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BMJ-Neonatal Jaundice PDF
BMJ-Neonatal Jaundice PDF
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.
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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Neonatal jaundice Basics
(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:
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
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Neonatal jaundice Basics
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]
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Neonatal jaundice Basics
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
Created by BMJ Knowledge Centre
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]
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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.
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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.
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Neonatal jaundice Diagnosis
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.
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]
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Neonatal jaundice Diagnosis
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.
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]
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]
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Neonatal jaundice Diagnosis
• Risk of jaundice increases with decreasing gestational age.
male (common)
• Neonatal jaundice is more common in males.
hepatosplenomegaly (uncommon)
• Suggests hepatocellular disease.
DIAGNOSIS
microcephaly (uncommon)
• Suggests congenital infection.
chorioretinitis (uncommon)
• Suggests congenital infection.
cephalhaematoma (uncommon)
• Extravasation of blood.
hypertonia (uncommon)
• Late sign of bilirubin encephalopathy.
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Neonatal jaundice Diagnosis
retrocollis (uncommon)
• Late sign of bilirubin encephalopathy.
opisthotonus (uncommon)
• Late sign of bilirubin encephalopathy.
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
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Neonatal jaundice Diagnosis
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
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Neonatal jaundice Diagnosis
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
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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
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Neonatal jaundice Treatment
(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
• 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:
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]
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Neonatal jaundice Treatment
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.
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Neonatal jaundice Treatment
Acute ( summary )
physiological hyperbilirubinaemia
pathological hyperbilirubinaemia:
unconjugated
plus phototherapy
plus hydration
plus hydration
plus phototherapy
plus hydration
pathological hyperbilirubinaemia:
conjugated
2nd phototherapy
plus hydration
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Neonatal jaundice Treatment
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
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Neonatal jaundice Treatment
Acute
physiological hyperbilirubinaemia
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Neonatal jaundice Treatment
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/
content/114/1/297#xref-fig-4-1)
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Neonatal jaundice Treatment
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.
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Neonatal jaundice Treatment
Acute
(http://pediatrics.aappublications.org/
content/114/1/297#xref-fig-3-1)
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Neonatal jaundice Treatment
Acute
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.
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Neonatal jaundice Treatment
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.
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Neonatal jaundice Treatment
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]
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Neonatal jaundice Treatment
Acute
Treatment recommended for SOME patients in
selected patient group
Primary options
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Neonatal jaundice Treatment
Acute
that do not require conjugation in the liver. The
most effective phototherapy wavelengths are
from 425-490 nm.[47]
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Neonatal jaundice Treatment
Acute
phototherapy and an increased risk of childhood
epilepsy (not febrile seizures), particularly in
boys.[58] [59]
plus hydration
Treatment recommended for ALL patients in
selected patient group
» 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
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Neonatal jaundice Treatment
Acute
thrombosis with embolisation, necrotising
enterocolitis, and graft-versus-host disease.
TREATMENT
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Neonatal jaundice Treatment
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
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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.
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Neonatal jaundice Follow up
Complications
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.
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.
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]
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]
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Neonatal jaundice Follow up
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.
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Neonatal jaundice Guidelines
Diagnostic guidelines
Europe
North America
Asia
Integrated plan for detection and management of neonatal jaundice (ht tps://
mpaeds.my/guideline-protocols/)
Published by: Ministry of Health Malaysia Last published: 2017
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Neonatal jaundice Guidelines
Oceania
Treatment guidelines
Europe
GUIDELINES
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
International
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
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Neonatal jaundice Guidelines
North America
Asia
Integrated plan for detection and management of neonatal jaundice (ht tps://
mpaeds.my/guideline-protocols/)
Published by: Ministry of Health Malaysia Last published: 2017
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Neonatal jaundice Guidelines
Oceania
GUIDELINES
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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
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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)
• 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://
www.ncbi.nlm.nih.gov/pubmed/8253490?tool=bestpractice.bmj.com)
References
1. Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for
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)
2. Kumar RK. Neonatal jaundice: an update for family physicians. Aust Fam Physician. 1999
Jul;28(7):679-82. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/10431423?tool=bestpractice.bmj.com)
5. Smitherman H, Stark AR, Bhutani VK. Early recognition of neonatal hyperbilirubinemia and its
emergent management. Semin Fetal Neonatal Med. 2006 Jun;11(3):214-24. Abstract (http://
www.ncbi.nlm.nih.gov/pubmed/16603425?tool=bestpractice.bmj.com)
6. Greco C, Arnolda G, Boo NY, et al. Neonatal Jaundice in Low- and Middle-Income Countries:
Lessons and Future Directions from the 2015 Don Ostrow Trieste Yellow Retreat. Neonatology.
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BMJ Best Practice topics are regularly updated and the most recent version of the topics
41
can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (.
