Neonatal Hyperbilirubinemia

1
Neonatal Hyperbilirubinemia

• Andrew Hopper MDLoma Linda UniversitySchool of
  Medicine

2
Introduction

• Newborns appear jaundiced when bilirubin gt 7
  mg/dL
• 2550 of term newborn and higher percent of
  preterm infants develop clinical jaundice
• 9.1 of well term newborns have maximum serum
  bilirubin gt 12.9 mg/dL
• Bilirubin level gt 15 mg/dL found in 3 of normal
  term infants

3
Bilirubin Metabolism - Heme degradation pathway

• heme oxygenase and cytochrome reductase form a
  complex with biliverdin reductase in the
  catabolism of heme to bilirubin

4
Physiologic Hyperbilirubinemia

• Indirect bilirubin does not exceed 5 mg/dL in the
  first 24 hours 12 to 15 mg/dL in healthy full
  term infants during the first week of life
• Bilirubin concentrations as high as 20 - 26 mg/dL
  can be explained only by physiologic jaundice of
  the newborn without any superimposed pathology
• Direct bilirubin levels should not exceed 1 mg/dL

5
Mechanisms involved in physiologic jaundice

• Increased bilirubin load on hepatocyte
• Defective hepatic uptake of bilirubin
• Defective bilirubin conjugation
• Defective bilirubin excretion

6
Non-physiologic hyperbilirubinemia

• Onset of jaundice before 24 hours of age
• Any increase in bilirubin that requires photoRx
• Rise in bilirubin levels gt 0.5 mg/dL/hour
• Signs of underlying illness in any infant
  (vomiting, lethargy, poor feeding, excessive
  weight loss, tachypnea, temperature instability
• Jaundice persistinggt 8 days in a term infant or gt
  14 days in a premature infant

7
History

• Family hx of jaundice
• hereditary hemolytic anemia
• Family hx of liver disease
• galactosemia, Gilberts, Crigler-Nijjar, or
  cystic fibrosis
• Sibling with jaundice
• blood group incompatibility, breast milk
  jaundice
• Maternal illness
• congenital viral or toxoplasmosis infection, IDM
• Hx of trauma during labor and delivery
• extravascular hemolysis delayed cord clamping
• Hx of delayed or infrequent stooling

8
Breast feeding vs. breast milk jaundice

• Breast milk jaundice
• late onset, may reach 20-30 mg/dL by 14 days of
  age. Levels stay elevated and then fall slowly at
  2 weeks of age, returns to normal by 4 to 12
  weeks of age
• If breast feeding is stopped, bilirubin will fall
  rapidly in 48 hr, when breast feeding resumed
  only 2-4 mg/dL rebound
• 70 recurrence rate in future pregnancies
• Mechanism is unknown interferes with bilirubin
  metabolism and ? enterohepatic circulation

9
Breast feeding vs. breast milk jaundice

• Breast feeding jaundice
• Early onset of elevated bilirubin levels in the
  first 3 to 4 days of life
• Etiology due to decreased intake of milk that
  leads to increased enterohepatic circulation

10
Physical examination

• Prematurity
• Small for gestational age
• Microcephaly
• Bruising, cephalohematoma
• Pallor

• Petechiae
• Hepatosplenomegaly
• Omphalitis
• Chorioretinitis
• Hypothyroidism

11
Clinical laboratory tests

• Total /direct serum bilirubin
• Blood type, Rh, direct Coombs test of the infant
• reserved for infants to be discharged early or if
  maternal blood type O
• Blood type, Rh, maternal antibody screen
• Peripheral smear for RBC morphology and
  reticulocyte count
• CBC with differential
• Identification of antibody on infants RBCs (if
  Coombs is positive)

12
Bilirubin Toxicity

• Difficult to determine toxicity for different
  groups of infants premature and low birth weight
  infants v. healthy full term infants
• Bilirubin entry into the brain occurs as free
  bilirubin or bilirubin bound to albumin in
  presence of disrupted blood-brain barrier
• 8.5 mg bilirubin will bind to 1 gm of albumin
• FFA and drugs interfere with bilirubin binding to
  albumin
• Acidosis affects bilirubin solubility and
  deposition into brain tissue
• Factors affecting blood-brain barrier
  hyperosmolarity, anoxia, hypercarbia and more
  permeable blood brain barrier in premature infants

