatory mediators associated with comorbidities of prematurity (e.g., respiratory distress
syndrome, infection); 3. dissociation increased by acidosis, ketosis, renal failure; 4. permeable blood-brain
barrier in term neonates and premature babies; 5. mutation in UGT1A1 gene results in Gilbert’s syndrome
or Crigler-Najjar syndrome I and II; 6. unconjugated bilirubin load increased by decreased gut motility
Created by BMJ Knowledge Centre
BASICS
Detail of liver lobule and its functions, highlighting pathologies that cause conjugated hyperbilirubinaemia.
Pathologies include: 1. portal vein thrombosis; 2. choledochal cyst; 3. infection (sepsis, E coli urinary tract
infection, hepatitis A or B, toxoplasmosis, cytomegalovirus, syphilis, herpes), metabolic (Rotor's syndrome,
galactosaemia, tyrosinaemia, alpha-1 antitrypsin deficiency, hypothyroidism, cystic fibrosis, Zellweger's
syndrome), drugs, idiopathic neonatal hepatitis, total parenteral nutrition, neonatal haemochromatosis,
shock/hypoxia/ischaemia; 4. bile duct paucity, biliary atresia, Alagille syndrome, idiopathic neonatal
cholestasis, progressive familial intrahepatic cholestasis, inspissated bile syndrome; 5. MRP2 (also known
as ABCC2) gene mutations on the canalicular membrane of hepatocytes result in Dubin-Johnson syndrome,
absence of OATP1B1 and OATP1B3 at the sinusoidal membrane of hepatocytes result in Rotor's syndrome
Classification
Physiological jaundice
Physiological jaundice is usually noted at postnatal day 2, peaks on days 3 to 5, and then decreases. Serum
bilirubin levels up to 205.2 micromol/L (12 mg/dL) are considered physiological in term neonates.
Pathological jaundice
Any jaundice in the first 24 hours of life is considered pathological. Bilirubin levels exceeding 95th percentile,
as defined by a nomogram, are pathological.[1]
7
Neonatal jaundice Prevention
Primary prevention
Appropriate support and advice to breastfeeding women, and increasing the frequency of breastfeeding to 8
to 12 times a day for first few days, should be recommended.
Screening
There is insufficient evidence to support universal screening for jaundice to prevent chronic bilirubin
encephalopathy.[40] [41] However, screening asymptomatic neonates is important for early recognition of
jaundice and/or signs of bilirubin encephalopathy in order to evaluate the aetiology, closely monitor the serum
bilirubin levels, and provide therapeutic intervention, if necessary. Because jaundice occurs mostly in the first
week of life, this is the best time to screen. Prior to discharge from hospital, jaundice should be assessed
every 8 to 12 hours in the newborn. Visual assessment of jaundice alone is considered unreliable and use of
transcutaneous bilirubinometer and total serum bilirubin are the usual recommended screening tools.[42] [43]
[44] [45]
The American Academy of Pediatrics recommends universal pre-discharge bilirubin screening using total
serum bilirubin (TSB) or transcutaneous bilirubin (TcB) levels that, when interpreted using the risk zones
PREVENTION
in the hour-specific nomogram, [Bhutani nomogram for designation of risk based on hour-specific serum
bilirubin values] (http://pediatrics.aappublications.org/content/114/1/297#p-152) provide a measurable
assessment of the degree of hyperbilirubinaemia.[43] Combining a pre-discharge measurement of TSB or
TcB with clinical risk factors is thought to improve the accuracy of risk prediction. A structured approach
to management and follow-up according to the pre-discharge TSB/TcB, gestational age, and other risk
factors for hyperbilirubinaemia is therefore suggested. When there are two or more successive TSB or TcB
measurements, it is helpful to plot them on the nomogram to assess the rate of bilirubin elevation. If TSB/TcB
levels are crossing nomogram percentiles, haemolysis is likely and further investigation and follow-up are
indicated.
Secondary prevention
Depending on aetiology, if unconjugated bilirubin levels are high (e.g., in partial conjugation enzyme defects),
lifelong intermittent phototherapy is required to prevent neurological damage. Specific treatment needs
to be continued in most cases of the metabolic/genetic/surgical aetiologies to keep levels of conjugated
hyperbilirubinaemia under control. Prevention of malnutrition and vitamin deficiencies is important in addition
to promotion of bile flow and avoidance of bleeding.
Neonatal jaundice Diagnosis
Case history
Case history #1
A baby boy of approximately 36 weeks gestational age is born to a primigravida mother. Pregnancy
and delivery are uncomplicated, with Apgar scores of 9 at 1 and 5 minutes. Mother's and baby's blood
groups are both O+. Mother chooses to exclusively breastfeed the baby. At 24 hours of life, the baby
is noted to be jaundiced and the total serum bilirubin is noted to be 119.7 micromol/L (7 mg/dL). He is
discharged home later the same day with an appointment for follow-up with the paediatrician at 1 week of
age. However, 48 hours later, the baby is brought to the emergency department. History from the mother
reveals that the baby has progressively become more jaundiced, is not breastfeeding well and is lethargic.
Examination also reveals evidence of moderate volume depletion and significant jaundice (including the
soles). The neurological examination is normal and total serum bilirubin is 342.1 micromol/L (20 mg/dL).
Case history #2
A term baby is born to a mother who had a previous baby with a history of jaundice in the newborn period,
not requiring hospitalisation. Pregnancy and delivery are uncomplicated, with Apgar scores of 8 and 9 at
1 and 5 minutes, respectively. Mother's and baby's blood groups are O+ and B+, respectively. At 12 hours
of life, the baby is noted to be jaundiced and the total serum bilirubin is 85.5 micromol/L (5 mg/dL). Tests
reveal direct Coombs' test to be positive and presence of microspherocytes on the peripheral smear.
Other presentations
The neonate may present with clinical signs of bilirubin encephalopathy. These include irritability with
a high-pitched cry, possibly fever and increased muscle tone (usually involving the extensor group
of muscles), and characteristically intermittent backwards arching of the neck (retrocollis) and trunk
(opisthotonus). Decreased tone and abnormal Moro reflex are possible manifestations.
DIAGNOSIS
Step-by-step diagnostic approach
Jaundice is usually noted by yellow discoloration of the skin and sclera with the naked eye.[34] [35] [36]
[37] However, visual estimation of the degree of jaundice can lead to errors, particularly in darkly pigmented
neonates. Therefore, every jaundiced neonate should have a transcutaneous bilirubin measurement.
Jaundice is physiological if it happens in postnatal day 2 and resolves by a week of life and transcutaneous
measurement is normal. All neonates with jaundice in the first 24 hours of life and those with increased
transcutaneous bilirubin after 24 hours of life need further evaluation.
Evaluation of pathological jaundice

If child is younger than 24 hours of age or transcutaneous bilirubin measurement is 205.2 micromol/
L (12 mg/dL), total serum bilirubin should be measured. If total serum bilirubin is >205.2 micromol/L
(12 mg/dL) or >95th percentile for age (in hours) on a nomogram, a Coombs' test should be done.[1]
[Bhutani nomogram for designation of risk based on hour-specific serum bilirubin values] (http://
pediatrics.aappublications.org/content/114/1/297#p-152) If the Coombs' test is positive, mother's and
neonate's ABO and Rh blood groups must be checked. If there is no incompatibility (incompatibility
9
occurs when mother is blood group O and neonate is A or B or when the mother is Rhesus -ve and the
neonate is Rhesus +ve), minor blood group antigens incompatibility should be considered. If negative,
direct serum bilirubin must be checked.
Direct bilirubin >34.2 micromol/L (2 mg/dL)

