Neonatal Jaundice

Overview

Neonatal jaundice refers to yellowness o the skin and mucous membranes due to elevated bilirubin within the first 28 days of life. Every baby should be examined for jaundice in bright natural light if possible. (sclera, gum, palm, and sole of feet) and if indicated, serum bilirubin measured and checked against appropriate normograms

• For which babies should we measure bilirubin (within 2 hours)
  • Jaundice on 1st day of life
  • Jaundice on sole and palms
  • Jaundice in preterms < 35 weeks
  • Jaundice plus any danger sign
  • Jaundice in a baby with FHx of sibling with jaundice that required exchnage transfusion or phototherapy
  • Jaundice in baby with Rh incompatibility
  • Jaundice in neonate admitted in NBU (investigate for causes of jaundice)
• For which babies should we start phototherapy if bilirubin measure is unavailable
  • Jaundice easily visible on the sole of the foot in a well baby
  • Preterm baby with ANY visible jaundice
  • Baby with easily visible jaundice + Inability to feed or other Sx of neurological impairment (also consider immediate exchange transfusion)

Physiological jaundice

Virtually all babies will have some degree of physiologic jaundice. Might not be noticeable, only slight. This happens as the baby transitions from reliance on the placenta to clear bilirubin onto the baby’s own hepatic system. Neonates also have a high hematocrit (of around 60) and have lower RBC lifespan causing high turnover

NEVER visible on the first day of life

TSB may rise up to 5mg/dL per day until day 3-5

Conjugated bilirubin never passes 2 mg/dL OR 20% of TSB (whichever is lower)

TSB peaks around day 3-5

Visible jaundice resolves by 1 week of age in a full-term AND 2 weeks in a premature infant (< 37 weeks gestation)

Pathologic Jaundice

Any jaundice that does not satisfy the criteria for physiologic jaundice AND has other sx of illness (such as difficulty feeding)

Visible jaundice on the first day of life

TSB rapidly rises by 5mg/dL over a 24 hr period

Conjugated bilirubin surpasses 2 mg/dL or 20% TSB (whichever is lower)

TSB continues to rise after day 5

Indirect Hyperbilirubinemia

Need to get a Hct, direct coomb’s test, or reticulocyte count to tell whether or not there is hemolysis.

• Initial approach
  • CBC + reticulocyte count: is there hemolysis or infection?
  • Metabolic profile (LFTs, albumin, Ca): hypoalbuminemia lowers threshold for bilirubin toxicity
  • Direct Coomb’s test: is hemolysis immune mediated (isoimmunization)?
  • TSH: is there hypothyroidism?
• Differentials
  • coombs (autoimmune hemolysis)
    • ABO incompatibility
    • Rh isoimmunization

Complications of Indirect Hyperbilirubinemia (Bilirubin encephalopathy; Kernicterus)

Unconjugated bilirubin anion is unbound to albumin, can cross the BBB, enter neurons, and disrupt energy metabolism, ultimately causing death.

Acute bilirubin toxicity sets in at TSB >30mg/dL

Chronic bilirubin toxicity (Kernicterus) is irreversible brain damage, primarily to the basal ganglia. Sets in at TSB >20mg/dL. Dx on MRI

Bilirubin-induced neurologic dysfunction (BIND) score

For monitoring the progress of a neonate w/hyperbilirubinemia

4-6 points: Progressive encephalopathy; likely reversible w/aggressive tx

7-9 points: Advanced and possible irreversible damage (Kernicterus)

Criteria	1 point	2 points	3 points
Mental status	Sleepy, poor feeding	Lethargy and irritability	Coma, seizures, apnea
Muscle tone	Slightly decreased	Mild-arching, hyper-or hypertonic	Opisthotonus
Cry	High-pitched	Shrill	Inconsolable

• Risk factors for bilirubin encephalopathy
  • Dehydration
  • Preterm
  • Respiratory distress
  • Sepsis
  • Hypoxia
  • Seizures
  • Acidosis
  • High rate of rise of bilirubin levels
• Why are premature neonates at higher risk for bilirubin toxicity
  • Decreased BBB integrity
  • Lower albumin levels
  • Lower affinity of abumin binding sites for bilirubin
• Signs and Symptoms of Acute bilirubin encephalopathy
  • Lethargy
  • Poor feeding
  • Irritability
  • High-pitched cry
  • Retrocolis
  • Opisthotonus
  • Apnea
  • Seizures
  • Coma
• Signs and Symptoms of Chronic bilirubin encephalopathy
  • Choreathetoid Cerebal Palsy
  • Hearing loss (sensorinueral)
  • Limited upward gaze and other gaze abnormalities
  • Normal intelligence

Rh Incompatibility

Attack on fetal RBCs by maternal anti-RH antibodies resulting in hemolysis. Ranges from moderate hemolytic anemia to hydrops fetalis (stillbirth)