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Bilirubin Toxicity

• Kernicterus
• Pathologic diagnosis, yellow staining of brain
  (basal ganglia, cranial nerve and brain stem
  nuclei) hippocampal cortex, subthalamic nuclei
  and cerebellum with neurologic injury

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Bilirubin Toxicity

• Acute bilirubin encephalopathy (kernicterus)
• Phase 1 hypotonia, lethargy, high-pitched cry,
  poor suck
• Phase 2 fever, hypertonia ? opisthotonus,
  rigidity, oculogyric crises, retrocollis, fever,
  seizures
• Phase 3 hypotonia replaces hypertonia, hearing
  and visual abnormalities, poor
  feeding, athetosis after about 1 week of age
• Chronic bilirubin encephalopathy choreoathetoid
  palsy, sensorineural hearing loss, upward gaze
  palsy, dental dysplasia, mild intellectual
  deficits

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Bilirubin toxicity

• Bilirubin toxicity and hemolytic disease
• In Rh hemolytic disease, direct association
  between elevated bilirubin and encephalopathy
• In full term infants, if total bilirubin lt 20
  mg/dL bilirubin encephalopathy is unlikely to
  occur
• Bilirubin toxicity and the healthy full-term
  infant
• Little evidence for adverse neurologic outcome
  with bilirubin lt 25-30 mg/dL
• Bilirubin gt20 mg/dL associated with abnormal
  BAER, cry characteristics, and neurobehavioral
  measures

16
Bilirubin toxicity

• Clinical Auditory Sequelae
• Deafness
• Hearing Impairment
• Auditory Neuropathy/Auditory dysynchrony
• Absent or abnormal BAER, normal otoacoustic
  emissions, normal cochlear microphonic response,
  variable degrees of hearing impairment, language
  delays
• (50 have hx prematurity and hyperbili)

17
Bilirubin toxicity

• Bilirubin toxicity and the low-birth-weight
  infant
• Kernicterus uncommon in premature infants
  bilirubin encephalopathy d/t other factors ICH,
  exposure to drugs that displace bilirubin from
  albumin, solutions that alter blood brain
  barrier, anoxia, hypercarbia, sepsis
• Bilirubin toxicity may not be a function of
  bilirubin levels per se but of the infants
  overall clinical status

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Management of Unconjugated Hyperbilirubinemia in
Term Infants

• Hemolytic disease
• Rh disease start photoRx immediately, perform
  exchange Tx if significant hemolysis or bilirubin
  predicted gt 20 mg/dL
• ABO start photoRx if bilirubin gt 10 mg/dL at 12
  hr, gt12 mg/dL at 18 hours, gt14 mg/dL at 24 hours,
  or gt15 mg/dL at any time

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Management of Unconjugated Hyperbilirubinemia in
Term Infants

• Healthy term infants
• Follow AAP guidelines
• Breast fed infants-encourage frequent nursing,
  supplement with formula if necessary
• If bilirubin reaches a level that requires
  photoRx and predicted to exceed 20 mg/dl, start
  photoRx and discontinue breast feeding for 48
  hours and supplement with formula

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Management of Unconjugated Hyperbilirubinemia in
Premature Infants

• Infants lt1000 gm
• photoRx started within 24 h, exchange Tx for
  bilirubin 10-12 mg/dL
• Infants 1000 1500 gm
• photoRx started for bilirubin 7-9 mg/dL, exchange
  Tx for bilirubin 12-15 mg/dL
• Infants 1500 2000 gm
• photoRx started for bilirubin 10-12 mg/dL,
  exchange Tx for bilirubin 15-18 mg/dL
• Infants 2000 2500 gm
• photoRx started for bilirubin 13-15 mg/dL,
  exchange Tx for bilirubin 18-20 mg/dL

21
Risk for pathologic hyperbilirubinemia based on
hour specific serum bilirubin
Bhutani, Peds 1036, 1999
22
Indications for photoRx

• Used when the bilirubin level may be hazardous to
  the infant if it were to increase
• Prophylactic photoRx may be indicated with
  extremely LBW infants or severely bruised infants
  or infants with hemolytic disease
• Contraindicated in infants with direct
  hyperbilirubinemia caused by liver disease or
  obstructive jaundice-may lead to bronze baby
  syndrome
• If both indirect and direct bilirubin are high,
  exchange transfusion is probably safer than
  photoRx because it is unknown whether bronze
  pigment is toxic