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Neonatal jaundice References
2016;110(3):172-80. Full text (https://www.doi.org/10.1159/000445708) Abstract (http://
www.ncbi.nlm.nih.gov/pubmed/27172942?tool=bestpractice.bmj.com)
REFERENCES
7. Setia S, Villaveces A, Dhillon P, et al. Neonatal jaundice in Asian, white, and mixed-race infants.
Arch Pediatr Adolesc Med. 2002 Mar;156(3):276-9. Full text (https://www.doi.org/10.1001/
archpedi.156.3.276) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/11876673?
tool=bestpractice.bmj.com)
8. Maisels MJ, Kring E. Transcutaneous bilirubin levels in the first 96 hours in a normal newborn
population of > or = 35 weeks' gestation. Pediatrics. 2006 Apr;117(4):1169-73. Abstract (http://
www.ncbi.nlm.nih.gov/pubmed/16585312?tool=bestpractice.bmj.com)
10. Maisels MJ. What's in a name? Physiologic and pathologic jaundice: the conundrum of defining
normal bilirubin levels in the newborn. Pediatrics. 2006 Aug;118(2):805-7. Abstract (http://
www.ncbi.nlm.nih.gov/pubmed/16882840?tool=bestpractice.bmj.com)
11. Yu Z, Zhu K, Wang L, et al. Association of neonatal hyperbilirubinemia with UGT1A1 gene
polymorphisms: a meta-analysis. Med Sci Monit. 2015 Oct 15;21:3104-14. Full text (https://
www.ncbi.nlm.nih.gov/pmc/articles/PMC4612146/) Abstract (http://www.ncbi.nlm.nih.gov/
pubmed/26467199?tool=bestpractice.bmj.com)
12. Klein CJ, Revenis M, Kusenda C, et al. Parenteral nutrition-associated conjugated hyperbilirubinemia
in hospitalized infants. J Am Diet Assoc. 2010 Nov;110(11):1684-95. Abstract (http://
www.ncbi.nlm.nih.gov/pubmed/21034882?tool=bestpractice.bmj.com)
13. Gottesman LE, Del Vecchio MT, Aronoff SC. Etiologies of conjugated hyperbilirubinemia in infancy: a
systematic review of 1692 subjects. BMC Pediatr. 2015 Nov 20;15:192. Full text () Abstract (http://
www.ncbi.nlm.nih.gov/pubmed/26589959?tool=bestpractice.bmj.com)
14. Lain SJ, Roberts CL, Bowen JR, et al. Early discharge of infants and risk of readmission for
jaundice. Pediatrics. 2015 Feb;135(2):314-21. Full text (http://pediatrics.aappublications.org/
content/135/2/314.long) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/25583922?
tool=bestpractice.bmj.com)
15. De Luca D, Jackson GL, Tridente A, et al. Transcutaneous bilirubin nomograms: a systematic
review of population differences and analysis of bilirubin kinetics. Arch Pediatr Adolesc Med. 2009
Nov;163(11):1054-9. Full text (http://archpedi.ama-assn.org/cgi/content/full/163/11/1054) Abstract
(http://www.ncbi.nlm.nih.gov/pubmed/19884597?tool=bestpractice.bmj.com)
16. Centers for Disease Control and Prevention. What are Jaundice and Kernicterus? Nov 2019 [internet
publication]. Full text (https://www.cdc.gov/ncbddd/jaundice/facts.html)
42 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 28, 2020.
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Neonatal jaundice References
17. Porter ML, Dennis BL. Hyperbilirubinemia in the term newborn. Am Fam Physician. 2002 Feb
15;65(4):599-606. Full text (https://www.aafp.org/afp/2002/0215/p599.html) Abstract (http://
www.ncbi.nlm.nih.gov/pubmed/11871676?tool=bestpractice.bmj.com)
REFERENCES
18. Abu-Heija AT, Al-Bash M, Mathew M. Gestational and Pregestational Diabetes Mellitus in Omani
Women: Comparison of obstetric and perinatal outcomes. Sultan Qaboos Univ Med J. 2015
Nov;15(4):e496-500. Full text (https://www.doi.org/10.18295/squmj.2015.15.04.009) Abstract (http://
www.ncbi.nlm.nih.gov/pubmed/26629376?tool=bestpractice.bmj.com)
19. Ghosh S, Ghosh K. Maternal and neonatal outcomes in gestational diabetes mellitus. J Indian Med
Assoc. 2013 May;111(5):330-1, 336. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/24765693?
tool=bestpractice.bmj.com)
20. Cosson E, Benchimol M, Carbillon L, et al. Universal rather than selective screening for gestational
diabetes mellitus may improve fetal outcomes. Diabetes Metab. 2006 Apr;32(2):140-6. Full text
(https://www.doi.org/10.1016/s1262-3636(07)70260-4) Abstract (http://www.ncbi.nlm.nih.gov/
pubmed/16735962?tool=bestpractice.bmj.com)
21. Khatun N, Latif SA, Uddin MM. Infant outcomes of gestational diabetes mellitus. Mymensingh
Med J. 2005 Jan;14(1):29-31. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/15695950?
tool=bestpractice.bmj.com)
22. Berk MA, Mimouni F, Miodovnik M, et al. Macrosomia in infants of insulin-dependent diabetic mothers.
Pediatrics. 1989 Jun;83(6):1029-34. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/2726329?
tool=bestpractice.bmj.com)
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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
Created by BMJ Knowledge Centre
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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
Created by BMJ Knowledge Centre
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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
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Neonatal jaundice Disclaimer
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