Clinical Case JR, 7 do hispanic BB, twin B, presented to UCCH ER with jaundice on 5/9/06 DOB – 5/3/06, at OSH in Indiana NVD, GA 38 weeks, APGARs 9/9 BWt 3.18 kg (7#0oz) Maternal Hx: 31 yo G2P3 now, good PNC, uncomplicated pregnancy PNL – B+/RPR NR/R Imm/HepB NR/HIV NR/GBS-

Perinatal course Initial PE unremarkable; + some facial bruising noted Wt 2.9 kg Feeding BM/E20 – well per GCN records Voiding and stooling well Discharged at 48 hrs D/C Wt – 2.03 kg Mom told that baby had “borderline” jaundice To call Pediatrician if she sees baby gets yellow

Baby was OK at home, eating well – 10-15 min each breast Stooling well – per mother On DOL 5 mother thought babies look yellow and called the PMD She was told to go to the hospital next day for Bili check

Labs Baby B+/Coombs- Mom B+

Work Up CBC – WBC 13.6, H/H 18.9/54, Plt 301 Diff N26, Bn4 Retic count 0.7%

Bilirubin 5/5/06 - @48 hrs (OSH) – 13.0/0.4 5/9/06 – DOL 7 – (OSH) – 30.9/0.6 5/9/04 – UCCH – 31.5/0.8 Sibling’s Bili was 21 – admitted to Peds Floor for phothotherapy

ER course VSS, baby was jaundiced and “sleepy” Placed under phothotherapy Given IVF Admitted to PICU for exchange transfusion

Here comes the NICU 0230 – NICU fellow received a call from upstairs to help with the exchange transfusion By 0530 baby was in the PICU Blood ordered UVC placed Double volume exchange transfusion was done Rpt Bili – 23.8/0.7 half way through the exchange

Neonatal Hyperbilirubinemia

WHAT IS HYPERBILIRUBINEMIA AND WHY DO WE WORRY ABOUT IT?

Jaundice A visible manifestation in the skin and sclera of elevated bilirubin concentrations Adults are usually jaundiced when bilirubin levels exceed 2 mg/dL Neonates appear jaundiced when serum total bilirubin (STB) levels reach 5-7 mg/dL

Some degree of jaundice develops in 60-70% of all neonates born on the United States More than 2.7 million neonates born each year in the United States will develop jaundice Chemical hyperbilirubinemia, a STB > 2.0 mg/dL, is virtually universal Although most jaundice is benign, there is a potential for neurological devastation and death and consequently all newborns must be assessed

WHY DO INFANTS DEVELOP HYPERBILIRUBINEMIA?

Increased Bilirubin Production Decreased Binding and Transport Capacity Limited Conjugation and Excretion Capacity Increased Enterohepatic Circulation of Bilirubin

Bilirubin is the breakdown product of hemoglobin Lysis of red cells releases heme from hemoglobin Heme is then converted to bilirubin and excreted

Bilirubin Synthesis There is increased production of bilirubin in the newborn because of: Increased rate of degradation A shortened circulating erythrocyte life span (70-90 days versus 120 days) of an increased mass A very large pool of hematopoietic tissue that ceases to function shortly after birth resulting in heme degradation An increased turnover of cytochromes (nonhemoglobin heme proteins) An increase in enterohepatic circulation

Binding and Transport Unconjugated bilirubin is quickly bound to albumin in the serum Newborns have reduced albumin concentrations and consequently a lower plasma binding capacity for bilirubin There is consequently more free bilirubin in the serum It is the free bilirubin that is believed to cause neurological damage in newborns

Conjugation and Excretion During fetal life, removal of bilirubin is accomplished by the placenta In the newborn, bilirubin excretion requires conversion of the nonpolar unconjugated bilirubin into a more polar water-soluble substance, conjugated bilirubin

Blood flow through the hepatic artery develops during the first week of life The ductus venosus allows blood to bypass the liver completely Conjugation depends on the maturity of the liver cell

UDPGT UDPGT in the newborn liver must be induced UDPGT activity is extremely low in infants born at less than 30 weeks, 0.1% of adult levels This activity increases to only 1% at term The activity reaches adult levels by 6-12 weeks of age

Conjugation Bilirubin dissociates from circulating albumin before its entry into the liver cell Bilirubin enters the liver by a process of carrier-mediated diffusion It is carried by hepatic ligandin (Y protein) and Z protein Bilirubin is presumed to be transported from the liver cell membrane to the endoplasmic reticulum, the site of the conjugating enzyme uridine diphosphate glucuronyl transferase (UDPGT) After conjugation, bilirubin is then excreted into bile in the intestine