If direct bilirubin is >34.2 micromol/L (2 mg/dL), various causes of conjugated hyperbilirubinaemia
such as hepatocellular disease secondary to infections/metabolic or genetic causes and extrahepatic
biliary disease needs to be considered and investigated.[38] Tests include liver function tests, blood
culture, urine for reducing substances, plasma amino acids, urine amino acids, urine culture, abdominal
ultrasound, and percutaneous liver biopsy.
Direct bilirubin <34.2 micromol/L (2 mg/dL)

If direct bilirubin is <34.2 micromol/L (2 mg/dL), causes of unconjugated hyperbilirubinaemia (such as
haemolytic anaemias, extravasation of blood, causes of increased enterohepatic circulation or conjugation
defects) should be checked by doing a full blood count. If haematocrit is >65%, polycythaemia should
be confirmed by obtaining the haematocrit level (either with a venous or an arterial sample). If the
haematocrit is normal or decreased, the reticulocyte count and peripheral smear should be checked. If
the reticulocyte count is increased, causes of haemolytic anaemia (blood group incompatibility, red blood
cell enzyme deficiencies) should be considered. Tests include blood groups and glucose-6-phosphate
dehydrogenase screening. If the blood smear is abnormal, specific red blood cell membrane defects
should be identified by the osmotic fragility test.
Risk factors
Strong
Asian
• Higher bilirubin levels were noted in neonates of Asian descent with peak levels occurring latest in
DIAGNOSIS
Hispanic neonates, and at intermediate time points in European and North American populations of
primarily white race/ethnicity.[14] [15] [16] The mechanism possibly involves increased production
secondary to genetic influences.
American-Indian
• American-Indian neonates had higher mean maximal total serum bilirubin, possibly a result of
increased production secondary to genetic influences.[17]
maternal diabetes
• Presence of maternal diabetes increases the risk for neonatal jaundice.[18] [19] [20] [21] Macrosomic
neonates of insulin-dependent diabetic mothers have high erythropoietin levels and increased
erythropoiesis.[22] [23] Diabetic mothers have a 3-fold increased concentration of beta-glucuronidase
in their breast milk.[22]
low birth weight

• Risk factor for neonatal jaundice.[27]
decreased gestational age
• Infants of a younger gestational age were more likely to reach bilirubin levels requiring intervention.[28]
[29] This is probably secondary to the immaturity of the enzymes involved in bilirubin metabolism.
decreased caloric intake and weight loss

• Neonates who had increased weight loss and poor caloric intake had significantly higher total
serum bilirubin.[30] [31] [17] [9] Potential mechanisms include decreased hepatic clearance of
bilirubin, increased activity of haem oxygenase, increased non-esterified fatty acid levels affecting
binding of bilirubin on the hepatic cell membrane, competitive binding with ligandin and inhibition of
diphosphoglucuronyl transferase.
breast feeding
• Increased incidence of jaundice has been observed in breastfed babies.[14] The early onset type is
probably secondary to delayed milk production and poor feeding, leading to decreased caloric intake
and dehydration and resulting in higher total serum bilirubin levels. The late-onset type is thought to
be caused by increased enterohepatic circulation of bilirubin. Various factors in breast milk have been
implicated, including 3-alpha 20-beta pregnanediol, non-esterified free fatty acids (that inhibit hepatic
glucuronyl transferase), lipoprotein lipase, and beta-glucuronidase activities.
Weak
ox ytocin in labour
• Increased incidence of neonatal jaundice in neonates of mothers who received oxytocin has been
reported.[24] [25] This is because of haemolysis secondary to enhanced osmotic fragility of the
erythrocytes.[26]
delayed cord clamping (2-3 minutes)

• There was a significant increase in infants needing phototherapy for jaundice in the late compared with
early clamping group.[32]
DIAGNOSIS
genetic factors
• One case-control study conducted in Southeastern China (Fujian Province) reported that the G211
mutation in the UGT1A1 gene, ABO incompatibility, G6PD deficiency, and the SS genotype of the
repeats in the promoter region of the HO-1 gene are risk factors for neonatal hyperbilirubinaemia.[33]
History & examination factors

Key diagnostic factors
presence of risk factors (common)
• Key risk factors include Asian heritage, maternal diabetes, low birth weight, decreased gestational age,
decreased caloric intake and weight loss, and breastfeeding.
cephalocaudal progression (common)

• First appears in the face, progresses in a cephalocaudal direction as total serum bilirubin rises.
decreasing gestational age (common)
11
• Risk of jaundice increases with decreasing gestational age.
male (common)
• Neonatal jaundice is more common in males.
family history of jaundice (uncommon)

• History of jaundice in a previous sibling suggests blood group incompatibility, breast milk jaundice, or
glucose-6-phosphate dehydrogenase deficiency.
family history of anaemia (uncommon)

• In patients with a hereditary haemolytic anaemia (hereditary spherocytosis, hereditary elliptocytosis,
glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, sickle cell anaemia,
thalassaemia), clinical features include neonatal jaundice, gallstones, and anaemia. In some cases,
splenectomy is a therapeutic option (e.g., with sickle cell anaemia). Therefore, if there is a positive
family history of anaemia and/or splenectomy, such metabolic/genetic conditions should be suspected.
family history of splenectomy (uncommon)

• In patients with a hereditary haemolytic anaemia (hereditary spherocytosis, hereditary elliptocytosis,
glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, sickle cell anaemia,
thalassaemia), clinical features include neonatal jaundice, gallstones, and anaemia. In some cases,
splenectomy is a therapeutic option (e.g., with sickle cell anaemia). Therefore, if there is a positive
family history of anaemia and/or splenectomy, such metabolic/genetic conditions should be suspected.
maternal exposure to sulphonamides or antimalarials (uncommon)

• These result in increased destruction of red blood cells and increased haem production, which is
converted to excess unconjugated bilirubin. The immature liver is unable to handle the excess load of
bilirubin.
hepatosplenomegaly (uncommon)
• Suggests hepatocellular disease.
DIAGNOSIS
microcephaly (uncommon)
• Suggests congenital infection.
chorioretinitis (uncommon)
small for gestational age (uncommon)

cephalhaematoma (uncommon)
• Extravasation of blood.
hypertonia (uncommon)
• Late sign of bilirubin encephalopathy.
high-pitched cry (uncommon)

