Neonatal jaundice

Neonatal jaundice
Jaundice in newborn
Classification and external resources
ICD-10	P58, P59
ICD-9	773, 774
DiseasesDB	8881
MedlinePlus	001559
eMedicine	ped/1061
Patient UK	Neonatal jaundice
MeSH	D007567

Neonatal jaundice or Neonatal hyperbilirubinemia, or Neonatal icterus (from the Greek word ἴκτερος), attributive adjective: icteric, is a yellowing of the skin and other tissues of a newborn infant. A bilirubin level of more than 85 μmol/l (5 mg/dL) leads to a jaundiced appearance in neonates whereas in adults a level of 34 μmol/l (2 mg/dL) is needed for this to occur. In newborns, jaundice is detected by blanching the skin with pressure applied by a finger so that it reveals underlying skin and subcutaneous tissue.^[1] Jaundiced newborns have yellow discoloration of the white part of the eye, and yellowing of the face, extending down onto the chest.

Neonatal jaundice can make the newborn sleepy and interfere with feeding. Extreme jaundice can cause permanent brain damage from kernicterus.

In neonates, the yellow discoloration of the skin is first noted in the face and as the bilirubin level rises proceeds caudal to the trunk and then to the extremities.^[2] This condition is common in newborns affecting over half (50–60%) of all babies in the first week of life.^[3]

Infants whose palms and soles are yellow, have serum bilirubin level over 255 μmol/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.^[2] In infants, jaundice can be measured using invasive or non-invasive methods.

Classification

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 μmol/l (12 mg/dL).
2. 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.

1. Preterm infants - phase two can last more than one month.
2. Exclusively breastfed infants - phase two can last more than one month.

Causes

Mechanism involved in physiological jaundice are mainly:

• Relatively low activity of the enzyme glucuronosyltransferase which normally converts unconjugated bilirubin to conjugated bilirubin that can be excreted into the gastrointestinal tract.^[4] Before birth, this enzyme is actively down-regulated, since bilirubin needs to remain unconjugated in order to cross the placenta to avoid being accumulated in the fetus.^[5] After birth, it takes some time for this enzyme to gain function.
• Shorter life span of fetal red blood cells,^[4] being approximately 80 to 90 days in a full term infant,^[6] compared to 100 to 120 days in adults.
• Relatively low conversion of bilirubin to urobilinogen by the intestinal flora, resulting in relatively high absorption of bilirubin back into the circulation.^[4]

Pathological Jaundice of Neonates (Conjugated Pathological Hyperbilirubinemia)

Any of the following features characterizes pathological jaundice:

1. Clinical jaundice appearing in the first 24 hours or greater than 14 days of life.
2. 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.
3. Total bilirubin more than 331.5 μmol/l (19.5 mg/dL) (hyperbilirubinemia).
4. Direct bilirubin more than 34 μmol/l (2.0 mg/dL).

Differentiating Physiological and Pathological Jaundice

The aim of clinical assessment is to distinguish physiological from pathological jaundice. The signs which help to differentiate pathological jaundice of neonates from physiological jaundice of neonates are the presence of intrauterine growth restriction, stigma of intrauterine infections (e.g. cataracts, small head, and enlargement of the liver and spleen), cephalohematoma, bruising, signs of bleeding in the brain's ventricles. 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 red blood cell destruction in G6PD deficiency) are suggestive of pathological jaundice in neonates.^[7]

Causes

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 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.

If the neonatal jaundice does not clear up with simple phototherapy, other causes such as biliary atresia, PFIC, bile duct paucity, Alagille syndrome, alpha 1-antitrypsin deficiency, 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:

Neonatal jaundice

Unconjugated bilirubin

Conjugated bilirubin

Pathologic

Physiological jaundice of Neonates

Hepatic

Post-hepatic

Hemolytic

Non-hemolytic

Intrinsic causes

Extrinsic causes

Unconjugated

Hemolytic

Intrinsic causes of hemolysis

• Membrane conditions
  • Spherocytosis
  • Hereditary elliptocytosis
• 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, e.g. HbH disease

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)^[1]
  • Rh disease^[1]
  • Hemolytic disease of the newborn (anti-Kell)
  • Hemolytic disease of the newborn (anti-Rhc)
  • Other blood type mismatches causing hemolytic disease of the newborn

Non-hemolytic causes

• Breast milk jaundice
• Cephalohematoma
• Polycythemia
• Urinary tract infection
• Sepsis
• Hypothyroidism
• Gilbert's syndrome
• Crigler-Najjar syndrome
• High GI obstruction

Conjugated (Direct)

Liver causes

• Infections
  • Sepsis
  • Hepatitis A
  • Hepatitis B
  • TORCH infections
• Metabolic
  • Galactosemia
  • Alpha-1-antitrypsin deficiency, which is commonly missed, and must be considered in DDx
  • Cystic fibrosis
  • Dubin-Johnson Syndrome
  • Rotor syndrome
• Drugs
• Total parenteral nutrition
• Idiopathic

Post-liver

• Biliary atresia or bile duct obstruction
  • Alagille syndrome
  • Choledochal cyst

Non-organic causes

Breastfeeding failure jaundice

"Breastfeeding jaundice" or "lack of breastfeeding jaundice," is caused by insufficient breast milk intake,^[8] 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.

