Neonates: Neonatal Jaundice

Question 1

How common is neonatal jaundice?

Answer 1

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

Although most cases are not caused by an underlying pathology, jaundice can indicate serious disease and may result in long-term morbidity and even mortality if untreated.

Question 2

When is neonatal jaundice ALWAYS pathological?

Answer 2

In the first 24 hours

Question 3

Give 4 causes of jaundice in the first 24 hours?

Answer 3

Haemolytic disease:

1) rhesus haemolytic disease

2) ABO haemolytic disease

3) hereditary spherocytosis

4) glucose-6-phosphodehydrogenase

Question 4

What is jaundice?

Answer 4

Describes the condition of abnormally high bilirubin in the blood.

RBCs contain unconjugated bilirubin.

When RBCs break down, the release unconjugated bilirubin into the blood.

Unconjugated bilirubin is conjugated in the liver.

Conjugated bilirubin is excreted in two ways: via the biliary system into the gastrointestinal tract and via the urine.

Question 5

Where is bilirubin conjugated?

Answer 5

Liver

Question 6

Jaundice in a healthy baby, born at term.

What are the 2 reasons behind physiological neonatal jaundice?

Answer 6

1) Increased RBC breakdown

2) Immature liver not able to process high bilirubin concentrations

3) A relatively high concentration of β-glucuronidase in the small intestine

Question 7

Why is there increased RBC breakdown in neonates?

Answer 7

In utero the foetus has a high concentration of Hb (to maximise oxygen exchange and delivery to the fetus).

These RBCs are more fragile than normal RBCs and break down, releasing bilirubin as high Hb is no longer needed.

Normally this bilirubin is excreted via the placenta, however at birth the foetus no longer has access to a placenta to excrete bilirubin.

Question 8

When is physiological neonatal jaundice most common?

Answer 8

From 2-10 days

Question 9

What type of babies is physiological jaundice more commonly seen in?

Answer 9

Breastfed babies

Question 10

Interventions in neonatal jaundice?

Answer 10

None

Question 11

When would neonatal jaundice caused by haemolytic disease present?

Answer 11

In the first 24 hours

Question 12

What is bilirubin produced from?

Answer 12

Breakdown of RBCs

Question 13

What happens to circulating unconjugated bilirubin?

Answer 13

Most binds to albumin but some circulates as ‘free’ bilirubin –> this is lipid-soluble and can cross the blood-brain barrier.

Question 14

What enzyme converts unconjugated bilirubin to conjugated bilirubin in the liver?

Answer 14

UDP-glucuronosyltransferase (UGT)

Question 15

Pathway of bilirubin metabolism:

Answer 15

1) Bilirubin is produced from the breakdown of RBCs

2) UDP-glucuronosyltransferase (UGT), converts unconjugated bilirubin to conjugated bilirubin in the liver

3) 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.

4) This unconjugated bilirubin re-enters the circulating pool of bilirubin via the enterohepatic circulation.

5) The remaining conjugated bilirubin is metabolised by intestinal bacteria to produce urobilinogen and stercobilinogen

6) Urobilinogen is oxidised to urobilin, which gives urine its yellow colour.

7) Stercobilinogen is oxidised to stercobilin, which gives faeces its brown colour.

Question 16

Can unconjugated bilirubin cross the BBB?

Answer 16

Yes - is lipid soluble

Question 17

Can conjugated bilirubin cross the BBB?

Answer 17

No - is water soluble but lipid insoluble

Question 18

What are the 2 metabolites of conujgated bilirubin?

Answer 18

1) Urobilinogen

2) Stercobilinogen

Question 19

What gives urine its yellow colour?

Answer 19

Urobilin

Question 20

What is urobilinogen oxidised to?

Answer 20

Urobilin

Question 21

What is stercobilinogen oxidised to?

Answer 21

Stercobilin

Question 22

What gives faeces its brown colour?

Answer 22

Stercobilin

Question 23

Which neonates are more prone to jaundice?

Answer 23

1) Preterm babies: tend to have higher bilirubin levels and more prolonged jaundice than term infants.

