Jaundice

Question 1

What is jaundice?

Answer 1

Jaundice is a yellow discolouration of the sclerae and skin due to excess bilirubin in the blood (hyperbilirubinaemia).

Question 2

How common is neonatal jaundice?

Answer 2

Neonatal jaundice is extremely common. Around 60% of term babies and 80% of preterm babies will develop jaundice in the first week of life.

Question 3

Briefly describe the bilirubin metabolism in a neonate

Answer 3

Bilirubin is produced from the breakdown of red blood cells (RBCs). Most unconjugated bilirubin circulates bound to albumin, but some circulate as ‘free’ bilirubin, which is lipid-soluble and can cross the blood-brain barrier.

An enzyme in the liver, called UDP-glucuronosyltransferase (UGT), converts unconjugated bilirubin to conjugated bilirubin by adding an amino acid. Conjugated bilirubin is water-soluble but lipid insoluble, so it cannot cross the blood-brain barrier.

Conjugated bilirubin is transported to the small intestines via the biliary system and some is converted back to unconjugated bilirubin by the enzyme β-glucuronidase. This unconjugated bilirubin re-enters the circulating pool of bilirubin via the enterohepatic circulation.

The remaining conjugated bilirubin is metabolised by intestinal bacteria to produce urobilinogen and stercobilinogen. Urobilinogen is oxidised to urobilin, which gives urine its yellow colour. Stercobilinogen is oxidised to stercobilin, which gives faeces its brown colour.

Question 4

What is physiological ‘normal’ jaundice?

Answer 4

Jaundice is often a normal phenomenon in neonates, with no underlying pathology. Physiological jaundice is unconjugated and usually presents on the second or third day of life.

Question 5

What causes physiological ‘normal’ jaundice?

Answer 5

Mechanisms behind physiological jaundice include:

• Shorter lifespan of neonatal red blood cells
• Immature liver function at birth
• A relatively high concentration of β-glucuronidase in the small intestine

Question 6

How long should physiological ‘normal’ jaundice last in a neonate?

Answer 6

Starts at day 2-3, peaks day 5 and usually resolved by day 10. The baby remains well and does not require any intervention beyond routine neonatal care.

Question 7

What are the risk factors for physiological ‘normal’ jaundice?

Answer 7

Some neonates are more prone to jaundice:

• Preterm babies
  
  • Tend to have higher bilirubin levels and more prolonged jaundice than term infants.
• Breastfed babies
  
  • Experience more marked and prolonged jaundice than formula-fed infants for reasons that are not completely understood. Prolonged jaundice in breastfed babies is sometimes referred to as ‘breast milk’ jaundice.
• Babies with significant bruising or cephalohaematoma
  
  • Which can occur in difficult deliveries. The breakdown of RBCs within the cephalohaematoma causes higher bilirubin levels and predisposes to jaundice.

Question 8

What are the 2 categories that pathological jaundice can be split into?

Answer 8

The causes of neonatal jaundice can be split into increased production or decreased clearance.

Question 9

Give examples of pathological causes of jaundice due to increased production of bilirubin

Answer 9

Increased production of bilirubin:

• Haemolytic disease of the newborn
• ABO incompatibility
• Haemorrhage
• Intraventricular haemorrhage
• Cephalo-haematoma
• Polycythaemia
• Sepsis and disseminated intravascular coagulation
• G6PD deficiency

Question 10

Give examples of pathological causes of jaundice due to decreased clearance of bilirubin

Answer 10

Decreased clearance of bilirubin:

• Prematurity
• Breast milk jaundice
• Neonatal cholestasis
• Extrahepatic biliary atresia
• Endocrine disorders (hypothyroid and hypopituitary)
• Gilbert syndrome

Question 11

When is jaundice always pathological in the neonate?

Answer 11

Jaundice in the first 24 hours of life and conjugated jaundice is pathological.

Question 12

What are the risk factors for jaundice?

Answer 12

Risk factors for pathological hyperbilirubinaemia: to be asked in history

• Prematurity, low birth weight, small for dates
• Previous sibling required phototherapy
• Exclusively breast fed
• Jaundice <24 hours
• Infant of diabetic mother

Question 13

Briefly describe breastfeeding jaundice

Answer 13

Babies that are breastfed are more likely to have neonatal jaundice. There are several potential reasons for this. Components of breast milk inhibit the ability of the liver to process the bilirubin. Breastfed babies are more likely to become dehydrated if not feeding adequately. Inadequate breastfeeding may lead to slow passage of stools, increasing absorption of bilirubin in the intestines.

Breastfeeding should still be encouraged, as the benefits of breastfeeding outweigh the risks of breast milk jaundice. Mothers may need extra support and advice to ensure adequate breastfeeding.

Question 14

What is prolonged jaundice? What can cause it?