Increased Enterohepatic Circulation Conjugated bilirubin is unstable and can be easily hydrolyzed back to unconjugated bilirubin and reabsorbed through the intestinal mucosa High mucosal beta-glucuronidase activity leads to increased hydrolysis An alkaline environment also facilitates hydrolysis In the newborn, the relative lack of intestinal bacterial flora to reduce bilirubin to urobilinogen further increases the bilirubin pool

Neonatal Hyperbilirubinemia Physiologic Jaundice A progressive rise in unconjugated bilirubin to a peak of 5-6 mg/dL between 60 and 72 hours of life in white and African-American babies and 10-14 mg/dL between 72-120 hours of life in Asian babies A rapid decline in TSBs occurs by the 5th or 7-10th day respectively

Pathologic Unconjugated Hyperbilirubinemia Pathologic hyperbilirubinemia is defined as a prolonged or exaggerated hyperbilirubinemia Occurs because of disorders of: Production Hepatic Uptake Conjugation Enterohepatic Circulation

Disorders of Production Isoimmunization Erythrocyte Enzymatic Defects Erythrocyte Structural Defects Infection Sequestration Polycythemia

Isoimmunization Rh Incompatibility ABO Incompatibility Other Blood Group Incompatibilities

Rh Incompatibility This is a blood group incompatibility between the mother and newborn that can cause severe hemolytic anemia in the fetus and newborn The Rh antibody is produced by a Rh negative mother after being exposed to a Rh antigen from fetal blood The initial response is to make IgM antibodies Later IgG are produced which cross the placenta and bind to fetal red blood cells which are consequently destroyed Infants do not appear jaundiced at birth, but severe anemia can lead to hydrops and death After birth, infants may develop hyperbilirubinemia rapidly

The D antigen may produce sensitization with a fetomaternal hemorrhage as small as 0.1 mL At one time this was the most common cause of kernicterus; but with the use of RhoGAM (anti-D immunoglobulin G) and careful fetal monitoring, the incidence and severity have decreased

ABO Incompatibility This is a hemolytic disease caused by a reaction of maternal anti-A or anti-B antibodies with fetal A or B antigens Usually milder than Rh Almost exclusively in type O mothers Jaundice appears at 24-72 hours Half of infants with a positive Coombs show hemolysis and some with a negative Coombs have hemolysis

Minor Blood Groups Kell, Kidd, Duffy, Lutheran < 2 % of hemolysis from isoimmunization

Erythrocyte Enzymatic Defects Glucose-6-Phosphate Dehydrogenase Deficiency Pyruvate Kinase Deficiency These defects may have profound effects on erythrocyte function and life span

Glucose-6-Phosphate Dehydrogenase Deficiency Glucose-6-phosphate dehydrogenase deficiency (G6PD) is a common disease, especially in people of Mediterranean; African; and Asian decent G6PD deficiency occurs in 11-13% of African Americans Estimated 200-400 million people carry the gene X-linked Presentation is heterogeneous Hemolysis occurs, but can be absent Hyperbilirubinemia occurs between 24 and 72 hours of life

RBCs are unable to activate the pentose phosphate metabolic pathway And consequently cannot defend against oxidative stress Sepsis and Vitamin K analogues Severity of disease depends on type and amount of stress

Pyruvate Kinase Deficiency This is the second most common cause of enzymatic-related hemolytic anemia Autosomal recessive It is common in people of Northern European decent It is an enzyme required for production of ATP in RBCs

Its deficiency leads to decreased RBC life span and hemolysis

Erythrocyte Structural Defects Hereditary Spherocytosis Hereditary Elliptocytosis These defects alter RBC structure and cause sequestration

Hereditary Elliptocytosis Incidence of 1:4000 Autosomal dominant Abnormality in spectrin or glycophorin C Hemolysis and hyperbilirubinemia are unusual in the newborn period

Hereditary Spherocytosis Incidence of 1:5000 Autosomal dominant Heterogeneous presentation Fifty percent present with hemolytic anemia, hyperbilirubinemia, reticulocytosis, and increased erythrocyte osmotic fragility

Infection Hyperbilirubinemia is believed to be secondary to hemolysis Sepsis may impair conjugation also leading to increased bilirubin levels

Sequestration Sequestration of blood in body cavities may lead to hyperbilirubinemia as the body metabolizes hemoglobin Cephalohematomas, subdural hematomas, subgaleal hematomas Excessive bruising