retrocollis (uncommon)
opisthotonus (uncommon)
Other diagnostic factors

perinatal asphy xia (uncommon)
• May cause decreased binding of bilirubin to albumin and increased availability of the free
(unconjugated) bilirubin to cross the blood-brain barrier.
macrosomia (uncommon)
• Suggests maternal diabetes, increased risk.
plethora (uncommon)
• Suggests polycythaemia.
hypotonia (uncommon)
• Early sign of bilirubin encephalopathy.
lethargy (uncommon)
• Early sign of bilirubin encephalopathy.
DIAGNOSIS
13
Diagnostic tests
1st test to order
Test Result
transcutaneous bilirubinometer physiological or elevated
• Screening test. Needs confirmation by measurement of total serum
bilirubin if transcutaneous measurement value is >205.2 micromol/L
(12 mg/dL).
total serum bilirubin increased
• Best test to confirm diagnosis. Collect blood and keep away from
strong light sources; send for laboratory processing as soon as
possible. Specific value as per age (hour)-specific nomogram. Total
serum bilirubin >205.2 micromol/L (12 mg/dL) should be investigated
further.
direct Coombs' test positive or negative
• To diagnose ABO or Rh iso-immunisation.
direct serum bilirubin increased or decreased
• Direct fraction >34.2 micromol/L (2 mg/dL) needs a focused work-up
for conjugated jaundice. Indirect bilirubin is the unconjugated fraction,
derived by subtracting the direct bilirubin value from the total serum
bilirubin.
haematocrit haemolytic anaemia if
<45%; polycythaemia if
• Capillary samples usually suffice. Needs central (venous or arterial)
>65%
to confirm polycythaemia.
FBC high or low WBC or
platelet counts
• High or low WBC count can suggest sepsis. Thrombocytopenia can
suggest sepsis.
reticulocyte count normal or increased
DIAGNOSIS
• Increased counts are suggestive of haemolysis.

peripheral blood smear normal or abnormal red
blood cell shapes/size
• Evidence of haemolysis. May aid in the diagnosis of hereditary
spherocytosis.
blood groups ABO and Rh status
• If mother is O and the neonate A or B, suggests ABO incompatibility.
Rh-negative mother with Rh-positive neonate is suggestive of Rh
incompatibility.
Other tests to consider
Test Result
glucose-6-phosphate dehydrogenase screening normal or decreased
enzyme levels
• Should be done after a couple of weeks to avoid false negative,
because of higher enzyme levels in younger red blood cells in the
circulation.
osmotic fragility test positive or negative
• Positive in hereditary spherocytosis.
blood culture positive or negative
• Positive in sepsis.
liver function tests normal, increased or
• Decreased albumin levels may be helpful to evaluate bilirubin binding decreased
capacity and risk of bilirubin toxicity. Liver enzymes may be increased
in congenital infections.
urine for reducing substances present or absent
• Present in galactosaemia, if neonate is receiving galactose-
containing feeds.
plasma amino acids normal or increased
• Abnormal in specific inborn errors of metabolism.
urine organic acids normal or increased
• Abnormal in specific inborn errors of metabolism.
urine culture positive or negative
• Positive in urinary tract infection.
abdominal ultrasound normal or abnormal
• Abnormal in specific cases of hepatocellular disease or obstructive
causes of conjugated jaundice.[39]
DIAGNOSIS
percutaneous liver biopsy normal or abnormal
• Abnormal in paucity of intrahepatic bile ducts, metabolic and storage
disorders, infection.[39]
Differential diagnosis
Condition Differentiating signs / Differentiating tests

symptoms
Carotenaemia • Yellow colour seen mostly • Total serum bilirubin levels
in palms and soles but not will be normal. Increased
seen in sclera and mucous serum carotene levels.
membranes.
[Fig-3]
15
Neonatal jaundice Treatment
Recommendations
The main goal of treatment for unconjugated hyperbilirubinaemia is to prevent bilirubin toxicity, specifically
bilirubin encephalopathy and kernicterus.[34] [35] [36] [37] [46] The Bhutani nomograms help assess
risk based on the bilirubin level. [Bhutani nomogram for designation of risk based on hour-specific
serum bilirubin values] (http://pediatrics.aappublications.org/content/114/1/297#p-152) [Bhutani
nomogram guidelines for phototherapy in hospitalised infants of 35 or more weeks’ gestation] (http://
pediatrics.aappublications.org/content/114/1/297#xref-fig-3-1) [Bhutani nomogram guidelines for
exchange transfusion in infants 35 or more weeks’ gestation] (http://pediatrics.aappublications.org/
content/114/1/297#xref-fig-4-1)
Unconjugated hyperbilirubinaemia
Phototherapy
• Neonates whose total serum bilirubin levels exceed the 95th percentile in an hour-specific
nomogram are treated with phototherapy to decrease bilirubin levels. [Bhutani nomogram
guidelines for phototherapy in hospitalised infants of 35 or more weeks’ gestation] (http://
pediatrics.aappublications.org/content/114/1/297#xref-fig-3-1) Phototherapy may be initiated in
these neonates if clinical judgement suggests that the bilirubin is expected to increase.
• Phototherapy uses light energy to cause photochemical reactions to transform bilirubin into isomers
that are less lipophilic and more easily excretable, and make breakdown products that do not
require conjugation in the liver. The most effective phototherapy wavelengths are from 425 nm to
490 nm.[47]
• Double-light phototherapy is often considered to be more effective than single-light or fibreoptic
phototherapy.[48] [49] [50] Fibreoptic and light-emitting diode (LED) phototherapy units are
alternatives to conventional phototherapy in term neonates.[51] [52] [53] LED phototherapy is as
efficacious as conventional therapy,[54] and overhead use (versus illumination from beneath the
infant) shortened the mean duration of phototherapy and increased the rate of decrease in total
serum bilirubin (TSB).[55] [56] [53]
• Special blue compact fluorescent lamp phototherapy had no superiority over special blue standard
length tube light phototherapy in terms of efficacy and adverse effects on the neonate and effects
on nursing staff.[57]
• The risk/benefit profile is excellent, with immediate onset of action on switching on the phototherapy
light. Adverse effects are generally mild and include insensible water loss, loose stools, skin rash,
and potential retinal damage. These can be prevented by maintaining adequate hydration and
ensuring the baby wears eye shields during phototherapy.
• Two large retrospective studies showed an association between neonatal phototherapy and
childhood epilepsy, but not febrile seizures.[58] [59] In both studies, the effect was seen only in
boys. While the sex difference may be attributed to the known increased susceptibility of male
infants to perinatal injury, how phototherapy increases the risk of childhood seizures is not known.
These data are limited for several reasons, including lack of information about the dose or type of
phototherapy used and reliance on International Classification of Diseases (ICD)-9 codes for some
TREATMENT
of the covariate data. Nevertheless, it may be prudent to initiate phototherapy strictly at threshold
values (i.e., avoiding prophylactic treatment) and to terminate it once serum bilirubin falls below
these levels.
• One radnomised controlled trial reported that aggressive phototherapy did not impact on the
outcome of neurodevelopmental impairment or death in extremely low birth weight (ELBW) infants
(birth weight <1000 g), compared with conservative phototherapy.[60] However, a systematic review
of 9 studies showed that prophylactic phototherapy may reduce long-term neurodevelopmental
impairment.[61] While aggressive phototherapy did reduce the rate of neurodevelopmental
impairment alone, there was an increase in mortality among infants with birth weights 500 g to 750
g.[60] Hence, an aggressive phototherapy approach is not recommended for ELBW infants.
Hydration
• Breastfeeding/bottle-feeding can be continued in most circumstances while on phototherapy.

