# Neonatal jaundice

Neonatal jaundice is a common condition that is observed in newborns that are born both term and preterm. Neonatal jaundice typically presents in the first week of postnatal life, or life after birth. Jaundice in the newborn period is often self-limiting and harmless, however more serious pathologic causes of jaundice must not be missed.
In most of cases there is no specific underlying physiologic disorder. In other cases it results from red blood cell breakdown, liver disease, infection, hypothyroidism, or metabolic disorders (pathologic). Concerns, in otherwise healthy babies, occur when jaundice is noticed in the first day of life, there is a rapid rise in levels, jaundice lasts more than two weeks, or the baby appears unwell. In those with concerning findings further investigations to determine the underlying cause are recommended.
The need for treatment depends on bilirubin levels, the age of the child, and the underlying cause. Treatments may include more frequent feeding, phototherapy, or exchange transfusions. In those who are born early more aggressive treatment tends to be required.

## Sign and symptoms

Jaundice is the clinical manifestation of hyperbilirubinemia and can be visible to the naked eye. Hyperbilirubinemia occurs when the level of bilirubin is elevated. Jaundice most commonly appears as yellowing of the sclera, the white parts of the eye, as well as yellowing of the skin. Depending on the newborn's complexion, the jaundice may be more or less visible. Jaundice causes a yellow coloring to the skin because of the buildup of unconjugated bilirubin. Unconjugated bilirubin is lipid, or fat soluble. The level of hyperbilirubinemia must be closely monitored to ensure the newborn's safety and so that it does not reach a level that requires intervention. The typical pattern of jaundice begins at the newborn's head and spreads downwards eventually reaching the feet if bilirubin levels become high enough.

### Complications
#### Kernicterus

More serious signs of hyperbilirubinemia, include poor feeding, a high-pitched cry, irritability and drowsiness. When bilirubin levels reach extreme elevation, kernicterus can occur. Kernicterus is also known as bilirubin encephalopathy and can cause severe neurological issues for the neonate. Kernicterus cannot be caused by conjugated bilirubin, which is water soluble. Kernicterus is caused by unconjugated bilirubin and because it is lipid-soluble, this allows bilirubin to cross the blood brain barrier. Kernicterus can have devastating consequences for the newborn. Large studies have suggested that kernicterus can occur in newborns when the bilirubin level is >20 mg/dL.

#### Pathophysiology of Newborn Jaundice

Bilirubin
Bilirubin is produced in a few different ways in the newborn. The majority of bilirubin comes from the breakdown of red blood cells, specifically, the heme component of the cell. Bilirubin can also be a product of myoglobin, muscle cells, and certain enzymes. In fetal development, bilirubin first appears at 14 weeks gestation.
When red blood cells complete a lifespan, they must be broken down. This usually happens between every 1.5 to 3 months in a newborn. One major breakdown product of the red blood cell is heme. After the red blood cells are broken down to heme, heme must then be further broken down by the body. Heme is broken down further by something called the reticuloendothelial system. The reticuloendothelial system is found in the spleen, liver and in cells called phagocytes. These cells further break down heme into byproducts that are released by the lungs and eventually into the yellow pigment bilirubin.
After bilirubin is created, it binds to a protein called albumin and once bound is delivered to the liver. Bilirubin binding to albumin can be decreased in a sick neonate. The older the gestational age of the neonate, the more binding occurs between bilirubin and albumin. The bilirubin must then travel to the liver because it needs to go through a process called conjugation. Before bilirubin reaches the liver, it is considered unconjugated or indirect bilirubin. Unconjugated or indirect bilirubin is insoluble, and cannot be dissolved in water. Unconjugated bilirubin can cross the blood-brain barrier. It is dangerous if bilirubin crosses the blood brain barrier because it can lead to a serious condition called kernicterus.
Once it reaches the liver, the bilirubin is then taken up by cells in the liver that are called hepatocytes. Within hepatocytes, UDP glucuronate beta-glucuronosyl transferase, an enzyme that with glucuronic acid molecules, catalyzes the conversion of unconjugated insoluble bilirubin to a conjugated more soluble form. Overall, this process is important because it allows the newborn to get rid of excess bilirubin.
In the newborn period, there are less bacteria available in the digestive tract to further reduce and excrete bilirubin. In the newborn, the immaturity of the conjugation system, liver and, decreased red blood cell life cycle all put the newborn at risk for hyperbilirubinemia. Specifically, newborns have low levels of uridine diphosphate glucuronyl transferase, the enzyme responsible for conjugating bilirubin so that it can be soluble and can be more easily removed from the body. When compared to an adults' ability to conjugate bilirubin with this enzyme, it is believed that uridine diphosphate glucuronyl transferase’s activity is 1% that of its full adult potential in the newborn.
There are two types of hyperbilirubinemia, conjugated, which is also called direct, and unconjugated, which is also called indirect. Most newborns experience unconjugated/indirect hyperbilirubinemia in the first week of life after birth. Unconjugated hyperbilirubinemia can be transient and normal for most neonates. There are some types of unconjugated hyperbilirubinemia present at birth that however, are not benign. Serious disorders genetic conditions such as Gilbert Syndrome, Crigler-Najjar and disorders of glucuronosyltransferase cause unconjugated hyperbilirubinemia. This leads to decreased conjugation which causes the unconjugated hyperbilirubinemia. Conjugated hyperbilirubinemia is always abnormal in the newborn period.

