Neonatal hyperbilirubinemia JFK pediatric core curriculum MGH Center for Global Health Pediatric Global Health Leadership Fellowship Credits: Brett Nelson, MD, MPH Rachel Siegel, MD Susan O’Brien, MD

Discussion outline Bilirubin pathophysiology Physiologic and non-physiologic jaundice Causes of non-physiologic jaundice Unconjugated hyperbilirubinemia Conjugated hyperbilirubinemia Workup Treatment

Bilirubin pathophysiology Bilirubin is breakdown product of heme, from circulating RBCs Carried by albumin to hepatocytes, where processed for excretion In hepatocytes, uridine diphosphogluconurate glucuronosyltransferase (UGT) catalyzes conjugation of bilirubin with glucuronic acid Conjugated bilirubin is now more water soluble and can be excreted in bile (and urine)

Bilirubin pathophysiology

Epidemiology: neonatal jaundice Neonatal jaundice is quite common >50% of normal newborns and 80% of preterm infants have some degree of jaundice Two types of neonatal jaundice: Normal / physiological Abnormal / non-physiological

Reasons for physiologic jaundice In term newborns, bilirubin production is 2-3 times higher than in adults Hematocrit of 50-60%, shorter RBC life span (90 days), and increased turnover of RBCs Bilirubin clearance decreased in newborns, mainly due to deficiency of enzyme UGT UGT activity in term infants at 7 days is ~1% of adult liver and doesn’t reach adult levels until 14 weeks Increase enterohepatic circulation of bilirubin, further increasing bilirubin load

Greater concerns in preterm infants Even more RBC turnover and destruction Physiologically impaired conjugation and elimination of bilirubin An even less mature liver Reduced bowel motility due to inadequate oral intake Delayed elimination of meconium Increased enterohepatic circulation

Physiologic jaundice Jaundice appears around 72 hrs of life Bilirubin peaks <14 mg/dl Direct bilirubin <10% of total bilirubin Rate of rise <5mg/dL/day Jaundice resolves in 1-2 weeks in term infants, 2 weeks in preterm infants Otherwise the jaundice is abnormal…

Two forms of hyperbilirubinemia Unconjugated / indirect hyperbilirubinemia: Pre-hepatic cause, or impairment in conjugation VS. Conjugated / direct hyperbilirubinemia: Injury at the level of the hepatocytes, or post-hepatic obstruction Consider diagnosis of conjugated hyperbilirubinemia if direct bilirubin is >3mg/dL, or is >10% of total bilirubin

Non-physiologic jaundice Early jaundice Starts on first day of life Jaundice of long duration >14 days in term or >21 days in preterm infants Deep jaundice Palms and soles deep yellow Objectively, high bilirubin lab levels Jaundice with fever

Differential diagnosis: Unconjugated hyperbilirubinemia Breastfeeding jaundice Occurs at 1-3 days of age; due to dehydration and lack of stooling (treat by increasing feeding frequency) Breast milk jaundice Occurs at 4-10 days of age; substance in breast milk inhibits glucuronyl transferase (treat by temporary switch to formula) Hemolysis ABO/Rh incompatibility RBC membrane defects Alpha thalassemia G6PD deficiency Cephalohematoma Polycythemia Infection Hypothyroidism Gilbert’s impaired conjugation, associated with stress, no overt hemolysis Crigler-Najjar’s absent (type 1) or diminished (type 2) UDP-glucoronyl transferase

Differential diagnosis: Conjugated hyperbilirubinemia Biliary atresia ~60% of cases; an obliterative process of bile ducts; diagnosed by U/S or biopsy Infection Hepatitis B, TORCH Metabolic Galactosemia Alpha-1-antitrypsin deficiency: most common genetic cause Dubin Johnson or Rotor’s syndrome: defective liver secretion of bilirubin Iatrogenic Drug-mediated TPN-related: occurs in ~2/3 of infants given TPN over 2 weeks of duration; unknown mechanism, possibly mediated by bacterial endotoxins, oxidative stress, glutathione depletion Idiopathic neonatal non-infectious hepatitis (diagnosis of exclusion)

