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: Rh, ABO, other component incompatibilities RBC Biochemical defects: G6PD, pyruvate kinase deficiency RBC Structural Abnormalities: Spherocytosis, elliptocytosis, infantile pyknocytosis Infection: Bacterial, viral, protozoal Sequestration: Bruising, cephalohematomas, hemangiomas Polycythemia: 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 Well-Baby 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.

What is your working diagnosis? 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.

What is your working diagnosis? 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

What else would you want to know? 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):F317- 22. 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