#### Fetal Metabolism of Bilirubin

The metabolism of bilirubin differs in fetal life versus adult life. After birth, newborns transition from fetal metabolism to adult metabolism of bilirubin. Newborns produce an increased rate of bilirubin per kilogram body weight when compared to adults. In utero, fetal bilirubin passes through the placenta and is largely eliminated by maternal means. During fetal life, when bilirubin is eliminated by the placenta, it is lipid solid and unconjugated. Once the fetal bilirubin passes through the placenta, it goes into maternal plasma and eventually is eliminated by the maternal liver. After birth, the excretion through the placenta is no longer available to the fetus. The fetal liver also plays a role in elimination of bilirubin during fetal life to an extent.
Enterohepatic circulation
Enterohepatic circulation refers to the cycle in which bilirubin is metabolized in the liver, secreted into bile, then placed into the small intestine where it is then absorbed again and brought back to the liver. It is believed that there is increased enterohepatic circulation in a condition called “human milk jaundice”. Additionally, due to low nutritional volume intake in the first few days of newborn life, enterohepatic circulation is increased. The digestive tract in adults contains more bacteria than neonates. In adults, these bacteria can reduce conjugated bilirubin for further excretion.

## Causes

In newborns, jaundice tends to develop because of two factors—the breakdown of fetal hemoglobin as it is replaced with adult hemoglobin and the relatively immature metabolic pathways of the liver, which are unable to conjugate and so excrete bilirubin as quickly as an adult. This causes an accumulation of bilirubin in the blood (hyperbilirubinemia), leading to the symptoms of jaundice.
Physiological Jaundice and Pathologic Jaundice
In the newborn period, evaluating the timing of onset of neonatal jaundice is important. Timing of onset of the jaundice in the newborn period is important to determine if the jaundice is physiological or more serious and pathological. Generally, it is more concerning if a newborn develops jaundice in the first 24-48 hours of life as this is suggestive the reason for the jaundice is not physiological. In addition to timing of jaundice, neonatal jaundice can be also be broken down by unconjugated hyperbilirunemia and conjugated hyperbilirubinemia. The chart below helps breakdown the different categories of newborn jaundice.
| | | | | | | | | | | | | | | | | | | | | | | Neonatal jaundice | Neonatal jaundice | Neonatal jaundice | Neonatal jaundice | | | | | | | | |
| | | | | | | | | | | | | Unconjugated bilirubin | Unconjugated bilirubin | Unconjugated bilirubin | Unconjugated bilirubin | Unconjugated bilirubin | Unconjugated bilirubin | | | | | | | | | | | | | Conjugated bilirubin | Conjugated bilirubin | Conjugated bilirubin | Conjugated bilirubin | Conjugated bilirubin | Conjugated bilirubin |
| | | | | | | Pathologic | Pathologic | Pathologic | Pathologic | Pathologic | Pathologic | | | | | | | Physiological jaundice of neonates | Physiological jaundice of neonates | Physiological jaundice of neonates | Physiological jaundice of neonates | Physiological jaundice of neonates | Physiological jaundice of neonates | Hepatic | Hepatic | Hepatic | Hepatic | Hepatic | Hepatic | | | | | | | Post-hepatic | Post-hepatic | Post-hepatic | Post-hepatic | Post-hepatic | Post-hepatic |
| Hemolytic | Hemolytic | Hemolytic | Hemolytic | Hemolytic | Hemolytic | | | | | | | Non-hemolytic | Non-hemolytic | Non-hemolytic | Non-hemolytic | Non-hemolytic | Non-hemolytic | | | | | | | | | | | | | | | | | | | | |
| Intrinsic causes | Intrinsic causes | Intrinsic causes | Intrinsic causes | Intrinsic causes | Intrinsic causes | | | | | | | Extrinsic causes | Extrinsic causes | Extrinsic causes | Extrinsic causes | Extrinsic causes | Extrinsic causes | | | | | | | | | | | | | | | | | | | | |