Answer 14

Jaundice is “prolonged” when it lasts longer than would be expected in physiological jaundice. This is:

• More than 14 days in full term babies
• More than 21 days in premature babies

Prolonged jaundice should prompt further investigation to look for an underlying cause. These are particularly looking for conditions that will cause jaundice to persist after the initial neonatal period, such as biliary atresia, hypothyroidism and G6PD deficiency.

Question 15

What can cause conjugated jaundice?

Answer 15

Causes of conjugated jaundice include:

• Biliary atresia: early diagnosis and treatment of this condition is vital
• Neonatal hepatitis (e.g. cytomegalovirus, hepatitis B, rubella or herpes simplex virus)
• Galactosaemia and other inborn errors of metabolism

Question 16

Briefly describe biliary atresia

NoteL including clinical features, diagnosis and treatment

Answer 16

Biliary atresia is a congenital inflammatory disease of unknown cause. It results in completeobliteration of the extra-hepatic bile ducts after birth. If untreated, it progresses to liver cirrhosis and death.

It presents with prolonged conjugated jaundice, pale stools and dark urine. A liver ultrasound scan is helpful, but a percutaneous biopsy is the gold-standard diagnostic method. Biliary atresia is treated with a portoenterostomy (Kasai procedure) or liver transplantation.

All babies with conjugated jaundice need urgent further investigation and referral to a paediatric liver specialist. The longer biliary atresia goes untreated, the more irreversible damage is done to the liver.

Question 17

Briefly describe haemolytic disease of the newborn

Answer 17

Haemolytic disease of the newborn is a cause of haemolysis (red blood cells breaking down) and jaundice in the neonate. It is caused by incompatibility between the rhesus antigens on the surface of the red blood cells of the mother and fetus. The rhesus antigens on the red blood cells vary between individual. This is different to the ABO blood group system.

Within the rhesus group, there are many different types of antigens that can be present or absent depending on the persons blood type. The most important antigen within the rhesus blood group system is the rhesus D antigen.

When a woman that is rhesus D negative (does not have the rhesus D antigen) becomes pregnant, we have to consider the possibility that her child will be rhesus D positive (has the rhesus D antigen). It is likely at some point in the pregnancy the blood from the baby will find a way into her bloodstream. When this happens, the baby’s red blood cells display the rhesus D antigen. The mother’s immune system will recognise this rhesus D antigen as foreign and produce antibodies to the rhesus D antigen. The mother has then become sensitised to rhesus D antigens.

Usually, this sensitisation process does not cause problems during the first pregnancy (unless the sensitisation happens early on, such as during antepartum haemorrhage). During subsequent pregnancies, the mother’s anti-D antibodies can cross the placenta into the fetus. If that fetus is rhesus positive, these antibodies attach themselves to the red blood cells of the fetus and causes the immune system of the fetus to attack their own red blood cells. This leads to haemolysis, causing anaemia and high bilirubin levels. This leads to a condition called haemolytic disease of the newborn.

Question 18

Briefly describe the history for neonatal jaundice

Answer 18

The history may reveal risk factors for neonatal jaundice. NICE guidelines list the following risk factors for significant hyperbilirubinaemia (i.e. requiring treatment):

• Gestational age <38 weeks
• Previous sibling with neonatal jaundice requiring phototherapy
• Mother’s intention to breastfeed exclusively
• Visible jaundice in the first 24 hours of life

Other important areas to cover in the history include:

• Family history: a history of inherited diseases (e.g. G6PD deficiency or liver disease) or previous sibling with jaundice (suggests a higher chance of haemolytic disease of the newborn)
• Pregnancy history: congenital infections, diabetes (increases the risk of jaundice), maternal drugs (e.g. sulfonamides interfere with bilirubin-albumin binding), maternal blood group and any known antibodies
• Labour and delivery history: birth trauma (e.g. bruising or cephalohaematoma)
• Feeding history: breastfeeding or formula feeding, intake (poor intake causes delayed or infrequent stooling which increases enterohepatic circulation of bilirubin), vomiting (may be a sign of sepsis or galactosaemia)

Question 19

Briefly describe the clinical examination for neonatal jaundice

Answer 19

A thorough clinical examination should be performed.

To detect jaundice, the baby should be naked and examined in bright, natural light.

Jaundice is often most obvious in the sclerae and gums. The skin can be lightly pressed, which may reveal jaundice in the blanched skin.

It is important to assess if the baby is clinically well and whether there are any signs of infection or bilirubin encephalopathy.

Examination should include inspecting the nappy for stools and urine. Pale, chalky stools and dark urine suggest conjugated jaundice and an underlying pathological cause such as biliary atresia.

Jaundice in the first 24 hours of life and conjugated jaundice are always pathological and require urgent investigation for an underlying cause.