• Risk for Rh incompatibility
  • Rh- mother who has previousy carried an RH+ fetus and have developed anti-D antibodies
  • It is impossible for a Rh+ to develop Rh isoimmunization.
• Who should be screened for anti-D antibodies and when should they be screened?
  • Rh- mothers only
  • Initial and 3rd trimester visit
• What to do if anti-D antibodies are not detected n a RH- mother
  • Give Rh immune gobulin during 3rd trimester visit
• What to do if anti-D antibodies are detected in a Rh- mother
  • Cose consultation w/a perinatologist for fetal monitoring
• Erythroblastosis fetalis
  • Life-threatening anemia d/t severe hemolysis
  • Sx: Generalized edema, fetal heart failure
• Investigations
  • Kleihauer-Betke test: Mother
  • Direct Coomb’s test: Baby
• Treatment
  • Preventative administration of Rh immune globulin (after Rh incompatible birth)
  • Phototherapy
  • Exchange transfusion
• Antenatal monitoring
  • Serial US and doppler exams
    • Fetal heart for cardiomegaly
    • Fetal abdomen for ascites and hepatomegaly
  • Serial amniocentesis (look for bilirubin in amniotic fluid)
  • Intrauterine fetal transfusion if necessary
  • Early delivery if necessary
• Neonatal care
  • Tx as any NNJ
  • Fetal blood typing and Coomb’s test
  • Serial draws of bilirubin (babies fall under the medium or high risk category on the AB nomogram)
  • UV phototherapy; exchange transfusion if necessary
  • Monitor for 2-3 months for anemia as maternal Abs are cleared

ABO incompatibility

More common than Rh incompatibility, but is less of a problem and is not detected clinically in many cases. Attack on fetal RBCs by maternal anti-ABO antibodies. Typical presentation is a newborn w/jaundice on the first day of life.

20% of all pregnancies are of a type O mother with a type A or B baby (”set-up case”); of these, only 1/3 of the babies will have a positive Coomb’s test and even fewer will require treatment

• Investigations
  • LFTs: indirect hyperbilirubinemia
  • Direct Coomb’s test: Positive
  • ABO incompatibility
  • R/o Rh incompatibility
• Treatment
  • Monitor for anemia (for several months)
  • Phototherapy if necessary

Criggler-Najjar Syndrome

Criggler-Najjar Type I: Absence of UGT1A1 resulting in inability to conjugate bilirubin (Indirect hyperbilirubinemia) Does not respond to phenobarbital stimulation

Criggler-Najjar Type II: Deficiency of UGT1A, resulting in inability to conjugate bilirubin (indirect hyperbilirubinemia). Responds to phenobabiton stimulation (enzyme inducer

• Investigations
  • Coomb’s test: negative
  • Reticulocyte count: normal
  • Hematocrit: normal
• Treatment
  • Liver transplant (Type I)
  • UV phototherapy (Type II) + Phenobarbital (induces UDPT to reduce total bili by 30-80%)

Direct Hyperbilirubinemia

Ill-appearing babies are more likely to have infections or metabolic disorders. Well-appearing babies are more likely to have biliary atresia or anomalies of the biliary tree

• Intrahepatic causes of direct hyperbilirubinemia
  • Viral hepatitis (CMV, enteroviruses, HSV etc.)
  • Bacterial hepatitis (E. coli, T. pallidum, L. monocytogenes)
  • Disorders of metabolism (tyrosemia, fructose intolerance, galactosemia etc.)
  • Genetic disorders (CF, A1AT-deficiency, PF1C, Rotor, Dubin-Johnson etc.)
  • Endocrine disorders (Hypothyroidism, Hypopituitarism)
  • Paucity of interlobular bile ducts
  • Auroimmune hepatitis
• Extrahepatic causes of direct hyperbilirubinemia
  • Biliary atresia
  • Choledochal cyst
  • Caroli’s disease
  • Alagille syndrome
  • Inspissated bile
  • Cystic fibrosis
• Initial investigations for jaundice
  • CBC w/reticulates
  • LFTs including bilirubin
  • Coomb’s test
  • Albumin
  • PT/PTT
• Investigations if suspected hyperbilirubinemia (based on Hx/px)
  • Abdominal sonography
  • TORCH titres (including HepB, urine for CMV)
  • Cultures (blood, urine, CSF, nasopharyngeal)
  • HIDA
  • ERCP/MRCP
  • Percutaneous liver biopsy
  • Etx. (Urine for reducing sugars, succinylacetone; serum ferritin)

Dubin-Johnson Syndrome

Conjugated hyperbilirubinemia d/t to mutation of the MRP2 channel that transports conjugated bilirubin into the bile cannaliculi. AR inheritance. Typically asymptomatic and usually presents in teenage years as jaundice.

