Neonatal_jaundice

Neonatal jaundice

Neonatal jaundice is a yellowing of the skin and other tissues of a newborn infant. A bilirubin level of more than 5 mg/dL manifests clinical jaundice in neonates whereas in the adults 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.

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.

Infants whose jaundice is restricted to the face and part of the trunk above the umbilicus, all have the bilirubin less than 12 mg/dL. Infants whose palms and soles are yellow, have serum bilirubin level over 15 mg/dL.

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 of Neonates

Most Neonates 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 2 functionally distinct periods.

Phase One:

Term Infants: For term infants jaundice lasts for about 5 days. (Rapid rise of serum bilirubin levels up to 12 mg/dL.)
Preterm Infants: For preterm Infants jaundice lasts for about 7days (or 1week). (Rapid rise of serum bilirubin levels up to 15 mg/dL.)

Phase Two: Decline about 2 mg/dL for 2 weeks. And after that adult values are attained.

Preterm Infants: In preterm Infants Phase two can last more than 1 month.
In babies who receive exclusive breast feedings, Phase Two can last more than 1 month.

Factors responsible for Physiological Jaundice

Possible mechanisms involved in Physiological jaundice

Increase Bilirubin load on liver cells.

Increased Erythrocyte volume.
Increased labeled Bilirubin.
Increased enterohepatic circulation of bilirubin.
Decreased Erythrocyte survival.

Defective Hepatic uptake of bilirubin from Plasma

Decreased Ligadin (Y protein).
Increased binding of Y proteins by other anions.
Decreased Hepatic uptake especially in Phase Two

Defective billirubin conjugation

Decreased UDPG activity.

Defective bilirubin excretion

Pathological Jaundice of Neonates

(syn. Unconjugated pathological hyberbilirubinemia)

Any of the following features characterizes pathological jaundice:

Clinical jaundice appearing in the first 24 hours.
Increased in level of total bilirubin by more than 0.5 mg/dL per hour or 5 mg/dL per 24 hours.
Total bilirubin more than 15 mg/dL (hyperbilirubinemia).
Direct bilirubin more than 2.0 mg/dL.

Causes of Pathological Jaundice of Neonates

Increased production

Fetomaternal blood group incompatibility: Rh, ABO
Hereditary spherocytosis.
Non-spherocytic hemolytic anemia: G-6-PD deficiency., a-thalassemia, Vitamin K3 induced hemolysis, pyruvate kinase deficiency.
Sepsis.
Increased enterohepatic circulation: Pyloris stenosis, or large bowel obstruction.

Decreased clearance

Inborn errors of metabolism: Criggler-Najjar syndrome type I and II
Drugs and Hormones: Hypothryoidism, breast milk jaundice.

Differentiation between 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, benign 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

Systemic conditions

Enzyme conditions

Glucose-6-phosphate dehydrogenase deficiency (also called G6PD deficiency)
Pyruvate kinase deficiency

Globin synthesis defect

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

Hepatic causes

Infections

Metabolic

Post-hepatic

Biliary atresia
Bile duct obstruction

Non-organic causes

Breast feeding jaundice

"Breastfeeding jaundice," perhaps more appropriately called "starvation 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 cesarian 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 who is exclusively breastfed and in whom other causes of jaundice have been ruled out. The jaundice appears at the end of the first week of life and hence overlaps physiological jaundice. It can last for up to two months. Several factors are thought to be responsible for this condition.

First, in exclusively breastfed babies the establishment of normal gut flora is delayed. 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 and reabsorbed. This process of re-absorption is called entero-hepatic 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. Reduced conjugation of bilirubin leads to increased level 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.

Breast-milk jaundice does not usually cause any complication (like kernicterus) if the baby is otherwise healthy. The serum bilirubin level rarely goes above 20 mg /dL. It is usually not necessary to discontinue breast-feeding as the condition resolves spontaneously. Adequate hydration should be maintained by giving extra fluids if necessary.

Non-invasive measurement of jaundice

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 rechargable but expencive 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

Infants with neonatal jaundice are treated with colored light called phototherapy. Scientists 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 shows that blue light therapy helps reduce high bilirubin levels that cause neonatal jaundice.

Exposing infants to high levels of colored light breaks down the bilirubin. 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 (same molecule but with a different arrangement of the atoms) that changes the bilirubin into water-soluble isomers that can be passed without getting stuck in the liver.

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).

Light therapy may increase the risk of nevi, or skin moles, in childhood. Randomly, 36 nevi, or moles, received ultraviolet phototherapy. After exposure, the moles' average size increased from 4.7 mm² to 5.3 mm². This was observed in 28 of the 36 moles. Going further, an autoradiograph proved that each mole had an increase in melanocytes, keratinocytes and dermal cells (all skin cells) in comparison with the unexposed nevi, which in turn also increased the risk of melanoma (skin cancer) .

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 it's skin.

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.