### Physiologic Jaundice:

Physiologic jaundice in the newborn is common. Physiological jaundice occurs due to many factors related to normal newborn physiology including decreased uridine-diphosphate glucuronosyltransferase activity, decreased intestinal bacteria and decreased lifespan of red blood cells in neonates. All of these factors can contribute to transient unconjugated hyperbilirubinemia in the newborn, as they transition over the first few days from intrauterine to extrauterine life.
Physiologic jaundice in the newborn occurs frequently. 60% of full term newborns and 80% of prematurely born newborns experience hyperbilirubinemia. Typically within the first week, total bilirubin levels can reach levels higher than 5 mg/dL in many newborns. The elevation in bilirubin levels usually reaches its highest level between day of life 3-4, and then decreases.
Physiological jaundice typically occurs within the first week of life, as bilirubin levels steadily increase over the first 3-4 days. Typically, the bilirubin levels reach a peak and then steadily decline without the need for medical intervention. For physiologic jaundice, the timeline of the jaundice is typically as follows. Physiologic jaundice always begins after 24 hours of birth. The hyperbilirubinemia peaks at 48-96 hours of life and then will decline over a time period of 2-3 weeks. The timing of the onset of jaundice is a very important distinction, because jaundice that begins within the first 24 hours after birth, it is always considered pathologic. Additionally, the type of hyperbilirubinemia must be assessed in the newborn. If a newborn has conjugated hyperbilirubinemia, this is also always pathologic.
Most infants develop visible jaundice due to elevation of unconjugated bilirubin concentration during their first week. This is called physiological jaundice. This pattern of hyperbilirubinemia has been classified into two functionally distinct periods.
* Phase one
* Term infants - jaundice lasts for about 10 days with a rapid rise of serum bilirubin up to 204 μmol/L (12 mg/dL).
* Preterm infants - jaundice lasts for about two weeks, with a rapid rise of serum bilirubin up to 255 μmol/L (15 mg/dL).
* Phase two - bilirubin levels decline to about 34 μmol/L (2 mg/dL) for two weeks, eventually mimicking adult values.
* Preterm infants - phase two can last more than one month.
* Exclusively breastfed infants - phase two can last more than one month.
Unconjugated hyperbilirubinemia is the most common reason for jaundice in the newborn period. In the majority of cases, unconjugated hyperbilirubinemia occurs in healthy newborn infants and is self-limiting and physiologic. In most cases, the unconjugated hyperbilirubinemia and jaundice of the infant self -resolves as the newborns' bilirubin processing methods evolve within the first few weeks of extrauterine life.
Although in the majority of cases, unconjugated hyperbilirubinemia is physiologic, there are also instances where unconjugated hyperbilirubinemia can be pathologic in the neonate. Timing of the unconjugated bilirubin elevation is important in these cases. If the total serum bilirubin level is greater than 95% on bilirubin nanograms or if the bilirubin level increases too rapidly, then the unconjugated hyperbilirubinemia might be pathologic.

