Neonatal Hyperbilirubinemia
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Transcript Neonatal Hyperbilirubinemia
Neonatal Hyperbilirubinemia
MELISSA NELSON, MD
NEONATAL-PERINATAL FELLOW
YALE-NEW HAVEN HOSPITAL
Lecture Objectives:
Describe bilirubin metabolism
Understand clinical significance of hyperbilirubinemia
Learn diagnostic approach and further work-up
Distinguish indirect vs. direct hyperbilirubinemia
Develop differential diagnoses for each type
Understand management options for each type
Apply this knowledge to several clinical cases
Bilirubin:
Biologically active end product of heme metabolism
Bilirubin Metabolism:
* Unconjugated bilirubin is bound to albumin in plasma (hydrophobic)
Hyperbilirubinemia:
Imbalance of bilirubin production and elimination
In order to clear from body must be:
Conjugated in liver
Excreted in bile
Eliminated via urine and stool
Clinical Significance of Hyperbilirubinemia:
Most common reason that
neonates need medical
attention
“Physiologic jaundice” is a
normal phenomenon during
transition
Becomes concerning when
levels continue to rise
Unconjugated bilirubin is
neurotoxic
Hyperbilirubinemia & Clinical Outcomes:
Deposits in
skin and
mucous
membranes
Unconjugated
bilirubin
deposits in
the brain
Permanent
neuronal
damage
JAUNDICE
ACUTE BILIRUBIN
ENCEPHALOPATHY
KERNICTERUS
Clinical Symptoms:
Jaundice/Icterus:
Newborn icterus notable once total bilirubin > 5-6 mg/dL
(versus older children/adults once > 2 mg/dL)
Progresses cranially to caudally
CAUTION: Visual assessment is subjective, inaccurate, and
dependent on observer experience!
Keren et al Visual assessment of jaundice in term and late-preterm infants (2009)
Nurses at HUP used 5 point-scale to rate cephalocaudal extent of jaundice
Showed weak correlation between predicted and actual levels
Jaundice/Icterus:
Clinical Symptoms:
Acute Bilirubin Encephalopathy/Kernicterus:
Irritability, jitteriness, increased high-pitched crying
Lethargy and poor feeding
Back arching
Apnea
Seizures
Long-term: Choreoathetoid CP, upward gaze palsy, SN
hearing loss, dental dysplasia
Kernicterus:
* Bilirubin deposits typically in basal ganglia, hippocampus, substantia nigra, etc.
Diagnosis of Hyperbilirubinemia:
Careful clinical assessment and monitoring
Thorough history:
Pregnancy and delivery history
General health status and infectious risk
Feeding method and feeding progress
Vital signs and ins/outs (hydration status)
Risk factors for isoimmunization
Family history and ethnicity (ie. G6PD, spherocytosis, etc.)
Physical exam:
Activity level, feeding ability, bruising/hematoma, plethora
Diagnosis of Hyperbilirubinemia:
Transcutaneous measurement:
Use can reduce need for blood level
monitoring (Mishra et al, 2009)
Methods exist but not at every institution
Yale: Well-baby nursery uses TcB measures at
24:00 daily
Blood level measurement:
Blood level monitoring per hospital
protocol
Yale: NBSCU all babies checked at 24h of life
Yale: Well-baby nursery checks once within
certain range by TcB
Measure Total and Direct Bilirubin levels
Decisions for treatment based on total serum
bilirubin (TSB)
Diagnosis of Hyperbilirubinemia:
Frequent additional studies to obtain:
Blood type and Rh screening of mother and infant
DAT/Coombs testing in infant
CBC (consider reticulocyte count, blood smear)
Occasional additional studies to obtain:
Albumin levels
LFTs
TFTs
Imaging: Liver/GB ultrasound, HIDA scan (r/o biliary atresia)
Neonatal Hyperbilirubinemia:
Physiologic vs. Pathologic
Jaundice
< 24 hrs is always pathologic!
