Neonatal jaundice

Neonatal jaundice or Neonatal hyperbilirubinemia is a yellowing of the skin and other tissues of a newborn infant. A bilirubin level of more than 85 umol/l (5 mg/dL) manifests clinical jaundice in neonates whereas in adults a level of 34 umol/l (2 mg/dL) would look icteric. In newborns jaundice is detected by blanching the skin with digital pressure so that it reveals underlying skin and subcutaneous tissue. Jaundice newborns have an apparent icteric sclera, and yellowing of the face, extending down onto the chest.

In neonates the dermal icterus is first noted in the face and as the bilirubin level rises proceeds caudal to the trunk and then to the extremities.

This condition is common in newborns affecting over half (50 -60%) of all babies in the first week of life.

Notoriously inaccurate rules of thumb have been applied to the physical exam of the jaundiced infant. Some include estimation of serum bilirubin based on appearance. One such rule of thumb includes infants whose jaundice is restricted to the face and part of the trunk above the umbilicus, have the bilirubin less than 204 umol/l (12 mg/dL) (less dangerous level). Infants whose palms and soles are yellow, have serum bilirubin level over 255 umol/l (15 mg/dL) (more serious level).

Studies have shown that trained examiners assessment of levels of jaundice show moderate agreement with icterometer bilirubin measurements.

In infants jaundice can be measured using invasive or non-invasive methods. In non invasive method Ingram icterometer and Transcutaneous bilirubinometer are used.

Physiological jaundice
Most infants develop visible jaundice due to elevation of unconjugated bilirubin concentration during their first week. This common condition is called physiological jaundice. This pattern of hyperbilirubinemia has been classified into two functionally distinct periods.


 * Phase one
 * 1) Term infants - jaundice lasts for about 10 days with a rapid rise of serum bilirubin up to 204 umol/l (12 mg/dL).
 * 2) Preterm infants - jaundice lasts for about 2 week, with a rapid rise of serum bilirubin up to 255 umol/l (15 mg/dL).
 * Phase two - bilirubin levels decline to about 34 umol/l (2 mg/dL) for 2 weeks, eventually mimicking adult values.
 * 1) Preterm infants - phase two can last more than 1 month.
 * 2) Exclusively breastfed infants - phase two can last more than 1 month.

Causes
Possible mechanisms involved in physiological jaundice

1. Increase bilirubin load on liver cells: 2. Defective hepatic uptake of bilirubin from blood plasma: 3. Defective billirubin conjugation: 4. Defective bilirubin excretion
 * Increased red blood cell (RBC) volume
 * Increased labeled bilirubin
 * Increased circulation of bilirubin in the liver
 * Decreased RBC survival
 * Decreased ligadin (Y protein)
 * Increased binding of Y proteins by other anions
 * Decreased liver uptake especially in phase two
 * Decreased UDPG activity

Pathological Jaundice of Neonates (Unconjugated Pathological Hyperbilirubinemia)
Any of the following features characterizes pathological jaundice:
 * 1) Clinical jaundice appearing in the first 24 hours.
 * 2) Increases in the level of total bilirubin by more than 8.5 umol/l (0.5 mg/dL) per hour or (85 umol/l) 5 mg/dL per 24 hours.
 * 3) Total bilirubin more than 331.5 umol/l (19.5 mg/dL) (hyperbilirubinemia).
 * 4) Direct bilirubin more than 34 umol/l (2.0 mg/dL).

Differentiating Physiological and Pathological Jaundice
The aim of clinical assessment is to distinguish physiological from pathological jaundice. The sign which helps to differentiate pathological jaundice of neonates from physiological jaundice of neonates are presence of intrauterine retardation, stigma of intrauterine infections (e.g. cataracts, microcephaly, hepatosplenomegaly etc.), cephalhematoma, bruising, signs of intra ventricular hemorrhage etc. History of illness is noteworthy. Family history of jaundice and anemia, family history of neonatal or early infant death due to liver disease, maternal illness suggestive of viral infection (fever, rash or lymphadenopathy), Maternal drugs (e.g. Sulphonamides, anti-malarials causing hemolysis in G-6-PD deficiency) are suggestive of pathological jaundice in neonates.