### Pathologic Causes of Unconjugated Hyperbilirubinemia in the Neonatal Period

Causes of pathologic unconjugated hyperbilirubinemia are divided into different categories related to the processing of bilirubin.
Any of the following features suggests pathological jaundice:[[
* Clinical jaundice appearing in the first 24 hours or greater than 14 days of life.
* Increases in the level of total bilirubin by more than 8.5 μmol/L (0.5 mg/dL) per hour or (85 μmol/L) 5 mg/dL per 24 hours.
* Total bilirubin more than 331.5 μmol/L (19.5 mg/dL) (hyperbilirubinemia).
* Direct bilirubin more than 34 μmol/L (2.0 mg/dL).
The following are examples of what can cause increased bilirubin production leading to pathologic unconjugated hyperbilirubinemia in the newborn:
Hemolytic Causes of Unconjugated Hyperbilirubinemia
One reason for increased bilirubin production in the neonate occurs from an increased breakdown of red blood cells, this is called hemolysis. In some newborns, red blood cells can be destroyed due to what is called intrinsic hemolysis. Intrinsic means that there is something abnormal about the red blood cells, examples of which include red blood cell structure and metabolism. Intrinsic causes of increased red blood cell breakdown are often inherited.
Hemolytic Causes of Unconjugated Hyperbilirubinemia (Intrinsic and Extrinsic Hemolysis)
Intrinsic causes of hemolysis:
* Red blood cell membrane defects
** Hereditary spherocytosis: Genetic defects leading to abnormally shaped red blood cells. The red blood cells are shaped like a sphere instead of the normal biconcave disc shape. Due to this, the red blood cells are more easily destroyed and can cause hyperbilirubinemia
** Hereditary elliptocytosis: A hereditary disorder that causes the red blood cell shape to be elongated. Can cause hemolytic anemia
* Enzyme Conditions
** Glucose-6-phosphate dehydrogenase (G6PD) deficiency: G6PD is an enzyme that is found in every cell. It helps red blood cells survive oxidative damage. Males more commonly have this disorder because it is an x-linked inheritance. When a neonate has G6PD deficiency they are more likely to develop hyperbilirubinemia.
** Pyruvate kinase deficiency: Pyruvate kinase is an enzyme that helps provide red blood cells with the energy they need in the form of ATP. Red blood cells that are in the neonate use more energy when compared to adult red blood cells. Neonates with this genetic defect have red blood cells that have difficulty passing through the spleen and are destroyed. This is what leads to hyperbilirubinemia in the neonate.
** Congenital erythropoietic porphyria- An inherited enzyme defect of uroporphyrinogen III cosynthase leading to porphyrin deposts and hemolytic anemia
* Globin synthesis defect
** Sickle cell disease
** Alpha-thalassemia, e.g. HbH disease
Additionally, red blood cells can be destroyed due to extrinsic reasons. Extrinsic hemolysis happens when the red blood cells themselves are normal but they are destroyed for reasons external to the blood cell itself. Examples of extrinsic hemolysis that can lead to unconjugated hyperbilirubinemia in the newborn are hemolytic disease of the newborn and Rh disease.
Examples of extrinsic causes of hemolysis that lead to unconjugated hyperbilirubinemia in the newborn are:

#### Extrinsic causes of hemolysis

* Systemic conditions
** Sepsis: Sepsis can occur for a multitude of reasons in the newborn. Sepsis can occur from infections the newborn gets during or shortly before delivery such as Group B Streptococcus if the mother is note treated during delivery.
** Arteriovenous malformation
* Alloimmunity (The neonatal or cord blood gives a positive direct Coombs test and the maternal blood gives a positive indirect Coombs test)
** Hemolytic disease of the newborn (ABO)- See below
** Rh disease-See below
** Hemolytic disease of the newborn (anti-Kell)-See below
** Hemolytic disease of the newborn (anti-Rhc)
** Other blood type mismatches causing hemolytic disease of the newborn
Hemolytic disease of the newborn is also termed erythroblastosis fetalis. This occurs when in utero, the mother’s immune system stages a response against the fetus's paternally inherited red blood cell antigens. Many fetal red blood cell antigens can cause the mother to make antibodies, however ABO blood types or rhesus factor are the most common.
Infants whose mothers created antibodies to their blood cell type can present with jaundice on day of life one and a positive direct antiglobulin (DAT) test, Coombs test. This is because the mother’s antibodies bind to and destroy fetal red blood cells, which in turn cause early unconjugated hyperbilirubinemia.
Rhesus (Rh) factor is found on the surface of red blood cells. When a Rh-positive baby is born to a Rh-negative mother Rh hemolytic disease can occur. For a baby to be affected, the mother would have had to experience a previous exposure to the Rh+ antigen, whether that be through previous pregnancy, ectopic pregnancy or other exposures.
Kell blood groups can also cause hemolytic disease in the newborn. The kell antigen can be found on fetal red blood cells at around 10 weeks. It is important that the mother’s Kell status is determined. If a mother is Kell negative and has a Kell-positive baby, she can develop antibodies that can destroy the fetuses' red blood cells, causing hyperbilirubinemia.

