Introduction

Kernicterus, also called bilirubin encephalopathy, is a serious and potentially life-threatening condition that occurs due to increased bilirubin levels in the blood (hyperbilirubinemia). High concentrations of bilirubin can enter the brain and spinal cord of newborns, which can lead to permanent issues in growth and development. Therefore, it is crucial to identify and minimise risk factors for kernicterus, detect hyperbilirubinaemia early, and ensure proper management.¹

Understanding kernicterus

What is bilirubin?

When aged red blood cells are broken down, they produce a potentially toxic substance called bilirubin. However, the human body has developed an effective system to detoxify and excrete bilirubin.² When bilirubin is formed and released into the blood, it gets bound to albumin and transported to the liver. This form of bilirubin is called unconjugated bilirubin and is soluble in lipids. In the liver, unconjugated bilirubin undergoes a process of conjugation in which glucuronic acid is attached to the bilirubin molecule, producing conjugated bilirubin. Conjugated bilirubin is water-soluble, does not get transported back into the blood and is excreted in bile. This process prevents the circulation of high concentrations of unconjugated bilirubin in blood, which can cross the blood-brain barrier to enter the brain and cause serious damage.³

What causes high levels of unconjugated bilirubin?

Increased unconjugated bilirubin levels can be the result of the production of high amounts of bilirubin due to:³

• High red blood cell turnover, which exceeds the capacity of the liver to conjugate
• A problem in the uptake process of the liver
• An issue with the conjugation process within the liver 

Hyperbilirubinemia is common in newborns, usually mild, and resolves spontaneously.

What is kernicterus?

The brain is covered by a selectively permeable membrane, the blood-brain barrier, which regulates the movement of ions and other substances between the blood and the brain tissue to protect the brain from toxic substances.⁴ Unlike the conjugated form, unconjugated bilirubin is soluble in lipids and can easily cross the blood-brain barrier and enter the brain. Kernicterus develops when bilirubin deposits predominantly in the basal ganglia and causes damage and death of nerve cells.⁵ Even though many cases of hyperbilirubinemia and jaundice resolve without serious complications, it can rarely result in kernicterus.

Features of kernicterus

Excess unconjugated bilirubin in the blood deposits in the skin and leads to a yellowish discolouration of the skin and sclera (jaundice). Babies with kernicterus will have jaundice, as it is one of the first manifestations of hyperbilirubinemia. Appropriate treatment of early jaundice can prevent the development of kernicterus. 

Symptoms that may appear once brain damage (kernicterus) has occurred are:

• Poor feeding
• Sleepiness
• Floppy arms and legs 
• Irritability
• High-pitched cry
• Muscle rigidity and abnormal posturing (arching of neck and trunk)
• Irregular breathing patterns

Damage to the nerve cells can result in serious long-term complications like cerebral palsy, hearing loss, visual problems, movement problems, and intellectual disability.¹

Risk factors for kernicterus in term infants

Newborn babies have several risk factors that predispose them to kernicterus, which differ based on whether they were born at term or are preterm. Risk factors for kernicterus in term babies are as follows:

Blood type incompatibility

Humans have eight different blood groups depending on the antigens (molecules that can initiate an immune response) present on red blood cells. Based on the presence or absence of “a” and “b” antigens, individuals can have:

• Group A (antigen “a” present)
• Group B (antigen “b” present)
• Group AB (both antigen “a” and “b” present)
• Group O (both antigen “a” and “b” absent) 

Each blood group is further divided according to the presence of the Rhesus factor (Rh): if the factor is present, the blood group is positive; if absent, it is negative. Those who have blood group O and the Rh-negative groups can develop antibodies against the antigens they lack naturally or after exposure to certain factors. 

If the mother has antibodies against these antigens (“a”, “b” or the Rhesus factor), during pregnancy, they can cross the placenta and enter the baby’s blood. These antibodies can bind to antigens of the baby’s red blood cells (if the baby has an Rh or other antigen-positive group) and destroy the red cells. Increased turnover of red cells leads to increased amounts of bilirubin that can cause jaundice and kernicterus.⁶

Cephalohaematoma and bruising

During birth, harmless injuries can occur due to the shearing forces that can cause accumulation of blood under the scalp, known as a cephalohematoma. Once the collection of red blood cells undergoes breakdown, large amounts of bilirubin are produced.⁷

Polycythaemia

Polycythaemia is when you have more red blood cells than the normal amount. Foetuses have an environment with less oxygen when they are inside the uterus. As a response, they produce a higher than normal number of red cells. 0.4% to 5% of healthy newborn babies have polycythaemia.⁸ Some other factors, like diabetes of the mother, genetic defects, and delayed cord clamping, can also result in polycythaemia. Once born, the extra red cells break down quickly to adapt to normal levels, and this can lead to jaundice and kernicterus. 

People assigned male at birth 

Studies have found that people assigned male at birth have higher levels of bilirubin and are at an increased risk for kernicterus.¹

Ethnicity

Babies of African, South and East Asian, and Mediterranean descent develop kernicterus more frequently compared to babies of other ethnicities.¹

Hereditary defects of bilirubin metabolism

Gene mutations that result in deficiencies in enzymes required for bilirubin metabolism (conjugation and excretion) in the liver can lead to kernicterus. Gilbert syndrome and Crigler-Najjar syndrome are rare genetic disorders that can result in unconjugated hyperbilirubinemia.¹

Risk factors for kernicterus in preterm infants

Babies born before 37 weeks of gestation are considered preterm. Preterm newborns have significant differences in their physiology compared to term newborns, as they have had incomplete growth and development within the uterus. Risk factors for kernicterus in preterm babies are as follows:

Immature liver function

Preterm babies have poor blood supply to the liver and less developed liver metabolic pathways, which fail to break down and excrete bilirubin effectively, causing higher unconjugated bilirubin levels.⁹ It can take several weeks for the liver to start functioning fully. 