Polycythemia The increase in red blood cell mass has the potential to overload the newborn hemoglobin metabolism capacities

Disorders of Hepatic Uptake Gilberts Syndrome This is a benign disorder producing persistent unconjugated hyperbilirubinemia There is defective hepatic uptake and decreased UDPGT activity It usually occurs in the second decade of life, but can present in neonates

Disorders of Conjugation Crigler-Najjar Syndrome Transient Familial Neonatal Hyperbilirubinemia (Lucey-Driscoll Syndrome) Pyloric Stenosis Hypothyroidism

Crigler-Najjar Syndrome Type I There is absence of UDPGT activity Autosomal recessive 1:1,000,000 Severe unconjugated hyperbilirubinemia develops and persists beyond the first week of life No hemolysis Lifelong risk of kernicterus Lifelong phototherapy is needed

Type II There is various degree of decrease of UDPGT activity Typically benign There is unconjugated hyperbilirubinemia in the first few days of life that does not exceed 20 mg/dL Hyperbilirubinemia persists into adulthood The treatment is phenobarbital

Transient Familial Neonatal Hyperbilirubinemia Neonates develop severe nonhemolytic hyperbilirubinemia Their serum contains high concentrations of glucuronyl transferase inhibitors This inhibitor decreases by about 14 days of life and consequently hyperbilirubinemia resolves

Pyloric Stenosis 10-25% of babies with pyloric stenosis have hyperbilirubinemia at the time of presentation Hepatic glucuronyl tranferase activity is reduced Surgical correction improves bilirubin levels

Hypothyroidism UDPGT activity is deficient and remains low for weeks with hypothyroidism

Disorders of Enterohepatic Circulation Breast Feeding Jaundice Breast Milk Jaundice

Breast Feeding Jaundice Unconjugated hyperbilirubinemia is secondary to a suboptimal establishment of breastfeeding Newborns are under-hydrated and in a state of starvation. They also have delayed passage of meconium Enterohepatic reuptake of bilirubin is consequently increased, leading to hyperbilirubinemia Treatment and prevention include frequent feedings (8-12/day)

Breast Milk Jaundice Occurs after 3-5 days of life, typically at 2-3 weeks of life The etiology is unknown, but believed to be a factor in breast milk or an altered chemistry in breast milk that enhances intestinal reabsorption of bilirubin No need to stop breastfeeding unless bilirubin levels are dangerously high

WHY DO WE WORRY ABOUT HYPERBILIRUBINEMIA?

Sequelae Bilirubin may penetrate the brain cell and cause neuronal dysfunction or death if not carefully managed Bilirubin causes staining and necrosis of neurons in the basal ganglia, hippocampal cortex, subthalamic nuclei, and cerebellum which is followed by gliosis 50%of patients with kernicterus die

Acute Bilirubin Encephalopathy Phase 1 - poor suck, hypotonia, and depressed sensorium Phase 2 - fever and hypertonia or opisthotonos Phase 3 - less hypertonia, high pitched cry, hearing and visual abnormalities, poor feeding, athetosis

Kernicterus Long term sequelae: Chorioathetoid cerebral palsy Sensorineural hearing loss Upward gaze palsy Dental-enamel dysplasia Mental retardation

SO, WHAT CAN WE DO?

Diagnosis and Management There has been evidence that neonatal jaundice can be treated less aggressively, but there is not a consensus yet and until then it should be managed conservatively

Diagnosis All neonates are entitled to a thorough physical examination and evaluation to determine which neonates are at an increased risk for becoming abnormally jaundiced and developing sequelae

Risk Assessment Every newborn should be assessed, especially if discharged before 72 hours of life 2 options: TSB or TcB before discharge and plot results on the nomogram

Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316 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 Copyright ©2004 American Academy of Pediatrics

Assessment of risk Major Predischarge TSB or TcB in the high-risk zone Jaundice in the first 24h Hemolytic disease Gestational age 35-36 weeks Sibling received phototherapy Cephalohematoma or bruising Poor breastfeeding East Asian descent

Carbon Monoxide End Tidal Carbon Monoxide detection allows rapid noninvasive detection of infants at risk for hemolytic disease and consequently at high risk for neurological sequelae

Carbon Monoxide The breakdown of hemoglobin by heme oxygenase produces free iron and carbon monoxide in equimolar amounts The carbon monoxide formed by heme degradation is excreted unchanged by the lungs. Although there are other endogenous and exogenous sources of CO, quantitative estimation of its excretion or synthesis offers a reasonably accurate assessment of bilirubin synthesis