### Non-hemolytic causes of Unconjugated Hyperbilirubinema

* Breastfeeding jaundice: See below
* Breast milk jaundice: See below
* Cephalohematoma: Present after birth, a hemorrhage under the scalp. Typically self resolve within 4 weeks. Can cause jaundice in the newborn when they accumulated blood breaks down.
* Polycythemia: Newborns that have elevated numbers of red blood cells can have increased red blood cell breakdown causing hyperbilirubinemia. One cause of this is if there is a chronic low oxygen state while in the uterus
* Urinary tract infection
* Sepsis
* Hypothyroidism: Can cause prolonged jaundice in the newborn
* Gilbert's syndrome: Most prevalent genetic cause of unconjugated hyperbilirubinemia
* Crigler–Najjar syndrome: A serious genetic condition that causes hyperbilirubinemia within the first few days of life. Severe elevations in bilirubin can lead to kernicterus
* High GI obstruction (Pyloric stenosis, Bowel obstruction)

#### Breast Feeding Jaundice

Breastfeeding jaundice occurs due to low volume of breast milk consumption during the first week of life. This condition typically occurs because the mother’s milk supply is still coming in. During this time period, the newborn is not receiving adequate quantities of breastmilk during feeding. When the intake of breast milk is decreased, this causes a state of decreased bowel movements, dehydration and increased enterohepatic circulation of bilirubin. Due to this, the newborn can have increased unconjugated hyperbilirubinemia. To decrease the occurrence of breastfeeding jaundice, breastfeeding mothers need to receive breastfeeding support with frequent feedings to stimulate milk let-down. Exclusively formula fed infants do not experience breastfeeding jaundice.

#### Breast Milk Jaundice

Breast milk jaundice differs from breastfeeding jaundice. Breast milk jaundice is believed to be due to certain biochemical properties of the actual breast milk. Breast milk jaundice occurs week 1-2 of life and can last for as long as 12 weeks. The level of bilirubin in these newborns is often higher and it commonly takes a longer period of time for levels to decrease. If the baby continues to be breastfed, the bilirubin levels will typically decrease but can be elevated for up to ten weeks. One study found that infants that were mostly breastfed in the first month of life, 34% had transcutaneous bilirubin readings of ≥5 mg/dL, 9% had concentrations ≥10 mg/dL, and 1% had concentrations ≥12.9 mg/dL.
This late-onset jaundice may develop in up to one third of healthy breastfed infants. The following reasons can cause breast milk jaundice:
* The gut is sterile at birth and normal gut flora takes time to establish. The bacteria in the adult gut convert conjugated bilirubin to stercobilinogen which is then oxidized to stercobilin and excreted in the stool. In the absence of sufficient bacteria, the bilirubin is de-conjugated by brush border β-glucuronidase and reabsorbed. This process of re-absorption is called enterohepatic circulation. It has been suggested that bilirubin uptake in the gut (enterohepatic circulation) is increased in breast fed babies, possibly as the result of increased levels of epidermal growth factor (EGF) in breast milk. Breast milk also contains glucoronidase which will increase deconjugation and enterohepatic recirculation of bilirubin.
* The breast-milk of some women contains a metabolite of progesterone called 3-alpha-20-beta pregnanediol. This substance inhibits the action of the enzyme uridine diphosphoglucuronic acid (UDPGA) glucuronyl transferaseresponsible for conjugation and subsequent excretion of bilirubin. In the newborn liver, activity of glucuronyl transferase is only at 0.1-1% of adult levels, so conjugation of bilirubin is already reduced. Further inhibition of bilirubin conjugation leads to increased levels of bilirubin in the blood. However, these results have not been supported by subsequent studies.
* An enzyme in breast milk called lipoprotein lipase produces increased concentration of nonesterified free fatty acids that inhibit hepatic glucuronyl transferase, which again leads to decreased conjugation and subsequent excretion of bilirubin.

## Conjugated (Direct) Hyperbilirubinemia

Conjugated hyperbilirubinemia is also called direct hyperbilirubinemia. Elevated conjugated bilirubin in a neonate is always suggestive of an underlying disorder. Increased levels of conjugated bilirubin cannot cause kernicterus though, since this form of bilirubin is water soluble.
Whenever a newborn is born with conjugated hyperbilirubinemia, neonatal liver disease must be considered. The following are causes of conjugated (direct) hyperbilirubinemia in the newborn:

### Liver causes

* Infections
** Sepsis
** Hepatitis A: A viral infection of the liver. The infection is spread by fecal-oral route or by sexual contact. Hepatitis A is typically not transmitted from mother to newborn during pregnancy.
** Hepatitis B: A viral infection of the liver. There is a higher risk of transmission to the newborn if the mother is HBeAg-positive. Hepatitis B cannot pass through the placenta, however at birth there is a high risk of hepatitis B transmission. To prevent transmission to the newborn at birth, it is important that the infant receive the Hepatitis B vaccine and Hepatitis B Immune Globulin within 12 hours of birth
** TORCH infections: Includes toxoplasmosis, syphilis, HIV, varicella, mumps, parvovirus, rubella, cytomegalovirus and herpes infections.
* Metabolic
** Galactosemia:An inherited disorder that causes a buildup of galactose, a carbohydrate. There are multiple types of galactosemia. It can cause liver damage and conjugated hyperbilirubinemia
** Alpha 1-antitrypsin deficiency, which is commonly missed, and must be considered in DDx. An inherited disorder in which both the lungs and liver are diseased due to decreased levels of a protein called alpha-1 antitrypsin.
** Cystic fibrosis: An inherited disease that leads to a faulty protein. This faulty protein leads to the accumulation of mucus and widespread organ dysfunction. This disease can cause an obstruction of the biliary tract which leads to conjugated hyperbilirubinemia .
** Dubin–Johnson syndrome: An inherited disease of liver cells I which the ABCC2 gene is mutated. This mutation decreases the ability of liver cells to release bilirubin into bile. This causes buildup of conjugated bilirubin
** Rotor syndrome: A genetic disorder that occurs when two genes in liver cells are mutated. The fault genes cause liver cells to have reduced storage of bilirubin and cause hyperbilirubinemia
* Drugs
* Total parenteral nutrition: Also known as "TPN", is a source of complete nutrition that newborns can receive by intravenous methods if they cannot meet their nutritional needs by using their gastrointestinal tract.
* Idiopathic

### Post-liver

* Biliary atresia or bile duct obstruction
** Alagille syndrome- An inherited disorder with multiorgan system involvement. In the liver it causes a lack of intrahepatic bile ducts.
** Choledochal cyst- Also called choledochal malformation. Birth defects that involve the bile duct structure. Can cause jaundice and other liver issues

## Diagnosis

Monitoring of Hyperbilirubinemia in the Newborn
How are bilirubin levels evaluated in the newborn?
Even before the infant is born, risk factors for neonatal hyperbilirubinemia need to be considered. During pregnancy, the ABO blood type and Rh(D) type of the mother must be assessed. If there is incompatibility between mother and newborn, this could lead to the development of maternal antibodies and cause hemolytic disease of the fetus and newborn. Rh stands for rhesus factor and is a protein that is found on red blood cells. You can be either Rh+ and have the protein, or Rh- and not have the protein.
After birth, risk factors should be reviewed to determine if the newborn is at risk for high levels of bilirubin. There are certain risk factors that can lead to significant elevations of bilirubin levels in the newborn. One risk factor is if the newborn is born prematurely or born small for gestational age. The newborn’s family history should also be reviewed for risk factors. If there is a family history of genetic disorders of red blood cells, a sibling requiring phototherapy, or if the newborn is a large for gestational age infant born to a mother with maternal diabetes, these are all risk factors for the infant to develop hyperbilirubinemia. These newborns must be monitored more closely after birth to ensure intervention for high bilirubin levels is not needed.
Diagnosis of hyperbilirubineia can be made by measuring the serum bilirubin level in the blood. In those who are born after 35 weeks and are more than a day old, a transcutaneous bilirubinometer may also be used. The use of an icterometer, a piece of transparent plastic painted in five transverse strips of graded yellow lines, is not recommended.
Transcutaneous bilirubinometer: (TCB) This is hand held, portable and rechargeable but expensive. When pressure is applied to the photoprobe, a xenon tube generates a strobe light, and this light passes through the subcutaneous tissue. The reflected light returns through the second fiber optic bundle to the spectrophotometric module. The intensity of the yellow color in this light, after correcting for the hemoglobin, is measured and instantly displayed in arbitrary units. Bilirubin is not directly measured but TCB provides a good screening test for newborns.
Blood testing: In newborns blood is usually taken from the heel called a “heel stick” and sent to the lab to measure bilirubin levels
Physical exam: After delivery, all newborns should be assessed for jaundice by visual inspection every 12 hours. Visual inspection by a healthcare provider can provide some insight into bilirubin level in the newborn.
How are bilirubin levels interpreted?
Once the transcutaneous bilirubinometer or laboratory bilirubin test comes back, it must be interpreted to understand if the newborn requires treatment or not. If the infant has any risk factors, their bilirubin levels need to be monitored more closely and frequently.
To understand the need for treatment, multiple factors are considered, including the infant's gestational age, age in hours, total serum bilirubin level, and risk factors for neurotoxicity. After these factors are reviewed, a treatment threshold is then determined. Along with a healthcare provider's expertise, there are charts available that consider these factors to help determine if the threshold for therapy is reached.
For newborns born in the hospital, total serum bilirubin should be measured 24-48 hours after delivery. In the hospital, newborns should be regularly monitored by their healthcare providers for signs of jaundice. For infants born at home, bilirubin should also be tested 24-48 hours after they are born. Newborns should also follow closely with their pediatrician to monitor jaundice.
If there are multiple transcutaneous bilirubin (TcB) or total serum bilirubin (TSB) measurements, it is important to consider the rate of rise of bilirubin levels. In the first day of life if bilirubin increases at a rate of greater than or equal to 0.3 mg/dL per hour this is concerning. This could be due to a hemolytic process in the newborn, where their red blood cells are being destroyed. If the level of direct serum bilirubin is greater than 1.0 mg/dL this is also concerning and needs further workup.
In a premature newborn if the bilirubin level is >10 mg/dL , and if in a full term newborn the bilirubin level is >18 mg/dL, additional tests must be ordered. The healthcare provider should order reticulocyte count, hematocrit, direct Coombs test, blood smear, total and direct serum bilirubin concentration and blood group and Rh typing in both the newborn and the mother to further investigate the cause of hyperbilirubinemia.