The concern: Kernicterus Bilirubin exceeds albumin-binding capacity, crosses BBB, and deposits on basal ganglia and brainstem nuclei Risks increase with levels >20 mg/dl Or lower levels in setting of sepsis, meningitis, hemolysis, hypothermia, hypoglycemia, or prematurity Kernicterus is yellow staining of the basal ganglia and brainstem nuclei. Bilirubin encephalopathy is the clinical term to describe the condition that results from accumulation of bilirubin in the brain. Acute phase: infant is severely jaundiced, has a poor suck, lethargy, hypotonia If not treated, the infant may become hypertonic (opisthotonus, retrocollis), develop a fever and a high pitched cry. The chronic form: includes choreoathetoid cerebral palsy, upward gaze paresis, hearing loss, and mental retardation. Kernicterus is a devastating usually completely preventable effect of severe hyperbilirubinemia.

Signs of kernicterus Acute sequelae: Chronic sequelae: Poor suck, lethargy, hypotonia, seizure Then hypertonia (opisthotonus, retrocollis), fever, high-pitched cry Chronic sequelae: Choreoathetoid CP, gaze paresis, sensorineural hearing loss, mental retardation

Cause analysis of kernicterus Early discharge <48hrs without follow-up within 48hrs Failure to check bilirubin level when jaundice within 24hrs of life Failure to recognize risk factors Underestimating severity by visual assessment Delay in initiating treatment Failure to respond to parental concerns A root cause analysis of these recent cases identified the following concerns: Early d/c <48 hrs with no f/u within 48 hrs of d/c. Failure to respond to parental concerns regarding jaundice, poor feeding or lethargy. AAP Subcommittee on Neonatal Hyperbilirubinemia. Pediatrics 2001; 108: 763-765.

Work up: assess risk factors Maternal: Race or ethnic group (Asian, Mediterranean) ABO, Rh incompatibility Previous jaundiced infant Advanced maternal age Diabetes Infant: Gestation <38 weeks Bruising, cephalohematoma Infection G6PD deficiency Polycythemia Male gender Nutritional: Breastfeeding Weight loss Decreased feeding frequency Decreased stooling Decreased urine output These are some of the common maternal clinical risk factors: East Asian, Native American, Mediteranean Black infants have lower bilirubin levels than white infants but both peak at about 5-6 mg/dl on the 3rd day of life. Asian infants peak on the 4th or fifth day of life at mean levels of 9-12 mg/dl and sustain higher bilirubin levels for longer period of time.. Mechanism is not clear but may be due to an increase in bilirubin production or enterohepatic circulation rates in Asian infants. And these are some common infant risk factors G6PD Deficiency occurs in 11%- to 13% of blacks and is more common among immigrants from the Mediterranean countries and Southeast Asia. It has been associated with kernicterus. Screening of G6PD Deficiency is not routinely performed in most hospitals. (other enzyme, RBC structural defects) (Genetics- Less common- Gilbert’s disease, Crigler-Najaar) Examine infants in well lit area. Look for bruising, cephalohematomas, petechiae, hepatosplenomegaly and other signs of sepsis. Don’t get bili’s on babies who aren’t jaundiced. Normal bili= 5-6 mg/dl Clinical jaundice appears when the serum bilirubin levels reach >7 mg/dl. Breastfeeding infants who aren’t feeding well have low levels of intestinal bacteria that are capable of converting bilirubin to to it’s non-resorbable form increases enterohepatic circulation ALSO, WHEN DECIDING WHETHER TO TREAT OR DISCHARGE, CONSIDER SOCIAL RISK FACTORS: Parity Maternal age Access to medical care Phone Language Maternal depression Single parent Overwhelmed household need to be considered in planning whether or not to send a family home and in deciding how much support they will require.