2) Breastfed babies: experience more marked and prolonged jaundice than formula-fed infants

3) Babies with significant bruising or cephalohaematoma: occurs in difficult deliveries

Question 24

Is physiological jaundice conjugated or unconjugated?

Answer 24

Unconjugated

Question 25

Give some haemolytic causes of neonatal jaundice

Answer 25

1) Haemolytic disease of the newborn: caused by maternal Rhesus or ABO antibodies against the baby’s RBCs 2) Hereditary spherocytosis: an inherited disease where defects in RBC skeletal proteins cause RBCs to assume a spherical shape with a reduced lifespan 3) G6PD deficiency: an X-linked recessive condition where lack of G6PD makes RBCs susceptible to oxidative damage and haemolysis. It can cause severe neonatal jaundice.

Question 26

Give 4 endocine or metabolic causes of unconjugated neonatal jaundice

Answer 26

1) Gilbert’s syndrome 2) Crigler-Najjar syndrome 3) Congenital hypothyroidism 4) Galactosaemia and other inborn errors of metabolism (these may also cause conjugated jaundice)

Question 27

What is Gilbert's syndrome?

Answer 27

An autosomal recessive disorder with reduced UGT enzyme activity in the liver. This causes reduced ability to conjugate bilirubin, resulting in mild episodes of jaundice throughout life in response to certain triggers.

Question 28

What enzyme has reduced activity in Gilbert's syndrome?

Answer 28

UGT enzyme - enzyme in liver responsible for conjugating bilirubin.

Question 29

What is Crigler-Najjar syndrome?

Answer 29

A rare autosomal recessive disorder where no functioning UGT is produced in the liver. It presents with severe, prolonged jaundice that often results in neurological damage and death within one year of life.

Question 30

What are 3 causes of conjugated neonatal jaundice?

Answer 30

1) Biliary atresia 2) Neonatal hepatitis (e.g. CMV, hepatitis B, rubella or herpes simplex virus) 3) Galactosaemia and other inborn errors of metabolism

Question 31

What is a common cause of neonatal jaundice within the first 24 hours?

Answer 31

Neonatal sepsis

Question 32

Why is physiological jaundice exaggerated in premature neonates?

Answer 32

Due to the immature liver.

Question 33

What is haemolytic disease of the newborn (HDN)?

Answer 33

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.

Question 34

What must you consider when a woman that is rhesus D negative (does not have the rhesus D antigen) becomes pregnant?

Answer 34

Must consider the possibility that her child will be rhesus D positive (has the rhesus D antigen). 1) It is likely at some point in the pregnancy the blood from the baby will find a way into her bloodstream. 2) When this happens, the baby’s red blood cells display the rhesus D antigen. 3) The mother’s immune system will recognise this rhesus D antigen as foreign and produce antibodies to the rhesus D antigen. 4) The mother has then become sensitised to rhesus D antigens --> normally not a problem during 1st pregnancy 5) 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. 6) This leads to haemolysis, causing anaemia and high bilirubin levels (haemolytic disease of the newborn)

Question 35

When can the sensitisation process in a rhesus D negative mother be a problem in their first pregnancy?

Answer 35

If the sensitisation happens early on, such as during antepartum haemorrhage

Question 36

Risk factors for pathological hyperbilirubinaemia?

Answer 36

1) Prematurity, low birth weight, small for dates 2) Previous sibling required phototherapy 3) Exclusively breast fed 4) Jaundice <24 hours 5) Infant of diabetic mother

Question 37

What is biliary atresia?

Answer 37

A congenital inflammatory disease of unknown cause. It results in complete obliteration of the extra-hepatic bile ducts after birth. If untreated, it progresses to liver cirrhosis and death.

Question 38

How does biliary atresia present?

Answer 38

1) Prolonged conjugated jaundice 2) Pale stools 3) Dark urine

Question 39

What defines prolonged neonatal jaundice?

Answer 39

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

Question 40

What is the gold standard diagnostic method for biliary atresia?

Answer 40

A percutaneous biopsy

Question 41

Management of biliary atresia?