## Treatment

When to consider starting treatment for hyperbilirubinemia depends on multiple factors. Factors such as gestational age, albumin levels, presence of hemolytic diseases or other isoimmune diseases, sepsis or instability are all factors that should be reviewed.
The bilirubin levels for initiative of phototherapy varies depends on the age and health status of the newborn. However, any newborn with a total serum bilirubin greater than 359 μmol/L ( 21 mg/dL) should receive phototherapy.

### Phototherapy

One method of decreasing high levels of indirect,unconjugated bilirubin in the newborn is by using phototherapy. The newborn will be placed wearing a diaper and an eye protection mask under a blue phototherapy light. Phototherapy lights help decrease the level of bilirubin through the absorption of the light through the newborn's skin. Once absorbed through the skin, a photochemical reaction occurs. In this reaction, the indirect bilirubin is transformed into a more water-soluble form that can then leave the body through the liver and kidney. In addition to phototherapy lights, some newborns with elevated bilirubin levels can use biliblankets. Phototherapy is not suggested for use in newborns with conjugated hyperbilirubinemia. Phototherapy has been widely used for newborn hyperbilirubinemia with few noted long term side effects.
Home phototherapy can also be an option in some situations, but many factors must be monitored, including the quality of machine, how comfortable the family is, and how the bilirubin levels can be monitored.
Bronze baby syndrome is very rare but can be caused by phototherapy. The newborn becomes “gray” in color. It is believed that bronze baby syndrome is due to increased levels of direct bilirubin and are related to cholestatic jaundice.
Intravenous Immunoglobulin
Intravenous immunoglobulin, also called IVIG, can be used if the newborn has hyperbilirubinemia related to hemolytic disease due to isoimmunity, which includes ABO disease and Rh disease. It can be used in addition to phototherapy.
Exchange Transfusion
An exchange transfusion is the most intense therapy that is used for extremely high bilirubin levels or rapidly increasing bilirubin levels. It is used to prevent kernicterus in newborns.
In an exchange transfusion, an umbilical catheter is placed in a newborn's umbilical stump. This catheter provides access to a vein in the newborn. The newborn's blood containing the high bilirubin levels is removed through a catheter. Donor blood is replaced in a slow, well controlled manner under the supervision of a healthcare provider. Typically if the infant is full term, the total exchange equates to about twice the infant’s blood volume.An exchange transfusion can drastically reduce bilirubin levels and prevent the progression to kernicterus in high risk newborns.