Exchange transfusion
• A decision to undertake an exchange transfusion is made with reference to the Bhutani nomogram
for exchange transfusion. [Bhutani nomogram guidelines for exchange transfusion in infants 35 or
more weeks’ gestation] (http://pediatrics.aappublications.org/content/114/1/297#xref-fig-4-1)
• Immediate exchange transfusion is indicated if:
• Clinical signs such as hypertonia, arching, retrocollis, opisthotonos, fever, or high-pitched cry
are present, even if the TSB is falling
• The TSB is ≥5 mg/dL above the lines in the Bhutani nomogram for exchange transfusion.
• The risk of acute bilirubin encephalopathy is considered high if:
• Bilirubin values approach levels of 428 micromol/L (25 mg/dL)

• Lower bilirubin levels are associated with additional risk factors, including isoimmune
haemolytic disease, glucose-6-phosphate dehydrogenase deficiency, temperature instability,
significant lethargy, perinatal asphyxia, sepsis, and acidosis
• The jaundice is refractory to phototherapy (e.g., bilirubin not decreasing after 4 to 6 hours of
phototherapy).
• Supportive management includes hydration when the bilirubin value is at the 95th percentile
in an hour-specific nomogram.[62] Albumin transfusion can be considered prior to exchange
transfusion,[63] though the efficacy of these interventions has not been shown to be consistently
useful.[64] [65]
• Phototherapy should be continued while preparing for the exchange transfusion and continued after
the procedure as necessary while plotting TSB measurements on the relevant nomograms in order
to assess the requirement for continuing phototherapy or repeat exchange transfusions.
Intravenous immunoglobulin (IVIG)
• Use of IVIG in neonatal unconjugated hyperbilirubinaemia secondary to haemolytic disease

is controversial. IVIG has been shown to significantly reduce the need for exchange
transfusions,[66] but there are no definitive data proving its efficacy.[67] The reasons for
this discrepancy remain unexplained. The 2004 American Academy of Pediatrics guidelines
recommend administration of IVIG in isoimmune haemolytic disease if the TSB is rising despite
intensive phototherapy or the TSB level is within 34-51 micromol/L (2-3 mg/dL) of the exchange
transfusion level. A 2018 Cochrane review of 9 studies with 658 term and preterm infants with
TREATMENT
rhesus or ABO (or both) incompatibility, concluded that further studies are needed before the use of
IVIG for the treatment of alloimmune haemolytic disease of the newborn can be recommended.[68]
17
Conjugated hyperbilirubinaemia
The management of conjugated hyperbilirubinaemia is dependent on its aetiology. Phototherapy is contra-
indicated in these patients as it may lead to 'bronze baby' syndrome. Simple or exchange transfusions
are not indicated. Consultation with an appropriate specialist may be required for further management,
depending on the aetiology.
Physiological jaundice
No treatment is required for physiological jaundice.
Due to breast milk

In neonates with jaundice due to breast milk, interruption of breastfeeding for 24-48 hours and
supplemental feeding may be considered if serum bilirubin levels require phototherapy, which may result
in a reduction of bilirubin levels.[69]
Treatment details overview

Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
TREATMENT
Acute ( summary )
physiological hyperbilirubinaemia
1st reassurance and observation
pathological hyperbilirubinaemia:
unconjugated
acute bilirubin 1st immediate exchange transfusion

encephalopathy
plus phototherapy
plus hydration
adjunct intravenous immunoglobulin (IVIG)
total bilirubin above the 1st phototherapy

95th percentile in the
hour-specific nomogram
for phototherapy
plus hydration
total bilirubin levels 1st exchange transfusion

above the 95th percentile
on the hour-specific
nomogram for exchange
transfusion
plus phototherapy
plus hydration
conjugated
1st treatment of the underlying cause
breast milk jaundice
1st temporary cessation of breast feeding +

supplemental feeding
2nd phototherapy
plus hydration
3rd exchange transfusion

TREATMENT
19
Treatment options
Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
TREATMENT
Acute
physiological hyperbilirubinaemia
1st reassurance and observation
» Jaundice is physiological if it occurs in the

second postnatal day and resolves in 7-10 days
and transcutaneous measurement is normal.
» No treatment is required for physiological

jaundice.
unconjugated
acute bilirubin 1st immediate exchange transfusion

encephalopathy
» Signs of acute bilirubin encephalopathy include
hypertonia, arching, retrocollis, opisthotonos,
fever, and high-pitched cry, even if the total
serum bilirubin is falling.
» This is a medical emergency.
» Start as soon as blood can be arranged for the

exchange transfusion. The rationale is to remove
the unconjugated bilirubin by doing a double-
volume exchange transfusion, which should
allow the bilirubin to move out of the brain tissue
and hence decrease the risk of neurological
toxicities. An exchange transfusion will also
remove antibodies responsible for haemolytic
anaemia. In severe cases of erythroblastosis
and/or hydrops, it will also correct anaemia.
» There is insufficient evidence to support

or refute the use of single-volume exchange
transfusion as opposed to double-volume
exchange transfusion in jaundiced newborns.[70]
» The major potential complications of the

procedure include electrolyte disturbances,
bleeding, infection, cardiac arrhythmias,
thrombosis with embolisation, necrotising
enterocolitis, and graft-versus-host disease.
plus phototherapy
Treatment recommended for ALL patients in
selected patient group
» Start phototherapy while preparing for the
exchange transfusion and continue phototherapy
after the exchange transfusion. Continue to
TREATMENT
plot total serum bilirubin levels for gestational

age and hour after birth on nomograms to
assess need for continued phototherapy
or repeat exchange transfusion. [Bhutani
nomogram guidelines for phototherapy in
hospitalised infants of 35 or more weeks’
21
Acute
gestation] (http://pediatrics.aappublications.org/
content/114/1/297#xref-fig-3-1) [Bhutani
nomogram guidelines for exchange transfusion
in infants 35 or more weeks’ gestation]
(http://pediatrics.aappublications.org/
» Risk factors include isoimmune haemolytic

disease, glucose-6-phosphate dehydrogenase
deficiency, asphyxia, significant lethargy,
temperature instability, sepsis, acidosis, and
albumin <30 g/L (<3.0 g/dL; if measured).
» Phototherapy uses light energy to cause

photochemical reactions to transform bilirubin
into isomers that are less lipophilic and more
easily excretable, and make breakdown products
that do not require conjugation in the liver. The
most effective phototherapy wavelengths are
from 425-490 nm.[47]
» As first-line therapy, double-light phototherapy

is often considered to be more effective than
single-light or fibreoptic phototherapy.[53]
» Fibreoptic and light-emitting diode (LED)

phototherapy units are second-line alternatives
to conventional phototherapy in term
neonates.[51] [52] [53] LED phototherapy
is another second-line alternative as it is as
effective as conventional therapy,[54] and
overhead use (versus illumination from beneath
the infant) shortened the mean duration
of phototherapy and increased the rate of
decrease in TSB.[55] [53] Special blue compact
fluorescent lamp phototherapy had no superiority
over special blue standard length tube light
phototherapy in terms of efficacy and adverse
effects on the neonate and effects on nursing
staff.[57]
» The risk/benefit profile is excellent, with

immediate onset of action upon switching on
the phototherapy lights. Adverse effects are
generally mild and include insensible water loss,
loose stools, skin rash, and potential retinal
damage. These can be prevented by maintaining
adequate hydration and ensuring the baby wears
eye shields during phototherapy.
» Breastfeeding/bottle feeding can be continued