Physical Examination Detection of clinical jaundice requires digital pressure and the proper lighting, preferably daylight If clinical jaundice is detected, a total and direct serum bilirubin or transcutaneous bilirubin (TcB) should be measured and plotted on the nomogram

When should I do more? If: Cord bilirubin is greater than 4 mg/dL A rate of rise greater than or equal to 0.5 mg/dL/hour over a 4-8 hour period An increase of 5 mg/dL per day 13-15 mg/dL in a term infant 10 mg/dL in a preterm infant If jaundice persist greater than 10 days

Then what? Determination of maternal blood group and Rh type Screen for antibodies directed against minor erythrocyte antigens Determination of newborns blood type and Rh type Direct Coombs test Hemoglobin and Hematocrit Peripheral blood smear Reticulocyte count G6PD level

Algorithm for the management of jaundice in the newborn nursery Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316 Copyright ©2004 American Academy of Pediatrics

Guidelines for phototherapy in hospitalized infants of 35 or more weeks' gestation Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316 Copyright ©2004 American Academy of Pediatrics

Helpful resources Bili-Aid

Phototherapy The main mechanism of action Geometric photoisomerization of unconjugated bilirubin that can then be excreted without conjugation

Technique Wavelength Bilirubin absorbs light maximally in the blue range (420-500 nm), with a peak at 460 nm for albumin-bound bilirubin and 440 nm for free bilirubin Special blue lamps have a spectrum between 420-480

Irradiance The energy output measured in microwatts per square centimeter per nanometer Optimal level is 11 microwatts per square centimeter per nanometer Intensive phototherapy is 30 microwatts per square centimeter per nanometer

Positioning Surface area Within 10 cm of the patient for fluorescent tubes Surface area The greater the surface area exposed, the more effective the phototherapy

Hydration There is no evidence that excessive fluid administration affects the serum bilirubin concentration If admitted with dehydration, babies will need to be rehydrated and then fed Feeding inhibits enterohepatic circulation of bilirubin Important to watch fluid status for excretion of bilirubin

The TSB level for discontinuing phototherapy depends on the age at which phototherapy was started and the etiology For infants readmitted after birth admission, you can discontinue usually at 13-14 mg/dL with a follow up visit 24 hours after discharge There is no need for a rebound bilirubin, unless there is hemolytic disease

Pharmacological Therapy Phenobarbital Albumin Tin-mesoporphyrin Inhibits heme oxygenase Intravenous gamma-globulin Shown to reduce the need for exchange transfusions in isoimmune hemolytic disease

Guidelines for exchange transfusion in infants 35 or more weeks' gestation Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316 Copyright ©2004 American Academy of Pediatrics

Exchange transfusions are recommended if TSB is greater than or equal to 25 mg/dL in a healthy full term infant If rate of rise is greater than or equal to 0.5 mg/dL/hour If there is active hemolysis or other risk factors, then an exchange transfusion may be warranted at a lower bilirubin level

Exchange Transfusion With a exchange transfusion, approximately 85% of erythrocytes will be replaced Serum bilirubin levels should decrease by 50%

American Academy of Pediatrics In 1994 the AAP established practice parameters for the management of hyperbilirubinemia Revised in 2004

Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation Goals: Promote and support successful breastfeeding Establish nursery protocols for the identification and evaluation of hyperbilirubinemia Measure the total serum bilirubin or transcutaneous bilirubin levels on infants jaundiced in the first24 hours

Recognize that visual estimation of the degree of jaundice can lead to errors, particularly in darkly pigmented infants Interpret all bilirubin levels according to the infant’s age in hours Recognize that infants less than 38 weeks’ gestation, particularly those who are breast fed, are at higher risk of developing hyperbilirubinemai and require closer surveillance and monitoring Perform a systematic assessment on all infants before discharge for the risk of severe hyperbilirubinemia

Provide parents with written and verbal information about newborn jaundice Provide appropriate follow-up based on the time of discharge and the risk assessment Treat infants, when indicated, with phototherapy or exchange transfusion

Follow Up Infant Discharged Should Be Seen By Age < 24 hours 24 to 47.9 hours 48 to 72 hours Should Be Seen By Age 72 hours 96 hours 120 hours

Fanaroff, Martin. Neonatal-Perinatal Medicine, 7th Edition. Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation, Pediatrics 2004;114;297-316 Taeusch, Ballard, Gleason. Avery’s Diseases of the Newborn, 8th Edition