## External Links

* American Academy of Pediatrics has issued guidelines for managing this disease, which can be obtained for free.https://publications.aap.org/pediatrics/article/150/3/e2022058859/188726/Clinical-Practice-Guideline-Revision-Management-of
* National Institute for Health and Care Excellence (NICE) has issued guidelines for the recognition and treatment of neonatal jaundice in the United Kingdom.
* 1 2 3 4 5 6 7 8 "Neonatal Hyperbilirubinemia". Merck Manuals Professional Edition. August 2015. Retrieved 11 December 2017.
* ↑ "Jaundice in newborn babies under 28 days | Guidance and guidelines". NICE. October 2016. Retrieved 11 December 2017.
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* 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 "Neonatal Hyperbilirubinemia - Pediatrics". Merck Manual Professional Edition. Retrieved 19 March 2025.
* 1 2 Reddy, Dinesh K.; Pandey, Shivlal (2025), "Kernicterus", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32644546, retrieved 19 March 2025
* 1 2 3 4 5 6 7 8 Hansen, Thor Willy Ruud (1 June 2010). "Core Concepts: Bilirubin Metabolism". NeoReviews. 11 (6): e316 – e322. doi:10.1542/neo.11-6-e316. ISSN 1526-9906.
* 1 2 3 4 Kalakonda, Aditya; Jenkins, Bianca A.; John, Savio (2025), "Physiology, Bilirubin", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 29261920, retrieved 19 March 2025
* 1 2 Singh, Anand; Koritala, Thoyaja; Jialal, Ishwarlal (2025), "Unconjugated Hyperbilirubinemia", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 31747203, retrieved 19 March 2025
* ↑ Par, Emma J.; Hughes, Chase A.; DeRico, Pierce (May 2023). "Neonatal Hyperbilirubinemia: Evaluation and Treatment". American Family Physician. 107 (5): 525–534. ISSN 1532-0650. PMID 37192079.
* 1 2 3 4 5 6 7 Ansong-Assoku, Betty; Shah, Sanket D.; Adnan, Mohammad; Ankola, Pratibha A. (2025), "Neonatal Jaundice", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30422525, retrieved 19 March 2025
* 1 2 Coté, Charles J.; Lerman, Jerrold; Anderson, Brian J., eds. (2019). A practice of anesthesia for infants and children (Sixth ed.). Philadelphia, PA: Elsevier. ISBN 978-0-323-42974-0.
* ↑ Lauer, B. J.; Spector, N. D. (1 August 2011). "Hyperbilirubinemia in the Newborn". Pediatrics in Review. 32 (8): 341–349. doi:10.1542/pir.32-8-341. ISSN 0191-9601. PMID 21807875.
* ↑ Enegela, Ogboche A.; Anjum, Fatima (2025), "Pyruvate Kinase Deficiency", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32809416, retrieved 19 March 2025
* 1 2 Sarwar, Ayesha; Citla Sridhar, Divyaswathi (2025), "Rh Hemolytic Disease", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32809323, retrieved 19 March 2025
* 1 2 Maheshwari, Ashish; Zubair, Muhammad; Maheshwari, Apoorva (2025), "Kell Blood Group System", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 39536149, retrieved 19 March 2025
* ↑ Raines, Deborah A.; Krawiec, Conrad; Weisbrod, Luke J.; Jain, Sameer (2025), "Cephalohematoma", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 29262234, retrieved 19 March 2025
* 1 2 3 Bratton, Stephanie; Cantu, Rebecca M.; Stern, Mitchell (2025), "Breast Milk Jaundice", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 30726019, retrieved 19 March 2025
* 1 2 3 4 5 6 7 8 9 10 11 12 13 Kemper, Alex R.; Newman, Thomas B.; Slaughter, Jonathan L.; Maisels, M. Jeffrey; Watchko, Jon F.; Downs, Stephen M.; Grout, Randall W.; Bundy, David G.; Stark, Ann R.; Bogen, Debra L.; Holmes, Alison Volpe; Feldman-Winter, Lori B.; Bhutani, Vinod K.; Brown, Steven R.; Maradiaga Panayotti, Gabriela M. (5 August 2022). "Clinical Practice Guideline Revision: Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation". Pediatrics. 150 (3): e2022058859. doi:10.1542/peds.2022-058859. ISSN 0031-4005. PMID 35927462.
* ↑ Kamani, Lubna (2025), "Viral hepatitis in pregnancy", Hepatology, Elsevier, pp. 971–1001, doi:10.1016/b978-0-443-26711-6.00035-4, ISBN 978-0-443-30052-3, retrieved 19 March 2025
* ↑ PMC, Europe. "Europe PMC". europepmc.org. Retrieved 19 March 2025.
* ↑ Lauer, B. J.; Spector, N. D. (1 August 2011). "Hyperbilirubinemia in the Newborn". Pediatrics in Review. 32 (8): 341–349. doi:10.1542/pir.32-8-341. ISSN 0191-9601. PMID 21807875.