Indirect vs. Direct (Unconjugated vs. Conjugated)
Pre-term vs. Full-term Hyperbilirubinemia:
Pre-term infants at higher risk due to further
reduced activity of liver conjugating enzymes
Pre-term infants can develop encephalopathy or
kernicterus at lower total bilirubin levels
Indirect Hyperbilirubinemia:
Elevated levels of bilirubin due to imbalance in
production, transport, uptake, conjugation,
excretion, and reabsorption
Most concerning due to risk for
encephalopathy/kernicterus if not treated rapidly
Differential Dx of Indirect Hyperbilirubinemia:
Physiologic Jaundice
Disorders of Production
Disorders of Hepatic Uptake
Disorders of Conjugation
Other Causes
Differential Dx of Indirect Hyperbilirubinemia:
Physiologic Jaundice:
Progressive rise in total bilirubin between 48 and 120
hours of life (peaks at 72-96 hours)
Due to higher postnatal load of bilirubin and lower
amount of liver conjugating enzyme (UGT) activity
Occurs in virtually every newborn to some degree
Differential Dx of Indirect Hyperbilirubinemia:
Disorders of Production: Increased RBC destruction
Isoimmunization:
RBC Biochemical defects:
Bruising, cephalohematomas, hemangiomas
Polycythemia:
Bacterial, viral, protozoal
Sequestration:
Spherocytosis, elliptocytosis, infantile pyknocytosis
Infection:
G6PD, pyruvate kinase deficiency
RBC Structural Abnormalities:
Rh, ABO, other component incompatibilities
IDM, delayed cord clamping
Hemoglobinopathy
Differential Dx of Indirect Hyperbilirubinemia:
Disorders of Hepatic Uptake:
Gilbert Syndrome
Differential Dx of Indirect Hyperbilirubinemia:
Disorders of Conjugation:
Crigler-Najjar Syndrome Type I
Crigler-Najjar Syndrome Type II
Lucey-Driscoll Syndrome (transient familial neonatal
hyperbilirubinemia)
Hypothyroidism
Differential Dx of Indirect Hyperbilirubinemia:
Other Causes:
Breastfeeding Jaundice
Lack of volume
Breast Milk Jaundice
Unknown mechanism
Possibly unidentified component in breast milk that causes
increased enterohepatic recirculation?
Infant of Diabetic Mother
Management of Indirect Hyperbilirubinemia:
Careful assessment and monitoring
Visual assessment
Blood level monitoring per hospital
protocol at 24 hr of life or sooner as
indicated
Interpretation of risk levels and need
for treatment
Phototherapy
IVIg (reduces need for exchange when isoimmunization)
Exchange Transfusions
Phenobarbital (increases hepatic glucuronosyltransferase
activity; used in severe and prolonged cases only)
Management of Indirect Hyperbilirubinemia:
Indications for Phototherapy (Term/Near-Term Infants):
* Bhutani curves (as seen in AAP recommendations and YNHH NBSCU Guidelines)
Management of Indirect Hyperbilirubinemia:
Indications for Phototherapy (Pre-Term Infants):
Gestational Age (weeks)
Total bilirubin level (mg/dL)
32 – 34 6/7
9
28 – 31 6/7
6
< 28
5
* Based on data from YNHH NBSCU Guidelines
Treatment of Indirect Hyperbilirubinemia:
Phototherapy:
* Important factors: Spectrum, irradiance, distance, surface area
Management of Indirect Hyperbilirubinemia:
Indications for Exchange Transfusion (Term/Near-Term Infants):
* Adapted from AAP recommendations and YNHH NBSCU Guidelines
Treatment of Indirect Hyperbilirubinemia:
Exchange Transfusion:
Double-volume exchange
2 x blood volume = 2 x 80 cc/kg =
160 cc/kg
Takes about 1-1.5 hours
Exchange at rate of ~5cc/kg/3 min
Volume withdrawn/infused based
on weight
Direct Hyperbilirubinemia:
Considered elevated when:
Level > 2.0 mg/dL (severe > 5.0 mg/dL)
Level > 15% of total serum bilirubin
Risk factors:
Low gestational age
Early and/or prolonged exposure to TPN
Lack of enteral feeding
Sepsis
Clinical hallmarks: icterus, acholic stools, dark urine
Differential Dx of Direct Hyperbilirubinemia:
More common causes:
TPN-associated
Hepatitis: Idiopathic, Infectious, Toxic
Infection: Sepsis, TORCH, UTI
Biliary atresia
Inspissated bile plug
Choledochal cyst
Alpha-1-antitrypsin deficiency
Galactosemia
Differential Dx of Direct Hyperbilirubinemia:
Less common causes:
Cholelithiasis
Cystic fibrosis
Hypothyroidism
Rotor’s Syndrome
Dubin-Johnson Syndrome
Storage diseases (Niemann-Pick, Guacher’s)
Metabolic disorders (tyrosinemia, fructosemia)
Trisomy 21 or 18
Drug-induced
Shock
Alagille Syndrome
Zellweger Syndrome
Management of Direct Hyperbilirubinemia:
Diagnose underlying cause:
Basic work-up: LFTs, coags, CBC, cultures
Infectious work-up for TORCH or hepatitis
Imaging studies (RUQ U/S, HIDA scan)
Serum alpha-1-antitrypsin levels
Urine-reducing substances (galactosemia)
TFTs
Sweat test
Treatment of Direct Hyperbilirubinemia:
Treat underlying cause:
TPN-associated cholestasis:
Stop TPN or at least reduce (especially lipid) and advance feeds
“TPN-Cholestasis protocol” (remove trace elements certain days)
Ursodiol (Actigall) and ADEKs
Phenobarbital use controversial
Biliary atresia with Kasai procedure +/- liver transplant
Alpha-1-antitrypsin with liver transplant
Choledochal cyst with surgical removal
Galactosemia with dietary elimination
Supportive care if no treatment possible
Case #1:
FT baby girl born at 40 weeks
to G1P0 mother
BW 3200 g; Apgars 9,9
Pregnancy and delivery without
complications
Currently DOL #2 (48h of life)
Nurses noted that she looks like
this and call you to the WellBaby Nursery to evaluate her:
Case #1:
What else would you want to know?