Causes of jaundice
In neonates, jaundice tends to develop because of two factors - the breakdown of fetal hemoglobin as it is replaced with adult hemoglobin and the relatively immature hepatic metabolic pathways 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.

If the neonatal jaundice does not clear up with simple phototherapy, other causes such as biliary atresia, PFIC, bile duct paucity, Alagille's syndrome, alpha 1 and other pediatric liver diseases should be considered. The evaluation for these will include blood work and a variety of diagnostic tests. Prolonged neonatal jaundice is serious and should be followed up promptly.

Severe neonatal jaundice may indicate the presence of other conditions contributing to the elevated bilirubin levels, of which there are a large variety of possibilities (see below). These should be detected or excluded as part of the differential diagnosis to prevent the development of complications. They can be grouped into the following categories:

Intrinsic causes of hemolysis

 * Membrane conditions
 * Spherocytosis
 * Hereditary ellipsoidosis
 * Systemic conditions
 * Sepsis
 * Arteriovenous malformation
 * Enzyme conditions
 * Glucose-6-phosphate dehydrogenase deficiency (also called G6PD deficiency)
 * Pyruvate kinase deficiency
 * Globin synthesis defect
 * sickle cell disease
 * Alpha-thalassemia

Extrinsic causes of hemolysis

 * 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)


 * Rh disease
 * Hemolytic disease of the newborn (anti-Kell)
 * Hemolytic disease of the newborn (anti-Rhc)
 * Other blood type mismatches causing hemolytic disease of the newborn
 * Breast milk feeding.

Non-hemolytic causes

 * Cephalohematoma
 * Polycythemia
 * Sepsis
 * Hypothyroidism
 * Gilbert's syndrome
 * Crigler-Najjar syndrome

Hepatic causes

 * Infections
 * Sepsis
 * Hepatitis B
 * TORCH infections
 * Metabolic
 * Galactosemia
 * Alpha-1-antitrypsin deficiency
 * Cystic fibrosis
 * Drugs
 * Total parenteral nutrition
 * Idiopathic

Post-hepatic

 * Biliary atresia
 * Bile duct obstruction

Breast feeding jaundice
"Breastfeeding jaundice" or "lack of breastfeeding jaundice," is caused by insufficient breast milk intake, resulting in inadequate quantities of bowel movements to remove bilirubin from the body. This can usually be ameliorated by frequent breastfeeding sessions of sufficient duration to stimulate adequate milk production. Passage of the baby through the vagina during birth helps stimulate milk production in the mother's body, so infants born by cesarean section are at higher risk for this condition.

Breast milk jaundice
Whereas breast feeding jaundice is a mechanical problem, breast milk jaundice is more of a biochemical problem. The term applies to jaundice in a newborn baby on.


 * First, at birth, the gut is sterile, 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.


 * Second, 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 transferase responsible 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.


 * Third, 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.

Despite the advantages of breast feeding, there is a strong association of breast feeding with neonatal hyperbilirubinemia and thus risk of kernicterus, though this is uncommon. Serum bilirubin levels may reach as high as 30 mg/dL. Jaundice should be managed either with phototherapy or with exchange blood transfusion as is needed. Breast feeds however need not be discontinued. The child should be kept well hydrated and extra feeds given.

Non-invasive measurement of jaundice
Clinical Assessment Kramer's rule

This method is more accurate and less subjective in estimating jaundice.

Ingram icterometer: In this method a piece of transparent plastic known as Ingram icterometer is used. Ingram icterometer is painted in five transverse strips of graded yellow lines. The instrument is pressed against the nose and the yellow colour of the blanched skin is matched with the graded yellow lines and biluribin level is assigned.

Transcutaneous bilirubinometer: This is hand held, portable and rechargeable but expensive and sophisticated. 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.

Treatment
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 umol/l ( 21 mg/dL ) should receive phototherapy.

Phototherapy
The use of phototherapy was first discovered, accidentally, at Rochford Hospital in Essex, England. The ward sister (Charge Nurse) of the premature baby unit, firmly believed that the infants under her care benefited from fresh air and sunlight in the courtyard. Although this led to the first noticing of jaundice being improved with sunlight, further studies only progressed when a vial of blood sent for bilirubin measurement sat on a windowsill in the lab for several hours. The results indicated a much lower level of bilirubin than expected based on the patient's visible jaundice. Further investigation lead to the determination that blue light, wavelength of 420-448 nm, oxidized the bilirubin to biliverdin, a soluble product that does not contribute to kernicterus. Although some pediatricians began using phototherapy in the United Kingdom following Dr. Cremer's publishing the above facts in the Lancet in 1958, most hospitals only began to regularly use phototherapy ten years later when an American group independently made the same discovery.