Breast Milk jaundice

Whereas breast feeding jaundice is a mechanical problem, breast milk jaundice is a biochemical occurrence and the higher bilirubin possibly acts as an antioxidant. Breast milk jaundice occurs later in the newborn period, with the bilirubin level usually peaking in the sixth to 14th days of life. This late-onset jaundice may develop in up to one third of healthy breastfed infants.^[9]

• 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. 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.^[10] Breast milk also contains glucoronidase which will increase deconjugation and enterohepatic recirculation of bilirubin.

• 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.^[11] However, these results have not been supported by subsequent studies.^[12]

• 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.^[13]

Non-invasive measurement of jaundice

Clinical Assessment

This method is less accurate and more 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 bilirubin 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 μmol/l ( 21 mg/dL) should receive phototherapy.^[14]

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 420-480nm (peak 458nm), 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.^[15][16]

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.^[17]

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.^[18]

Phototherapy works through a process of isomerization that changes trans-bilirubin into the water-soluble cis-bilirubin isomer.^[19][20]

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 skin moles, in childhood. While an increased number of moles is related to an increased risk of skin cancer,^[21][22][23] 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.^[24]

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 μmol/l ( 25 mg/dL ).^[14]

Complications

Prolonged hyperbilirubinemia (severe jaundice) can result into chronic bilirubin encephalopathy (kernicterus).^[25][26] Quick and accurate treatment of neonatal jaundice helps to reduce the risk of neonates developing kernicterus.^[27]

Infants with kernicterus may have a fever^[28] or seizures.^[29] 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.^[30]

Exchange transfusions performed to lower high bilirubin levels are an aggressive treatment.^[31]

Guidelines

American Academy of Pediatrics has issued guidelines for managing this disease, which can be obtained for free.^[32]
National Institute for Health and Care Excellence (NICE) has issued guidelines for the recognition and treatment of neonatal jaundice in the United Kingdom.^[33]

References

External links

• Neonatal Hyperbilirubinemia Management and Learning Tool for Healthcare Providers
• Jaundice in the first two weeks of life
• BiliTool - Hyperbilirubinemia Risk Assessment for Newborns
• Children's Liver Disease Foundation - information on jaundice in babies
• Neonatal jaundice - Southern Illinois University School of Medicine
• Neonatal Jaundice at www.neonataljaundice.net
• Using LED to cure Neonatal Jaundice at Medicaid Phototherapy Unit

Certain conditions originating in the perinatal period / fetal disease (P, 760–779) Maternal factors and complications of pregnancy, labour and delivery placenta: Placenta praevia Placental insufficiency Twin-to-twin transfusion syndrome chorion/amnion: Chorioamnionitis umbilical cord: Umbilical cord prolapse Nuchal cord Single umbilical artery Length of gestation and fetal growth Small for gestational age/Large for gestational age Preterm birth/Postmature birth Intrauterine growth restriction Birth trauma scalp Cephalhematoma Chignon Caput succedaneum Subgaleal hemorrhage Brachial plexus lesion Erb's palsy Klumpke paralysis By system Respiratory Intrauterine hypoxia Infant respiratory distress syndrome Transient tachypnea of the newborn Meconium aspiration syndrome pleural disease Pneumothorax Pneumomediastinum Wilson–Mikity syndrome Bronchopulmonary dysplasia Cardiovascular Pneumopericardium Persistent fetal circulation Haemorrhagic and hematologic disease Vitamin K deficiency Haemorrhagic disease of the newborn HDN ABO Anti-Kell Rh c Rh D Rh E Hydrops fetalis Hyperbilirubinemia Kernicterus Neonatal jaundice Velamentous cord insertion Intraventricular hemorrhage Germinal matrix hemorrhage Anemia of prematurity Digestive Ileus Necrotizing enterocolitis Meconium peritonitis Integument and thermoregulation Erythema toxicum Sclerema neonatorum Nervous system Periventricular leukomalacia Musculoskeletal Gray baby syndrome muscle tone Congenital hypertonia Congenital hypotonia Infectious Vertically transmitted infection Congenital rubella syndrome Neonatal herpes simplex Omphalitis Neonatal sepsis Group B streptococcal infection Neonatal conjunctivitis Other Perinatal mortality Stillbirth Infant mortality Neonatal withdrawal Index of developmental medicine Description Embryology foetus membranes Cell lines endoderm mesoderm ectoderm Disease Due to toxins Syndromes Chromosomal Neonate Twins Index of obstetrics Description Pregnancy Development Anatomy membranes Disease Pregnancy and childbirth Placenta and neonate Infections Symptoms and signs Treatment Procedures Drugs oxytocins labor repressants