Answer 41

1) portoenterostomy (Kasai procedure) or 2) liver transplant

Question 42

What investigations are required in prolonged neonatal jaundice?

Answer 42

1) conjugated and unconjugated bilirubin levels 2) direct antiglobulin test (Coombs' test): for haemolysis 3) TFTs 4) FBC and blood film: for polycythaemia or anaemia 5) urine for MC&S and reducing sugars 6) U&Es and LFTs 7) G6PD levels for G6PD deficiency

Question 43

Causes of prolonged neonatal jaundice?

Answer 43

1) biliary atresia 2) hypothyroidism 3) galactosaemia 4) UTI 5) breast milk jaundice 6) prematurity 7) congenital infections e.g. CMV, toxoplasmosis

Question 44

Clinical features of neonatal jaundice?

Answer 44

1) Colour - baby should be naked and examined in bright, natural light - jaundice is often most obvious in the sclerae and gums - blanche the skin 2) Drowsy: difficult to rouse, not waking for feeds, very short feeds 3) Neuro: - altered muscle tone - seizures-needs immediate attention 4) Pale, chalky stools (conjugated jaundice) 5) Dark urine (conjugated jaundice)

Question 45

Which neonates require routine bilirubin checking?

Answer 45

All babies who are visibly jaundiced

Question 46

What are 2 options for measuring bilirubin levels in neonates?

Answer 46

1) Transcutaneous bilirubinometry 2) Serum bilirubin

Question 47

What is transcutaneous bilirubinometry?

Answer 47

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.

Question 48

When would transcutaneous bilirubinometry be used to over serum bilirubin and vice versa?

Answer 48

Transcutaneous bilirubinometer: - >35 weeks gestation - >24 hours old - Can be used for all subsequent measurements, providing the level remains <250 µmol/L and the child has not required treatment Serum bilirubin: - Babies who are visibly jaundiced <24 hours of life - Gestational age <35 weeks - Monitoring bilirubin after starting treatment.

Question 49

Which investigation is used to monitor bilirubin levels AFTER starting treatmnet?

Answer 49

Serum bilirubin

Question 50

Which investigation is used to monitor bilirubin levels in jaundiced neonates with a gestational age <35 weeks?

Answer 50

Serum bilirubin

Question 51

Which investigation is used to monitor bilirubin levels in neonates that are jaundiced <24 hours of life?

Answer 51

Serum bilirubin

Question 52

What investigations are required for babies who require TREATMENT for jaundice?

Answer 52

1) Blood packed cell volume (PCV) 2) Blood group of the mother and baby 3) Direct antiglobulin test (DAT, aka Coombs’ test) Also consider: - FBC and blood film - G6PD levels - Blood, urine and/or cerebrospinal fluid cultures: if signs of infection

Question 53

Purpose of a blood packed cell volume (PCV) in neonatal jaundice?

Answer 53

To assess the degree of anaemia or polycythaemia

Question 54

Purpose of investigating blood group of the mother and baby in neonatal jaundice?

Answer 54

To assess for incompatibility (i.e. haemolytic disease of the newborn)

Question 55

What does a positive Coombs test indicate?

Answer 55

Suggests immune-mediated haemolysis (i.e. haemolytic disease of the newborn).

Question 56

What does a negative Coombs test indicate?

Answer 56

suggests non-immune-mediated haemolysis (e.g. hereditary spherocytosis or G6PD deficiency)

Question 57

What are the 2 main methods to treating neonatal jaundice?

Answer 57

1) phototherapy 2) exchange transfusion Note - most babies will respond well to phototherapy and exchange transfusions are rarely used.

Question 58

What is the decision to begin treatment in neonatal jaundice based on?

Answer 58

Treatment threshold graphs. There are different graphs for different gestations and preterm babies have a lower threshold for starting treatment.

Question 59

What happens in phototherapy in the management of neonatal jaundice?

Answer 59

The baby is placed under blue-green light. The light converts the neurotoxic unconjugated bilirubin to a harmless, water-soluble isomer called lumirubin, which is readily excreted in the bile and urine.

Question 60

What is unconjugated bilirubin converted to during phototherapy?