in most circumstances while on phototherapy.
TREATMENT
» One randomised controlled trial reported that

aggressive phototherapy did not impact the
outcome of neurodevelopmental impairment
or death in extremely low birth weight (ELBW)
infants (birth weight <1000 g) compared with
Acute
conservative phototherapy.[60] However, a
systematic review of 9 studies showed that
prophylactic phototherapy may reduce long-
term neurodevelopmental impairment.[61]
While aggressive phototherapy did reduce
the rate of neurodevelopmental impairment
alone, there was an increase in mortality among
infants with birth weights 500-750 g.[60] Hence,
an aggressive phototherapy approach is not
recommended for ELBW infants.
» It may be prudent to initiate phototherapy

strictly at threshold values (i.e., avoiding
prophylactic treatment) and to terminate it
once serum bilirubin falls below these levels
because of an association between neonatal
phototherapy and an increased risk of childhood
epilepsy (not febrile seizures), particularly in
boys.[58] [59]
plus hydration
» Intravenous hydration is usually reserved for
neonates receiving phototherapy with bilirubin
levels close to the exchange value. Such
intravenous fluid supplementation may result in a
faster decline of bilirubin levels.[71]
» Otherwise, maintain hydration with enteral

breast milk or formula.
Treatment recommended for SOME patients in
Primary options
» normal immunoglobulin human: 0.5 to 1 g/

kg intravenously over 2 hours; repeat in 12
hours if necessary
» In infants with isoimmune haemolytic disease,

IVIG treatment may be commenced if the
total serum bilirubin is rising despite intensive
phototherapy or the total serum bilirubin level
is within 34 to 51 micromol/L (2-3 mg/dL) of the
exchange level, although the quality of evidence
supporting this therapy is low.[68]
total bilirubin above the 1st phototherapy
95th percentile in the
TREATMENT
hour-specific nomogram » Threshold levels are dependent on

for phototherapy gestational age, wellness, and presence of
additional risk factors. [Bhutani nomogram
guidelines for phototherapy in hospitalised
infants of 35 or more weeks’ gestation]
23
Acute


from 425-490 nm.[47]


neonates.[51] [52] [53] LED phototherapy
is another second-line alternative as it is as
effective as conventional therapy,[54] and
overhead use (versus illumination from beneath
the infant) shortened the mean duration of
phototherapy and increased the rate of decrease
in total serum bilirubin.[55] [53] Special blue
compact fluorescent lamp phototherapy had no
superiority over special blue standard length
tube light phototherapy in terms of efficacy and
adverse effects on the neonate and effects on
nursing staff.[57]



TREATMENT

Acute

boys.[58] [59]
plus hydration
» Treat any dehydration and maintain hydration
with enteral breast milk or formula.

total bilirubin levels above 1st exchange transfusion
the 95th percentile on the
hour-specific nomogram » Threshold levels are dependent on
for exchange transfusion gestational age, wellness, and presence of
guidelines for exchange transfusion in
infants 35 or more weeks’ gestation]

temperature instability, sepsis, and acidosis.
» Risk of acute bilirubin encephalopathy is

considered high when bilirubin values approach
levels >428 micromol/L (>25 mg/dL), or if lower
bilirubin levels are associated with additional risk
factors.
» Start as soon as the blood can be arranged

for the exchange transfusion. Continue
phototherapy while waiting to start the
TREATMENT
procedure, stop while doing the transfusion, and

restart phototherapy as soon as the exchange
transfusion is completed.
» The rationale is to remove the unconjugated

bilirubin by doing a double-volume exchange
25
Acute
transfusion, which should allow the bilirubin
to move out of the brain tissue and hence
decrease the risk of neurological toxicities. An
exchange transfusion will also remove antibodies
responsible for haemolytic anaemia. In severe
cases of erythroblastosis and/or hydrops, it will
correct anaemia.


plus phototherapy
» Provide intensive phototherapy for babies while
awaiting exchange transfusion and continue
phototherapy after exchange transfusion.
Continue to use nomograms to plot total serum
bilirubin (TSB) levels for gestational age and
hour after birth, and assess requirement for
further phototherapy or repeat exchange
transfusions.


from 425-490 nm.[47]


TREATMENT

neonates.[51] [52] [53] The second-line
alternative, LED phototherapy, is as efficacious
as conventional therapy,[54] and overhead use
(versus illumination from beneath the infant)
shortened the mean duration of phototherapy
Acute
and increased the rate of decrease in TSB.[55]
[53] Special blue compact fluorescent lamp
phototherapy had no superiority over special
blue standard length tube light phototherapy
in terms of efficacy and adverse effects on the
neonate and effects on nursing staff.[57]

the phototherapy light. Adverse effects are



boys.[58] [59]
plus hydration
TREATMENT
» Otherwise maintain hydration with enteral

breast milk or formula.
27
Acute
Treatment recommended for SOME patients in
Primary options
» normal immunoglobulin human: 0.5 to 1 g/

kg intravenously over 2 hours; repeat in 12
hours if necessary
» In infants with isoimmune haemolytic disease,

IVIG treatment may be commenced if the total
serum bilirubin level is rising despite intensive
phototherapy or is within 34-51 micromol/L (2-3
mg/dL) of the exchange level, although the
quality of evidence supporting this therapy is
low.[68]
conjugated
1st treatment of the underlying cause
» The management of conjugated

hyperbilirubinaemia is dependent on its
aetiology. Consultation with an appropriate
specialist may be required for further
management, depending on the aetiology found.
breast milk jaundice
1st temporary cessation of breast feeding +

supplemental feeding
» In neonates with jaundice due to breast milk,

interruption of breastfeeding for 24 to 48 hours
and supplemental feeding may be considered
if serum bilirubin levels require phototherapy,
which may result in a reduction of bilirubin
levels.[69]
2nd phototherapy
» Threshold levels are dependent on

gestational age, wellness, and presence of
guidelines for phototherapy in hospitalised
infants of 35 or more weeks’ gestation]

TREATMENT

Acute
from 425-490 nm.[47]

» Fibreoptic and light emitting diode (LED)

neonates.[51] [52] [53] The second-line
option LED phototherapy is as efficacious as
conventional therapy,[54] and overhead use
(versus illumination from beneath the infant)
shortened the mean duration of phototherapy
and increased the rate of decrease in total
serum bilirubin.[55] [53] Special blue compact
fluorescent lamp phototherapy had no superiority
over special blue standard length tube light
phototherapy in terms of efficacy and adverse
effects on the neonate and effects on nursing
staff.[57]

» Breastfeeding or bottle-feeding can be

continued in most circumstances while on
phototherapy.

aggressive phototherapy did not impact on the
TREATMENT

29
Acute
boys.[58] [59]
plus hydration
» Enteral hydration with breast milk or formula
is recommended unless total serum bilirubin is
very high.[69] Intravenous hydration is usually
reserved for neonates receiving phototherapy
with bilirubin levels close to the exchange value.
Such intravenous fluid supplementation may
result in a faster decline of bilirubin levels.[71]
3rd exchange transfusion
» Risk of acute bilirubin encephalopathy is

considered high when bilirubin values approach
levels >428 micromol/L (>25 mg/dL) or if lower
bilirubin levels are associated with additional
risk factors as per the Bhutani nomogram
[Bhutani nomogram guidelines for exchange
transfusion in infants 35 or more weeks’
gestation] (http://pediatrics.aappublications.org/
content/114/1/297#xref-fig-4-1) (such as
isoimmune haemolytic disease, glucose-6-
phosphate dehydrogenase deficiency,
temperature instability, significant lethargy,
perinatal asphyxia, sepsis, and acidosis or signs
of acute bilirubin encephalopathy).
» Start as soon as the blood can be arranged

for the exchange transfusion. Continue
phototherapy while waiting to start the
procedure, stop while doing the transfusion, and
restart phototherapy as soon as the exchange
transfusion is completed.
» The rationale is to remove the unconjugated

bilirubin by doing a double-volume exchange
transfusion, which should allow the bilirubin
to move out of the brain tissue and hence,
decrease the risk of neurological toxicities. An
exchange transfusion will also remove antibodies
responsible for haemolytic anaemia. In severe
cases of erythroblastosis and/or hydrops, it will
correct anaemia.