Work up: laboratory studies Where possible, confirm clinical jaundice with bilirubin levels Possible additional investigations, depending on likely diagnoses and lab availability: Hemoglobin/hematocrit (PCV) to look for hemolysis Blood smear Reticulocyte count WBC to look for signs of infection (WBC <5, WBC>20, or I:T ratio >20%) Blood type of baby and mother, and Coombs test Syphilis serology (e.g. VDRL) G6PD screen, thyroid function tests, liver ultrasound Additional laboratories: Reticulocyte to evaluate degree of hemolysis consider G6PD screen Once starting: We follow bilirubin values at 6-12 hour intervals. Frequent feeds Maintain hydration and nutrition Keep parents informed Document Consider stopping when: underlying issues are under control bili trend indicates rebound would be lower than that which requires phototherapy So, it seems straightforward but for many infants the question of who should get phototherapy and for how long still leaves a lot of clinicians biting their fingernails.

Treatment options: Unconjugated hyperbilirubinemia Hydration / feeding Consider formula supplementation with temporary interruption of breastfeeding Phototherapy… (see next slide) Antibiotics if suspected infection Antimalarials if fever and positive smear (Exchange transfusion) (IVIG in immune-mediated red cell destruction)

Diagnosis of jaundice can be very difficult in dark-skinned babies Scleral icterus may be more sensitive marker but is a later sign High level of suspicion is required!

Phototherapy Clinical indications1: Laboratory indications: Jaundice on day 1 Jaundice in premature infant Deep jaundice involving palms and soles of the feet Laboratory indications: In full-term infants, bilirubin levels per Bhutani curves In premature infants, when bilirubin level ≥5x weight (e.g. threshold for 3kg newborn = 3kg x 5 = 15mg/dl) 1. Pocket Book of Hospital Care for Children. WHO. 2005.

Bhutani curve: identifying risk Another excellent resource resource we use for guidance in treatment decision-making is a percentile-based bilirubin nomogram developed by Bhutani and published in Pediatrics in 1999. This normogram was developed using: 13,000 term and near term infants > 36 weeks no risk factors for hyperbilirubinemia TSB pre-discharge at 18-72 hours of life at the time of routine metabolic screening Racially diverse 60% were breastfed Follow-up TSB was obtained 2-4 days after discharge to determine the probability of subsequent, moderately severe hyperbilirubinemia (>17 mg/dl) (F/U on 2976/13,000) Using the nomogram, newborns can be designated as high risk (serum bilirubin concentrations >95 %ile) high or low intermediate risk and low risk (serum bilirubin concentrations below 40th % ile) Nomogram for designation of risk in 2840 well newborns at 36 or more weeks' gestational age with birth weight of 2000 g or more or 35 or more weeks' gestational age and birth weight of 2500 g or more based on the hour-specific serum bilirubin values. (Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316)

Bhutani curve: phototherapy Guidelines for phototherapy in hospitalized infants of 35 or more weeks' gestation. (Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316)

WHO guidelines: phototherapy Pocket Book of Hospital Care for Children. WHO. 2005.

Key points regarding treatment: Bilirubin levels above 20 are an emergency that need to be treated emergently Multiple unit phototherapy, up to 6-8 lights, if they are available, can and should be used If bilirubin is high, need to provide multi-unit therapy, encouragement of frequent feeding and possibly IV fluids as well

Treatment: Conjugated hyperbilirubinemia Phototherapy is contraindicated Treat underlying cause Phenobarbital increases conjugation and excretion of bilirubin; however, could affect cognitive development, therefore used cautiously Ursodiol increases biliary flow and improves cholestatic jaundice

Conclusion Neonatal jaundice is a very common condition Important to prevent kernicterus Pathologic jaundice is early, deep, quickly progressing, or of long duration Assess jaundice through identifying risk factors and laboratory analysis Bhutani curves guide phototherapy treatment for unconjugated hyperbilirubinemia Treat underlying cause of conjugated hyperbilirubinemia