How is she feeding? How is it going?
Is she stooling and voiding? How often?
What is her current weight?
How is she doing otherwise?
Does she have any risk factors?
Has she had her TcB checked?
Has she had blood bilirubin levels checked?
Case #1:
Her mother is breastfeeding her. She thinks it is
going well but this is her first baby and she is not
sure if her milk is in yet. She is feeding for 20
minutes every 4 hours.
Voided once and stooled several times since birth.
Current weight is 2850 g (about 11% less than BW).
She seems less active and is sleeping more today.
No known risk factors. Mother and baby are both B
positive.
Total/direct bilirubin is 18/1 mg/dL.
Case #1:
What is your working diagnosis?
BREASTFEEDING
JAUNDICE
Case #1:
What would you do
next?
Initiate phototherapy
Monitor serial
bilirubin levels
Encourage increased
frequency of feedings
(q 2-3h ATC) and
consider
supplementation prn
Request lactation
consult
Bhutani Curve: Phototherapy Indication
Case #2:
Late pre-term baby boy born at
35 weeks
BW 2500g; Apgars 8,9
Pregnancy and delivery
without complications
Currently DOL #1 (12 h of life)
Nurses noted that he looks like
this and called you into Room 1
to evaluate him:
Case #2:
What else would you want to know?
How is he feeding? How is it going?
Is he stooling and voiding? How often?
What is his current weight?
How is he doing otherwise?
Does he have any risk factors?
Has he had his TcB checked?
Has he had blood bilirubin levels checked?
Case #2:
He is taking Neosure formula 2 ounces q 2-3 hours.
Voided twice and stooled several times since birth.
Current weight is 2500 g (same as BW).
He is less active and sleeping more today.
Mother is O positive and baby is A positive.
Total/direct bilirubin is 18/1 mg/dL.
Coombs positive.
Case #2:
What is your working diagnosis?
ABO
INCOMPATIBILITY
Case #2:
What would you do next?
Exchange transfusion
Bhutani Curve: Phototherapy Indication
Exchange Transfusion Indication
Case #3:
Pre-term baby boy born at 28 weeks
Currently DOL 21
BW 900 g; Apgars 5,8
Noted to have scleral icterus
Bilirubin levels 7.2/3.4 mg/dL
Case #3:
What else would you want to know?
Does he have any risk factors?
How has he been acting clinically?
Has he been receiving TPN? Any enteral feeds?
Has he had any signs of infection?
Does he have any syndromic features?
What were his newborn screen results?
Case #3:
No known risk factors.
He has been acting well without infectious
symptoms.
He had NEC on DOL #4 and has an ostomy and
mucous fistula. He has been on TPN since then.
No features concerning for syndromes.
Newborn screening results were normal.
Case #3:
What is your working diagnosis?
TPN-ASSOCIATED CHOLESTASIS
Case #3:
What would you do next?
Try to advance enteral feeds and reduce TPN as soon as
clinically possible
Start “cholestasis protocol”
Monitor bilirubin levels with LFTs every 2 weeks
Consider further work-up if bilirubin levels do not improve
over time once off TPN
Summary:
Hyperbilirubinemia is a common and potential
serious issue in neonates
Important to recognize and diagnose early in order
to initiate prompt treatment when possible
References/Further Reading:
Yale-NHH NBSCU Guidelines: “Indications for phototherapy and
exchange transfusion”
Lange: “Neonatology: Management, Procedures, On-Call Problems,
Diseases and Drugs”
Fanaroff and Martin chapters on hyperbilirubinemia
Keren R et al. Visual assessment of jaundice in term and late preterm
infants. Arch Dis Child Fetal Neonatal Ed. 2009 Sep;94(5):F31722. Epub 2009 Mar 22.
Mishra S et al. Transcutaneous bilirubinometry reduces the need for
blood sampling in neonates with visible jaundice. Acta Paediatr.
2009 Dec;98(12):1916-9. Epub 2009 Oct 7.
All images found on google images