TREATMENT

Acute
TREATMENT
31
Emerging
Stannsoporfin
Stannsoporfin (also known as tin-mesoporphyrin) works by inhibiting haem oxygenase, an important
initial step in the production of bilirubin. Not approved in many countries as yet, but it has been used on a
compassionate basis.[72] An alternative option, if this treatment fails, would be an exchange transfusion.
Stannsoporfin can be used in all neonates not responding to intensive phototherapy, in an attempt to avoid
exchange transfusion and can be given any time while on phototherapy.[73] A single intramuscular injection
given prior to discharge decreased the duration of phototherapy, reversed the trajectory of total bilirubin
levels, and reduced subsequent hyperbilirubinaemia severity.[74] The drug has received fast track status
from the FDA. In August 2018, the FDA rejected approval of the drug requesting further evaluation to be
considered before resubmitting an application for approval.
Filtered sunlight
In a non-inferiority randomised controlled trial conducted in Nigeria, filtered sunlight was found to be as safe
and effective as conventional phototherapy.[75] It is important to note that this study was conducted in infants
who were at least 35 weeks of gestation or weighed >2.2 kg, had a postnatal age of up to 14 days, and had
bilirubin levels not exceeding 257 micromol/L (15 mg/dL).[75]
Ursodiol
A hydrophobic bile acid that decreases the secretion of cholesterol from the liver and its intestinal absorption
in neonates with parenteral nutrition, biliary atresia, and cystic fibrosis. The risk/benefit profile is unknown.
Clofibrate
Clofibrate enhances activity of the glucuronyl transferase enzyme, thus increasing the conjugation of
unconjugated bilirubin in the liver. Meta-analyses of clinical trials have suggested that clofibrate therapy
decreases the need and duration of phototherapy as well as the peak total serum bilirubin levels. These
effects were more obvious for term infants and in those without haemolytic disease. However, none of the
studies reported on bilirubin encephalopathy or neonatal mortality rates.[76] [77] A study from 2017 reported
that a single dose of clofibrate prior to starting phototherapy resulted in a significant reduction in the duration
of phototherapy.[78] Thus, while there appears to be some short-term benefit of this therapy, additional trials
are needed to confirm long-term neurodevelopmental outcomes before definite recommendations can be
made.
TREATMENT
Neonatal jaundice Follow up
Recommendations
Monitoring
FOLLOW UP
• Neonates treated for unconjugated hyperbilirubinaemia should be monitored for total serum
bilirubin and haematocrit levels.
• In neonates with haemolytic anaemia (secondary to blood group incompatibility), polycythaemia,
and extravasation of blood, monitoring for haematocrit levels is important to exclude late-onset
anaemia and any ongoing problems in normal bilirubin conjugation and excretion.
• Hearing and neurodevelopmental assessments should also be done to identify any residual effects
of bilirubin encephalopathy.[42]
• Surgical causes of increased enterohepatic circulation need follow-up with paediatric surgeons to
ensure proper excretion of bile.
• Neonates with partial specific enzymatic conjugation defects need periodic monitoring of total
serum bilirubin levels to avoid sustained high values.
• Neonates with conjugated hyperbilirubinaemia need monitoring dictated by its aetiology: those with
metabolic/genetic defects and clinical syndromes (such as alpha1-antitrypsin deficiency, cystic
fibrosis, Zellweger's, Dubin-Johnson, and Rotor's) need follow-up and monitoring by a specialised
team that can manage their varied clinical problems in addition to conjugated hyperbilirubinaemia.
Neonates with conjugated hyperbilirubinaemia due to hepatitis secondary to infection usually do not
require follow-up monitoring once the infection is treated and the hepatitis resolves.
Patient instructions
Follow-up with paediatrician 48 hours after discharge to check total serum bilirubin and haematocrit
values. Continue with breastfeeding or bottle feeding as usual.
33
Complications
Complications Timeframe Likelihood

FOLLOW UP
neurological damage short term medium
Early bilirubin-induced neurological toxicity can be detected by measuring brain stem auditory evoked
responses. It is presumably a result of entry of bilirubin specifically into the neural cells of the auditory
pathway.
In jaundiced neonates, there is absence or prolonged wave peak latencies and inter peak latencies.
Treated babies showed a tendency toward recovery in their auditory evoked responses.[79] [80]
Treatment consists of phototherapy and/or exchange transfusion to decrease serum unconjugated bilirubin
levels, which in turn would presumably decrease brain bilirubin levels and normalise the auditory evoked
responses.
acute bilirubin encephalopathy short term medium
Bilirubin is a cellular poison in the brain and is preferentially taken up by the basal ganglia, globus
pallidus, putamen, and caudate nuclei. It is said to disrupt the energy metabolism of the cells by affecting
mitochondrial function.
The initial phase is characterised by lethargy, hypotonia, and poor sucking with a high-pitched cry.
In the intermediate phase, the baby is irritable, with variable tone and a high-pitched cry.
In the advanced phase, the baby goes into deep stupor or coma, with hypertonia (retrocollis and/or
opisthotonus).
Treatment consists of phototherapy and/or exchange transfusion to decrease serum unconjugated bilirubin
levels, which in turn would presumably decrease brain bilirubin levels and normalise neurological function.
exchange transfusion complications short term medium
These include electrolyte disturbances, bleeding, infection, cardiac arrhythmias, thrombosis with
embolisation, necrotising enterocolitis, and graft-versus-host disease. Irradiation of blood is recommended
prior to using it for exchange transfusion to decrease the risk of graft-versus-host disease.
Proper monitoring is essential during exchange transfusions. Treatment is given if the infant is
symptomatic and/or has abnormal laboratory results for specific complications: for example, calcium
infusion for hypocalcaemia, platelet transfusions for thrombocytopenia.[42] [43] [47]
phototherapy complications short term low
This includes insensible water loss, loose stools, skin rash, and potential retinal damage.
These can be usually managed by ensuring adequate hydration, and placing eye shields over the eyes
during phototherapy.
The skin rash is benign and resolves after phototherapy is stopped.[42] [43] [47]
Complications Timeframe Likelihood