Question 20

What investigations should be ordered for neonatal jaundice?

Answer 20

• Full blood count and blood film
• Conjugated bilirubin
• Blood type testing of mother and baby for ABO or rhesus incompatibility
• Direct antiglobulin test (Coombs test)
• Thyroid function
• Blood and urine cultures if infection is suspected
• Glucose-6-phosphate-dehydrogenase (G6PD)

Question 21

Why investigate using FBC and blood film?

Answer 21

Investigate for polycythaemia or anaemia.

Question 22

Why investigate bilirubin?

Answer 22

It is important to measure the bilirubin level for all babies who are visibly jaundiced. This can be achieved with:

• Transcutaneous bilirubinometry
  
  • A bedside test that evaluates light absorption through the skin over the forehead or sternum. It is not as accurate as serum bilirubin but is non-invasive.
• Serum bilirubin
  
  • NICE guidelines recommend that serum levels are used for babies who are visibly jaundiced <24 hours of life, with a gestational age <35 weeks, or when monitoring bilirubin after starting treatment. Serum bilirubin is also used to confirm a high transcutaneous level.

Question 23

Why investigate using direct antiglobulin test (Coomb’s test)?

Answer 23

A positive DAT suggests immune-mediated haemolysis (i.e. haemolytic disease of the newborn). A negative DAT suggests non-immune-mediated haemolysis (e.g. hereditary spherocytosis or G6PD deficiency)

Question 24

Why investigate glucose-6-phosphate-dehydrogenase (G6PD) levels?

Answer 24

Glucose-6-phosphate-dehydrogenase (G6PD) levels for G6PD deficiency especially if there is a positive family history or in Mediterranean, Asian or African ethnicity.

Question 25

Briefly describe the role of a treatment threshold chart in managing neonatal jaundice

Answer 25

In jaundiced neonates, total bilirubin levels are monitored and plotted on treatment threshold charts. These charts are specific for the gestational age of the baby at birth. The age of the baby is plotted on the x-axis and the total bilirubin level on the y-axis. If the total bilirubin reaches the threshold on the chart, they need to be commenced on treatment to lower their bilirubin level.

Question 26

Briefly describe the management options for jaundice

Answer 26

There are two main methods to treat neonatal jaundice: phototherapy and exchange transfusion. Most babies will respond well to phototherapy and exchange transfusions are rarely used.

The decision to begin treatment is based on treatment threshold graphs produced by NICE. There are different graphs for different gestations and preterm babies have a lower threshold for starting treatment.

Question 27

When is phototherapy and exchange transfusion used?

Answer 27

Phototherapy is usually adequate to correct neonatal jaundice. Extremely high levels may require an exchange transfusion. Exchange transfusions involve removing blood from the neonate and replacing it with donor blood.

Question 28

Briefly describe phototherapy

Answer 28

Phototherapy converts unconjugated bilirubin into isomers that can be excreted in the bile and urine without requiring conjugation in the liver. Phototherapy involves removing clothing down to the nappy to expose the skin and eye patches to protect the eyes. Blue light is the best at breaking down bilirubin. A light-box shines blue light on the baby’s skin. Little or no UV light is used. Double phototherapy involves two light-boxes. Bilirubin is closely monitored during treatment. Once phototherapy is complete, a rebound bilirubin should be measured 12 – 18 hours after stopping to ensure the levels do not rise about the treatment threshold again.

Question 29

Briefly describe exchange transfusion

Answer 29

Exchange transfusions reduce bilirubin levels by swapping the baby’s blood with donor blood. This may be required for dangerously high levels of bilirubin.

A small volume of the baby’s blood is removed as donor blood is injected. This process is repeated many times. As well as lowering serum bilirubin levels, exchange transfusions can also remove a significant proportion of the antibodies responsible for haemolytic disease of the newborn.

Exchange transfusions have a high rate of complications, so they are reserved for the most severe cases of neonatal jaundice which are not responding to intense phototherapy or where babies are showing signs of acute bilirubin encephalopathy.

Question 30

What is the main complication of neonatal jaundice?

Answer 30

The main complication is bilirubin encephalopathy (kernicterus), which can occur with high levels of unconjugated bilirubin.

Question 31

Briefly describe bilirubin encephalopathy (Kernicterus)

Answer 31

Unconjugated bilirubin is lipid-soluble and can cross the blood-brain barrier. It accumulates in the brainstem nuclei, basal ganglia, hippocampus and cerebellum and is neurotoxic.

Bilirubin encephalopathy initially presents with lethargy, hypotonia and poor suck reflex. This progresses to hypertonia, opisthotonos, fever, seizures and a high-pitched cry.

Early damage to the brain can be reversible but if hyperbilirubinemia is pronounced or prolonged then it can lead to cerebral palsy, sensorineural hearing loss or cognitive impairment.