Immature blood-brain barrier

Newborns have immature, more permeable blood-brain barriers. Preterm babies have an even more immature and weak barrier that lets lipid-soluble substances easily cross into the brain, which increases the risk of kernicterus.⁹

Feeding difficulties

Preterm newborns do not have sucking, swallowing and breathing coordination properly developed. Therefore, they might not be able to be breastfed like a healthy term baby.¹⁰ They may need to be fed through tubes or may have to be completely fed artificially through nutrients delivered directly to the bloodstream (parenteral nutrition). Lipids delivered as parenteral nutrition can displace bilirubin bound to albumin, increasing free circulating unconjugated bilirubin in the blood. Challenges in feeding can also disrupt bilirubin excretion by causing dehydration.¹¹

Infections and other concurrent illnesses

Preterm neonates acquire infections more easily as they have immature immune systems and have to undergo many invasive procedures. Infections can increase red cell destruction and impair liver functions, increasing the risk.¹

Diagnostic and monitoring strategies

Regular physical examination should be done to identify early jaundice and prevent kernicterus. Yellowish discolouration of the body and whites of the eye, when detected, should be investigated and treated. With the involvement of the nervous system, bulging of the soft spots of the skull (fontanelles), increased heart rate and rapid breathing may be observed.¹ Rigidity of arms and legs, abnormal arching of the back, lethargy and irritability will indicate more advanced disease. 

If jaundice is suspected, blood tests need to be done to confirm the diagnosis and initiate management. It evaluates:

• Total, direct, and indirect bilirubin levels
• Blood group and Rhesus status of the mother and baby
• Coombs test: it can detect if antibodies have been formed against red cell antigens, leading to increased red cell damage
• Full blood count: it  can assess the haemoglobin level and rule out ongoing infections
• Reticulocyte count: reticulocytes are immature blood cells which rise in number when red cells are excessively destroyed

Transcutaneous bilirubinometry is a non-invasive method of measuring bilirubin. A small device is used to direct light onto the skin and detect the amount absorbed by bilirubin by measuring the intensity of the reflected light.¹² It gives immediate results, is painless, convenient, cheaper and provides a method for early detection. However, when positive, a blood test needs to be done to confirm the exact levels of bilirubin.¹²  

Prevention and management

The goal in managing kernicterus is to lower bilirubin levels to minimise further brain damage. The three main options for management of hyperbilirubinemia are:

Phototherapy 

Phototherapy is an effective and safe way of reducing bilirubin levels and is accepted as the first option of management worldwide.¹³ Blue light is used to convert unconjugated bilirubin to a water-soluble form that can be easily excreted from the body. Dehydration, skin rash, and bronze discolouration of skin are identified side effects. It is important to protect the eyes with a cover during phototherapy to prevent permanent retinal damage.¹³

Exchange transfusion

The newborn’s blood is removed and replaced with blood that does not contain bilirubin. Exchange transfusions are done when bilirubin levels are very high with brain damage, but attempts to reduce them by other means are unsuccessful. Infections, circulatory overload, high potassium, low calcium and glucose can occur with the procedure.¹ 

Intravenous immunoglobulin

Intravenous immunoglobulin is used to manage hyperbilirubinemia due to increased red cell destruction secondary to antibody-mediated damage (in blood group incompatibilities). It reduces the need for exchange transfusions.¹ 

It is crucial to detect jaundice and begin appropriate management early to prevent kernicterus. Risk factors for hyperbilirubinemia should be documented during pregnancy, including the mother's blood group, history of jaundice in siblings, family history of inherited disorders of bilirubin metabolism, or disorders of excessive red cell breakdown. Parents should be educated to identify early signs of jaundice, and regular assessment of the baby should be done following discharge.¹⁴

Summary

• Kernicterus is a serious condition where brain damage occurs due to high unconjugated bilirubin levels that cross the immature blood-brain barrier and deposit in the basal ganglia, causing nerve cell damage
• Yellowish discolouration of skin (also called jaundice) is an early sign of hyperbilirubinemia. In the late stages of kernicterus, poor feeding, lethargy, high-pitched crying, and muscle rigidity occur
• Risk factors for kernicterus in term neonates include blood group incompatibility, cephalohematoma and other birth trauma, polycythemia, male gender, certain ethnic backgrounds, and genetic disorders of bilirubin metabolism
• Immature liver function, an underdeveloped blood-brain barrier, feeding difficulties, and infections increase the risk of kernicterus in preterm babies
• Clinical examination provides clues to jaundice and kernicterus. It can be confirmed by blood tests – bilirubin levels, blood grouping, full blood count, and reticulocyte count
• Transcutaneous bilirubinometry is a quick, non-invasive, and convenient method of detecting hyperbilirubinemia
• Management of kernicterus aims to reduce bilirubin levels in the blood and is achieved by phototherapy, exchange transfusion, and administration of intravenous immunoglobulin
• Risk assessment, parental education, and early identification and management of jaundice with regular follow-up are crucial in preventing kernicterus