kernicterus (chronic bilirubin encephalopathy) variable low
FOLLOW UP
Kernicterus is diagnosed pathologically by gross yellow staining and necroses of neurons in the basal
ganglia, hippocampal area, and cerebellum. It occurs secondary to the entry of bilirubin into the brain,
which causes a disruption of cellular energy metabolism in the basal ganglia, hippocampal area, and
cerebellum.
The condition is rare: the pilot kernicterus registry in the US reported 125 babies affected from 1984 to
2002.
Cerebral cortex is usually spared. If the neonate survives, the clinical features include chorio-athetoid
cerebral palsy, paralysis of upward gaze, sensorineural hearing loss, dental dysplasia, and intellectual
deficits (less often in the mental retardation range).[47]
Kernicterus can be prevented by early and aggressive phototherapy and/or exchange transfusion.
Prognosis
Most neonates with neonatal unconjugated hyperbilirubinaemia do well after phototherapy and/or exchange
transfusion. Kernicterus should be preventable if recommendations for hyperbilirubinaemia management are
carried out in a timely manner.[43]
For neonates with haemolytic anaemia secondary to blood group incompatibility, haemolysis should not
present as a problem once the maternal antibodies are gone.
Babies with polycythaemia and extravasation of blood should not have any problem once the extra
haemoglobin breakdown is taken care of.
Surgical causes of increased enterohepatic circulation should resolve once the specific condition is treated.
Bilirubin levels of babies with partial specific enzymatic conjugation defects can usually be kept under control
with night-time phototherapy.
For babies with conjugated hyperbilirubinaemia, the outlook depends on the aetiology of the condition. The
clinical course is variable in babies with alpha 1-antitrypsin deficiency and cystic fibrosis. In babies with
Zellweger's syndrome, the prognosis is poor, with most neonates dying during the first year or surviving with
severe mental retardation and seizures. Patients with Dubin-Johnson and Rotor's syndromes (inherited as
autosomal recessive) have an excellent prognosis. The prognosis of babies with other metabolic/genetic
defects depends on early recognition and management of the specific enzyme deficiencies and accumulation
of metabolites. Parenteral-induced cholestasis should improve if enteral feeding can be established. Some of
the infectious aetiologies (such as congenital syphilis, bacterial) of hepatitis improve with specific treatments;
others resolve over time. Supportive treatment is needed for survivors of kernicterus. Rehabilitative treatment
is recommended for the specific neurological deficits.
35
Neonatal jaundice Guidelines
Diagnostic guidelines
Europe
Jaundice in newborn babies under 28 days (ht tp://guidance.nice.org.uk/

CG98)
Published by: National Institute for Health and Care Excellence Last published: 2016
North America
Management of hyperbilirubinemia in the newborn infant 35 or more weeks of

gestation (ht tp://pediatrics.aappublications.org/content/114/1/297.long)
Published by: American Academy of Pediatrics Last published: 2004
Management of hyperbilirubinemia in the newborn infant 35 or

GUIDELINES
more weeks of gestation: an update with clarifications (ht tp://

pediatrics.aappublications.org/content/124/4/1193)
Published by: American Academy of Pediatrics Subcommittee on Last published: 2009
Hyperbilirubinemia
Guidelines for detection, management and prevention of hyperbilirubinemia

in term and late preterm newborn infants (ht tp://www.cps.ca/en/documents/
authors-auteurs/fetus-and-newborn-commit tee)
Published by: Canadian Paediatric Society Last published: 2007 (re-
affirmed 2018)
Asia
Guidelines on evaluation and management of neonatal jaundice (ht tps://

www.ams.edu.sg/policy-advocacy/guidelines-consensus-statements-for-
healthcare-professionals)
Published by: Academy of Medicine Singapore/College of Paediatrics Last published: 2018
and Child Health Singapore
Integrated plan for detection and management of neonatal jaundice (ht tps://
mpaeds.my/guideline-protocols/)
Published by: Ministry of Health Malaysia Last published: 2017
Oceania
Maternity and neonatal clinical guideline: neonatal jaundice (ht tp://

www.health.qld.gov.au/qcg/html/publications.asp)
Published by: Queensland Clinical Guidelines Last published: 2019
Neonatal - jaundice identification and management in neonates ≥32 weeks

gestation (ht tp://www.health.nsw.gov.au/policies/Pages/default.aspx)
Published by: New South Wales Government Last published: 2016
Treatment guidelines
Europe
GUIDELINES
Jaundice in newborn babies under 28 days (ht tp://guidance.nice.org.uk/
CG98)
Postnatal care up to 8 weeks after birth (ht tp://guidance.nice.org.uk/CG37)

International
Postnatal care of the mother and newborn (ht tp://www.who.int/publications/

guidelines/child_health/en/)
Published by: World Health Organization Last published: 2013
Pocket book of hospital care for children: guidelines for the management of
common childhood illnesses (ht tp://www.who.int/publications/guidelines/
child_health/en/)
Published by: World Health Organization Last published: 2013
37
North America
Technical report: phototherapy to prevent severe neonatal hyperbilirubinemia

in the newborn infant 35 or more weeks of gestation (ht tp://
pediatrics.aappublications.org/content/128/4/e1046)
Published by: American Academy of Pediatrics Last published: 2011
Prevention of acute bilirubin encephalopathy and kernicterus in newborns

(ht tp://nann.org/about/position-statements)
Published by: National Association of Neonatal Nurses Last published: 2010
Management of hyperbilirubinemia in the newborn infant 35 or

more weeks of gestation: an update with clarifications (ht tp://
pediatrics.aappublications.org/content/124/4/1193)
Hyperbilirubinemia
GUIDELINES
Guidelines for detection, management and prevention of hyperbilirubinemia

in term and late preterm newborn infants (ht tp://www.cps.ca/en/documents/
authors-auteurs/fetus-and-newborn-commit tee)
Published by: Canadian Paediatric Society Last published: 2007 (re-
affirmed 2018)
Management of hyperbilirubinemia in the newborn infant 35 or more weeks of

gestation (ht tp://pediatrics.aappublications.org/content/114/1/297)
Hyperbilirubinemia
Asia
Guidelines on evaluation and management of neonatal jaundice (ht tps://

www.ams.edu.sg/policy-advocacy/guidelines-consensus-statements-for-
healthcare-professionals)
Published by: Academy of Medicine Singapore/College of Paediatrics Last published: 2018
and Child Health Singapore
Integrated plan for detection and management of neonatal jaundice (ht tps://
mpaeds.my/guideline-protocols/)
Published by: Ministry of Health Malaysia Last published: 2017
Oceania
Neonatal jaundice (ht tp://www.health.qld.gov.au/qcg/html/publications.asp)