23
Factors influencing efficiency of phototherapy

• Types of Light
• Dose-response relation
• Exposed body surface area
• Intermittent v. continuous
• Cholestyramine and agar
• Home phototherapy

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Side effects of phototherapy

• ?insensible water loss
• Watery diarrhea and increased fecal water loss
• Hypocalcemia
• Retinal damage when eyes have been unprotected
• Bronze baby syndrome
• Tryptophan reduced in Aa solutions exposed to
  photoRx
• Maternal-infant interactions disrupted

25
Exchange Transfusion

• Removes partially hemolyzed and antibody-coated
  RBCs as well as unattached antibodies and
  replaces them with donor RBCs lacking the
  sensitizing antigen
• As bilirubin is removed from the plasma,
  extravascular bilirubin will rapidly equilibrate
  and bind to the albumin in the exchanged blood.
• Within ½ hour of exchange, bilirubin levels
  return to 60 of their pre-exchange levels

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Indications for exchange transfusion

• When photoRx fails to prevent rise in bilirubin
  to toxic levels
• Correct anemia and improve congestive heart
  failure in hydropic infants with hemolytic
  disease
• Stop hemolysis and bilirubin production by
  removing antibody and sensitized RBCs

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Indications for exchange transfusion

• Exchange transfusion should be considered
• cord bilirubin gt 4.5 mg/dL and cord Hb lt 11 gm/dL
• Bilirubin rising gt 1 mg/dL/hour
• Bilirubin level gt 20 mg/dL
• Progression of anemia in spite of adequate
  control of bilirubin
• Repeat exchanges are done for the same reasons

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Case Study 1

• A 25 year old primagravida mother, blood type O,
  presents with SPROM at 39 wks gestation. The
  patient is then given oxytocin to augment the
  labor. 24 h after admission, she is completely
  effaced and 10 cm dilated but develops fever to
  101. A male infant is delivered by forceps with
  Apgars 71 and 95. The infant has a large
  cephalohematoma and facial bruising. The infant
  does well for 24 h, but is feeding poorly at 36
  h, appears lethargic and icteric. The infants
  total bilirubin is 15 mg/dL, blood type A and
  Coombs positive serology.

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Case Study 1

• List the factors that might be responsible for
  the elevated bilirubin level in this infant
• Describe the mechanisms by which each of these
  factors alters bilirubin metabolic pathways

30
Case Study 1

• List are the factors that might be responsible
  for the elevated bilirubin level in this infant
• ABO, sepsis, race, oxytocin, and bruising
• Describe the mechanisms by which each of these
  factors alters bilirubin metabolic pathways
• ABO RBC lysis
• Sepsis RBC lysis, liver function
• Race Asians more susceptible than whites or
  blacks mechanism unknown
• Oxytocin may or may not cause hemolysis, depends
  on administration of large volume of sodium free
  fluid
• Bruising sequestration of blood, RBC lysis

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Case Study 2

• A 20 y.o. G2P0 Ab1 white female presents at 34
  wks gestation with abdominal pain and vaginal
  bleeding. She delivers precipitously a 2,200 g
  female infant with Apgars 31 and 85. Infant has
  acrocyanosis, nasal flaring, grunting and
  tachypnea. Because of persistent acidosis and
  hypoxia, the infant is intubated and placed on
  mechanical ventilation and improves during the
  next 2 days. At 72 h, the infant has total
  bilirubin of 15 mg/dL. Phototherapy is begun.
  On day 4 of life, the infant has a total
  bilirubin of 19 mg/dL.

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Case Study 2

• 1. What are six factors in preterm infants that
  predispose them to bilirubin toxicity?
• 2. When should an exchange transfusion be
  considered in this infant?
• 3. List the clinical features of kernicterus in
  term and preterm infants

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Factors enhancing bilirubin neurotoxicity with
asphyxia

• Impaired bilirubin-albumin binding and ?free
  bilirubin (endogenous anions)
• ? proportion of bilirubin as bilirubin acid
  (acidosis)
• ? blood-brain transport of bilirubin (hypercarbia
  and/or ? bilirubin acid)
• Enhanced susceptibility of neurons to bilirubin
  injury (hypoxia-ischemia)
• Enhanced susceptibility of neurons to
  hypoxic-ischemic excitotoxic injury (free
  bilirubin)

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Management of the jaundiced full-term neonate