Answer 60

lumirubin

Question 61

How do exchange transfusions work in neonatal jaundice?

Answer 61

Exchange transfusions reduce bilirubin levels by swapping the baby’s blood with donor blood. A small volume of the baby’s blood is removed as donor blood is injected. This may be required for dangerously high levels of bilirubin. 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.

Question 62

Who are exchange transfusions reserved for in neonatal jaundice?

Answer 62

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 63

What is found on a treatment threshold charts for neonatal jaundice?

Answer 63

Age of the baby - plotted on x-axis Total bilirubin level - plotted on 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 64

When is treatment for neonatal jaundice initiated according to treatment graph?

Answer 64

1) If level is on or above the phototherapy line 2) If level is below phototherapy line: a) >50µmol/L below, clinically well with no risk factors for neonatal jaundice do not routinely repeat level b) <50µmol/L below, clinically well repeat level within 18 hours (risk factors present) to 24 hours (no risk factors present)

Question 65

How often should bilirubin levels be monitored during treatment for neonatal jaundice?

Answer 65

Repeat bilirubin 4-6 hours post initiation to ensure not still rising, 6-12 hourly once level is stable or reducing.

Question 66

When can phototherapy for neonatal jaundice be stopped?

Answer 66

Stop phototherapy once level >50µmol/L below treatment line on the threshold graphs. Check for rebound of hyperbilirubinaemia 12-18 hours after stopping phototherapy.

Question 67

What can be used as adjunct to intensified phototherapy in rhesus haemolytic disease or ABO haemolytic disease?

Answer 67

IV Immunglobulin

Question 68

What is the key complication of neonatal jaundice?

Answer 68

Bilirubin encephalopathy (kernicterus). This occurs with high levels of unconjugated bilirubin.

Question 69

What is Kernicterus?

Answer 69

A type of brain damage caused by excessive bilirubin levels. Unconjugated bilirubin is lipid-soluble and can cross the BBB. It accumulates in the brainstem nuclei, basal ganglia, hippocampus and cerebellum and is neurotoxic.

Question 70

How does bilirubin encephalopathy (kernicterus) present?

Answer 70

- lethargy - hypotonia - poor suck reflex This progresses to: - hypertonia - opisthotonos - fever - seizures - a high-pitched cry

Question 71

Prognosis of kernicterus?

Answer 71

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

Question 72

1st line investigation in suspected pathological neonatal jaundice?

Answer 72

Coombs test +ve when mothers Abs attack baby's RBC (due to ABO or Rh incompatibility).

Question 73

When are doses of anti D given?

Answer 73

1) 28 weeks gestation 2) Within 24 hours of birth

Question 74

What is the most common scenario of ABO incompatibility causing HDN?

Answer 74

Mother has O blood group and baby has A or B blood type. Typically there are already anti-A and anti-B antibodies present in the mother's circulation (even without any sensitisation from a prior pregnancy). This is because A and B antigens are similar to common enivornmental antigens (e.g. bacteria, dust or pollen). Exposure to these antigens results in the generation of anti-A and anti-B antibodies --> these Abs cross the placenta and cause haemolysis in the 1st pregnancy.

Question 75

If the Coombs test is negative in neonatal jaundice, what is the next step?

Answer 75

Check Hb level. If low --> may be a blood collection outside vessels e.g. cephalohaematoma due to trauma during delivery. If high --> increased load of RBCs is slowly getting broken down --> common in babies of diabetic mothers, twin-twin transfusion syndrome, delayed cord clamping.

Question 76

How can a cephalohaematoma cause neonatal jaundice?

Answer 76

Blood collection outside vessels breaks down and gets absorbed as bilirubin.

Question 77

If Hb is normal in neonatal jaundice, what is next step?

Answer 77

Check reticulocyte count, LDH & haptoglobin. Then consider blood film.

Question 78

Possible investigations in neonatal jaundice?

Answer 78

1) Coombs test 2) Hb level 3) Reticulocyte count, LDH & haptoglobin 4) Blood film 5) Enzyme levels e.g. G6PD 6) Hb electrophoresis --> haemoglobinopathies e.g. sickle cell, thalassaemia