Infants with neonatal jaundice are treated with colored light called phototherapy. Physicians randomly assigned 66 infants 35 weeks of gestation to receive phototherapy. After 15±5 the levels of bilirubin, a yellowish bile pigment that in excessive amounts causes jaundice, were decreased down to 0.27±0.25 mg/dl/h in the blue light. This suggests that blue light therapy helps reduce high bilirubin levels that cause neonatal jaundice.

Exposing infants to high levels of colored light changes trans-bilirubin to the more water soluble cis-form which is excreted in the bile. Scientists studied 616 capillary blood samples from jaundiced newborn infants. These samples were randomly divided into three groups. One group contained 133 samples and would receive phototherapy with blue light. Another group contained 202 samples would receive room light, or white light. The final group contained 215 samples, and were left in a dark room. The total bilirubin levels were checked at 0, 2, 4, 6, 24, and 48 hours. There was a significant decrease in bilirubin in the first group exposed to phototherapy after two hours, but no change occurred in the white light and dark room group. After 6 hours, there was a significant change in bilirubin level in the white light group but not the dark room group. It took 48 hours to record a change in the dark room group’s bilirubin level. Phototherapy is the most effective way of breaking down a neonate’s bilirubin.

Phototherapy works through a process of isomerization that changes trans-bilirubin into the water-soluble cis-bilirubin isomer.

In phototherapy, blue light is typically used because it is more effective at breaking down bilirubin (Amato, Inaebnit, 1991). Two matched groups of newborn infants with jaundice were exposed to intensive green or blue light phototherapy. The efficiency of the treatment was measured by the rate of decline of serum bilirubin, which in excessive amounts causes jaundice, concentration after 6, 12 and 24 hours of light exposure. A more rapid response was obtained using the blue lamps than the green lamps. However, a shorter phototherapy recovery period was noticed in babies exposed to the green lamps(1). Green light is not commonly used because exposure time must be longer to see dramatic results(1).

Ultraviolet light therapy may increase the risk of or skin moles, in childhood. While an increased number of moles is related to an increased risk of skin cancer,  it is not ultraviolet light that is used for treating neonatal jaundice. Rather, it is simply a specific frequency of blue light that does not carry these risks.

Increased feedings help move bilirubin through the neonate’s metabolic system.

The light can be applied with overhead lamps, which means that the baby's eyes need to be covered, or with a device called a Biliblanket, which sits under the baby's clothing close to its skin.

Exchange transfusions
Much like with phototherapy the level at which exchange transfusions should occur depends on the health status and age of the newborn. It should however be used for any newborn with a total serum bilirubin of greater than 428 umol/l ( 25 mg/dL ).

Complications
Prolonged hyperbilirubinemia (severe jaundice) can result into chronic bilirubin encephalopathy (kernicterus). Quick and accurate treatment of neonatal jaundice helps to reduce the risk of neonates developing kernicterus.

An effect of kernicterus is a fever. A male full term neonate had hyperbilirubinemia (kernicterus) and jaundice at the age of 4 days old. He displayed symptoms of increased lethargy, refusal to eat, and had a fever. The neonate who was diagnosed with kernicterus displayed symptoms of a fever. Another effect of kernicterus is seizures. The Neonatal Unit at Allied Hospital Faisalabad studied 200 neonates of either gender who presented seizures during their hospital stay from April 2003 to June 2004. The seizures were evaluated and one cause of the seizures was kernicterus. 4.5%, or 9 neonates, displayed seizures caused by kernicterus.

High pitched crying is an effect of kernicterus. Scientists used a computer to record and measure cranial nerves 8, 9 and 12 in 50 infants who were divided into two groups equally depending upon bilirubin concentrations. Of the 50 infants, 43 had tracings of high pitched crying. Exchange transfusions performed to lower high bilirubin levels are an aggressive treatment.

Guidelines
American Academy of Pediatrics has issued guidelines for managing this disease, which can be obtained for free.