• Management depends on the cause!
• Hemolytic jaundice
• indicated by anemia, reticulocytosis and positive
  indirect Coombs test
• phototherapy indicated when rapid rise of
  bilirubin (gt0.5 to 1 mg/dl per hour)
• exchange transfusion when bilirubin gt 20 mg/dl
• Non-hemolytic jaundice
• phototherapy for bilirubin gt 18 to 20 mg/dl at
  49-72 h, ? 15 mg/dl at 25-48 h
• exchange transfusion for bilirubin ? 25 mg/dl at
  49-72 h, ? 20 mg/dl at 25-48 h

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Mechanisms involved in physiologic
hyperbilirubinemia

• Increased bilirubin production
• ? RBC volume
• ? RBC survival
• Defective hepatic uptake of bilirubin from plasma
• ? Y-protein (ligandin)
• Binding of Y-proteins by other anions
• ? caloric intake in the first 48-72 hours
• Defective bilirubin conjugation
• ? UDP-glucuronyl transferase
• Defective bilirubin excretion
• Increased enterohepatic circulation

36
Neonatal Hyperbilirubinemia

• What are six factors in preterm infants that
  predispose them to bilirubin toxicity?
• they exhibit ? ability to conjugate bilirubin
• experience higher levels of bilirubin
• they have ? serum albumin concentrations
• blood-brain barrier more prone to disruption
• ??likelihood of hypothermia and hypoglycemia
• ??likelihood of sepsis

37
Neonatal Hyperbilirubinemia

• When should an exchange transfusion be considered
  in this infant?
• Perform an exchange transfusion at a serum
  bilirubin of 15 - 20 mg/dL. A more precise
  answer would depend on whether other risk factors
  for kernicterus exist (e.g., acid-base status,
  albumin level, degree of illness)

38
Case Study 3

• You are asked to evaluate a 15 day old infant
  born to IDM. Initial hospital course was benign.
  Infant has been nursing well at home and was
  noted to be icteric on 2nd day of life. Total
  bilirubin was 13 mg/dL and Coombs neg. The
  infant was d/cd home on day 3 with bilirubin of
  14 mg/dL. At 2 wks, baby appears well other than
  intense icterus. Total bilirubin is now 22 mg/dL
  with a direct bilirubin of 1.2 mg/dL.

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Neonatal Hyperbilirubinemia

• 1. What are the possible causes of this infants
  hyperbilirubinemia?
• 2. How should this infant be managed?
• 3. Should this infant have received an exchange
  transfusion for the jaundice detected at the 2 wk
  follow up visit?
• 4. What alternative therapies are available and
  what are their modes of action?

40
Neonatal Hyperbilirubinemia

• 1. What are the possible causes of this infants
  hyperbilirubinemia?
• 2. How should this infant be managed?
• 3. Should this infant have received an exchange
  transfusion for the jaundice detected at the 2 wk
  follow up visit?
• 4. What alternative therapies are available and
  what are their modes of action?

41
Neonatal hyperbilirubinemia

• 1. What are the possible causes of this infants
  hyperbilirubinemia?
• This infant appears well and has no laboratory
  evidence of hemolysis. The most likely diagnosis
  is late onset breast milk jaundice. A urine
  specimen should be sent to rule out UTI. More
  unusual cases of hyperbilirubinemia (e.g.
  metabolic disease) should be considered if
  bilirubin does not decline with interruption of
  feedings.

42
Neonatal hyperbilirubinemia

• 2. How should this infant be managed?
• Breast feeding should be interrupted for 24 to 72
  h and replace temporarily with glucose and water,
  or formula
• 3. Should this infant have received an exchange
  transfusion for the jaundice detected at the 2 wk
  follow up visit?
• Not unless bilirubin exceeds 25 mg/dL
• 4. What alternative therapies are available and
  what are their modes of action?
• diet, bilirubin binding agents, phenobarbital,
  bilirubin oxidase, metalloporphyrins

43
Neonatal hyperbilirubinemia

• Of the following factors, which are associated
  with breast milk jaundice or with exaggerated
  jaundice in infants of diabetic mothers?
• birth wt 4,500 g
• jaundice at 48 h
• jaundice at 2 wks
• increased RBC breakdown
• increased enterohepatic circulation
• delayed hepatic conjugation
• delayed transition to adult Hb
• increased bilirubin production