Published by: Queensland Health Statewide Maternity and Neonatal Last published: 2019
Clinical Guidelines Program
Neonatal - jaundice identification and management in neonates ≥32 weeks

gestation (ht tp://www.health.nsw.gov.au/policies/Pages/default.aspx)
Published by: New South Wales Government Last published: 2016
GUIDELINES
39
Neonatal jaundice Online resources
Online resources
1. Bhutani nomogram for designation of risk based on hour-specific serum bilirubin values (http://
pediatrics.aappublications.org/content/114/1/297#p-152) (external link)
2. Bhutani nomogram guidelines for phototherapy in hospitalised infants of 35 or more weeks’ gestation
(http://pediatrics.aappublications.org/content/114/1/297#xref-fig-3-1) (external link)
3. Bhutani nomogram guidelines for exchange transfusion in infants 35 or more weeks’ gestation (http://
pediatrics.aappublications.org/content/114/1/297#xref-fig-4-1) (external link)
ONLINE RESOURCES
Neonatal jaundice References
Key articles
• Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for
REFERENCES
subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics. 1999
Jan;103(1):6-14. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/9917432?tool=bestpractice.bmj.com)
• Queensland Clinical Guidelines. Maternity and neonatal clinical guideline: neonatal jaundice. Jun 2019
[internet publication]. Full text (https://www.health.qld.gov.au/__data/assets/pdf_file/0018/142038/g-
jaundice.pdf)
• Maisels MJ, Bhutani VK, Bogen D, et al. Hyperbilirubinemia in the newborn infant ≥35 weeks'
gestation: an update with clarifications. Pediatrics. 2009 Oct;124(4):1193-8. Abstract (http://
www.ncbi.nlm.nih.gov/pubmed/19786452?tool=bestpractice.bmj.com)
• Mehta S, Kumar P, Narang A. A randomized controlled trial of fluid supplementation in term

neonates with severe hyperbilirubinemia. J Pediatr. 2005 Dec;147(6):781-5. Abstract (http://
• Bhandari V, Narang A, Mann SB, et al. Brain stem electric response audiometry in neonates
with hyperbilirubinemia. Indian J Pediatr. 1993 May-Jun;60(3):409-13. Abstract (http://
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Neonatal jaundice Images
Images
IMAGES
Figure 1: Metabolic pathway of bilirubin with pathologies relating to unconjugated hyperbilirubinaemia. 1. ABO
incompatibility, Rhesus incompatibility, shorter RBC lifespan in neonates, bruising during delivery; 2. induced
by inflammatory mediators associated with comorbidities of prematurity (e.g., respiratory distress syndrome,
infection); 3. dissociation increased by acidosis, ketosis, renal failure; 4. permeable blood-brain barrier in term
neonates and premature babies; 5. mutation in UGT1A1 gene results in Gilbert’s syndrome or Crigler-Najjar
syndrome I and II; 6. unconjugated bilirubin load increased by decreased gut motility
49
IMAGES Neonatal jaundice Images
Figure 2: Detail of liver lobule and its functions, highlighting pathologies that cause conjugated
hyperbilirubinaemia. Pathologies include: 1. portal vein thrombosis; 2. choledochal cyst; 3. infection (sepsis,
E coli urinary tract infection, hepatitis A or B, toxoplasmosis, cytomegalovirus, syphilis, herpes), metabolic
(Rotor's syndrome, galactosaemia, tyrosinaemia, alpha-1 antitrypsin deficiency, hypothyroidism, cystic
fibrosis, Zellweger's syndrome), drugs, idiopathic neonatal hepatitis, total parenteral nutrition, neonatal
haemochromatosis, shock/hypoxia/ischaemia; 4. bile duct paucity, biliary atresia, Alagille syndrome,
idiopathic neonatal cholestasis, progressive familial intrahepatic cholestasis, inspissated bile syndrome; 5.
MRP2 (also known as ABCC2) gene mutations on the canalicular membrane of hepatocytes result in Dubin-
Johnson syndrome, absence of OATP1B1 and OATP1B3 at the sinusoidal membrane of hepatocytes result in
Rotor's syndrome
Neonatal jaundice Images
IMAGES
Figure 3: Yellow-orange discoloration of palms and soles contrasted with the mother’s normal skin colour
BMJ Case Reports 2009; doi:10.1136/bcr.2008.139014. Used with permission
51
Neonatal jaundice Disclaimer
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Neonatal jaundice Disclaimer
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53
Contributors:
// Authors:
Vineet Bhandari, MBBS, MD, DM

Professor of Pediatrics Obstetrics and Gynecology
Drexel University College of Medicine, Chief, Section of Neonatal Medicine, St. Christopher's Hospital for
Children/Hahnemann University Hospital/Temple University Hospital, Philadelphia, PA
DISCLOSURES: VB declares that he has no competing interests.
// Peer Reviewers:
Gautham K. Suresh, MD, DM, MS

Professor of Pediatrics
Baylor College of Medicine, Section Head and Service Chief of Neonatology, Texas Children's Hospital,
Houston, TX
DISCLOSURES: GKS declares that he has no competing interests.
Helen McElroy, MBChB, MRCPI, MSc

Consultant Neonatologist
Neonatology, Medway Maritime Hospital, Gillingham, UK
DISCLOSURES: HM declares that she has no competing interests.

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Neonatal jaundice

Straight to the point of care

Last updated: Apr 28, 2020

◊ Jaundice in the first 24 hours of life is considered pathological.

◊ Treatment for severe hyperbilirubinaemia includes phototherapy and/or exchange transfusion.

◊ The major complication of unconjugated hyperbilirubinaemia is kernicterus.

• Metabolic or genetic defects. Examples include alpha1-antitrypsin deficiency, cystic fibrosis,

Metabolic pathway of bilirubin with pathologies relating to unconjugated hyperbilirubinaemia. 1. ABO

Evaluation of pathological jaundice

Direct bilirubin >34.2 micromol/L (2 mg/dL)

Direct bilirubin <34.2 micromol/L (2 mg/dL)

low birth weight

decreased caloric intake and weight loss

delayed cord clamping (2-3 minutes)

History & examination factors

cephalocaudal progression (common)

decreasing gestational age (common)

family history of jaundice (uncommon)

family history of anaemia (uncommon)

family history of splenectomy (uncommon)

maternal exposure to sulphonamides or antimalarials (uncommon)

small for gestational age (uncommon)

high-pitched cry (uncommon)

Other diagnostic factors

• Increased counts are suggestive of haemolysis.

Other tests to consider

Condition Differentiating signs / Differentiating tests

• Breastfeeding/bottle-feeding can be continued in most circumstances while on phototherapy.

• Bilirubin values approach levels of 428 micromol/L (25 mg/dL)

• Use of IVIG in neonatal unconjugated hyperbilirubinaemia secondary to haemolytic disease

Due to breast milk

Treatment details overview

1st reassurance and observation

acute bilirubin 1st immediate exchange transfusion

adjunct intravenous immunoglobulin (IVIG)

total bilirubin above the 1st phototherapy

total bilirubin levels 1st exchange transfusion

adjunct intravenous immunoglobulin (IVIG)

1st treatment of the underlying cause

breast milk jaundice

1st temporary cessation of breast feeding +

3rd exchange transfusion

1st reassurance and observation

» Jaundice is physiological if it occurs in the

» No treatment is required for physiological

acute bilirubin 1st immediate exchange transfusion

» This is a medical emergency.

» Start as soon as blood can be arranged for the

» There is insufficient evidence to support

» The major potential complications of the

plot total serum bilirubin levels for gestational

» Risk factors include isoimmune haemolytic

» Phototherapy uses light energy to cause

» As first-line therapy, double-light phototherapy

» Fibreoptic and light-emitting diode (LED)

» The risk/benefit profile is excellent, with

» Breastfeeding/bottle feeding can be continued

» One randomised controlled trial reported that

» It may be prudent to initiate phototherapy

» Otherwise, maintain hydration with enteral

» normal immunoglobulin human: 0.5 to 1 g/

» In infants with isoimmune haemolytic disease,

hour-specific nomogram » Threshold levels are dependent on