• Investigaitons
  • Urinary Coproporphyrin I to Coproporphyrin III ratio: elevated
• Treatment
  • Symptomatic tx, usually not necessary

Neonatal hepatitis

Congenital or early acquired infection of the liver. Can be transmitted transplacentally, via cervical ascent, during delivery, or post-nataly (transfusion, breast milk). Cause is most often virulent

All ill-appearing babies w/direct hyperbilirubinemia should have titres run for common pathogens of NN hepatitis.

• Pathogens
  • HSV
  • Enteroviruses
  • CMV
  • VZV
  • Rubela virus
  • Adenovirus
  • Parvovirus
  • HHV-6
  • HBV
  • HIV
  • T. gondii
  • T. pallidum
  • E. coli
  • L. monocytogenes
  • S. agalactiae
  • M. tuberculosis
• Which infants have the highest likelihood of contracting Hep B if born to mother w/Hep B
  • Mom is HBeAg+ and HBeAb- at time of delivery
  • Mom has high levels of HBcAb
  • Mom has high levels of HBV DNA
• What to give baby born to mothers who are HBsAG+
  • Hepatitis B immune globulin (HBIG) within 24 hours of birth
  • Hepatitis B vaccine within 24 hours of birth
• Signs and symptoms
  • Baby appears ill
  • Feeds poorly
  • Lethargic
  • Hypotonic
  • Dark urine
  • Meconium/stool is usually unremarkable (not acholic)
• Investigations
  • Serology (titres for pathogens): including HSV, enteroviruses
• Treatment
  • Fluids
  • Adequate nutrition
  • ADEK supplementation
  • Supportive care
  • Antiviral/antibiotic therapy (if cause is identified)
    • Ganciclovir: CMV
    • Acyclovir: HSV, VZV
    • IVIg: Parvovirus, enterovirus
    • Penicillin: Syphillis
    • Pyrimethamin + sulfadiazine w/ leucovorin: Toxoplasmosis
    • INH, pyrizinamide, and rifampinu: MTB
    • Ampicillin/Gentamicin and surgical drainage if necessary: E. coli/Listeria/GBS

Biliary atresia

Conjugated hyperbilirubinemia d/t defect in the biliary tract resulting in cholestasis. Conjugated bilirubin is absorbed into blood stream causing a direct hyperbilirubinemia.

Defined as a progressive fibroinlammatory obliteration of the lumen of the biliary tree. Slight female preponderance. The K

• Sx
  • Baby normal on deliver and discharge
  • Develops jaundice 2-3 weekks of life
  • Dark urine
  • Acholic (clay-colored) stools
  • Failure to thrive within a few months
  • Sx of portal HTN (ascites, splenomegaly etc.) within a few months
• Investigations
  • LFTs: elevated ALP adn GGT
  • Abrominal Sonography: best initial, “triangular cord sign” along the porta hepatis, r/o choedochal cyst and extrinsic compression
  • HIDA scan: normal uptake, decreased excretion
  • Percutaenous liver biopsy
  • Intraoperative cholangiogram: most accurate dx
• Treatment
  • Kasai procedure (hepatoportoenterostomy): should be performed early (within 8 weeks of age)
  • Post-op nutritional supplementation: formula w/MCTGs is recommended
  • Monitor fat-soluble vitamins
  • Transplant

Choledochal cyst

A cystic lesion of all or part of the biliary tree. Clinical and laboratory findings are simiar to biliary atresia.

• Investigations
  • Abominal sonogram
  • MRI: definitive dx
• Treatment
  • Surgical correcition
  • Correct clotting anomalies and/or sepsis

Alagille syndrome

An AD disorder of the liver, heart and kidneys that results in bile duct paucity, impairing the ability of hepatocytes to efficiencyly release conjugated bilirubin. Dx is clinical if there are confirmed cases in the family. Otherwise get a chromosomal analysis for JAG1 mutation

• Long-term effects
  • Hypercholesterolemia
  • Chronic liver diseae
  • Risk of undernutrition
• Constellation of Signs
  • Conjugated hyperbilirubinemia
  • Congenital heart defect (most commonly TOF)
  • Butterfy verterba
  • Xanthomas
  • Characteristic facies (broad forehead, small pointed chin, deep set eyes, prominent ears)
• Treatment
  • Fat soluble vitamin supplementaiton
  • Diet high in MCTGs and carbs
  • Antihistamines (help with pruritus)
  • Frequent monitoring of lipids
    • Bile acid-sequestrants (Cholestyramine, Colestipol)
  • Routine sonography for HCC

Phototherapy

Phototherapy is the mainstay of Tx of neonatal jaundice.

Standard phototherapy: done with an irradiance of 25-30 uW/cm2/nm

Intensive phototherapy: done with an irradiance of 30-35 uW/cm2/nm

Exchange Transfusion

Exchange transfusion is done when TSB reaches threshold for transfusion as per the normograms.

• Other indications for exchange transfusion
  • Rapid rise in serum bilirubin
  • Poor/non-response to phototherapy
  • Presence of Sx of kerniterus
  • Other risk factors?