Neonatal Jaundice: When Do the Light Bulbs Go On? - Trinity Health

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Neonatal Jaundice: When Do the Light Bulbs Go On? - Trinity Health

Perinatal Symposium--2012

Neonatal Jaundice: When Do the Light

Bulbs Go On?”

Theodore R. Thompson, MD

Professor of Pediatrics

Division of Neonatology

University of Minnesota Medical School

I have no financial relationships to disclose.

I will not discuss off label use and/or investigational use

of drugs in my presentation


Objectives: Neonatal Jaundice

• Identify the four reasons that contribute significantly to the occurrence of

developmental/physiologic jaundice in newborn infants

• Outline how to (and “NOT to”) initially evaluate the newborn infant who is

jaundiced

• Outline methods/risk factors to help predict the newborn infant who is likely to

develop severe hyperbilirubinemia

• Describe when transcutaneous bilirubin measurements can and can NOT be used

as a screening tool

• Describe how to manage the jaundiced newborn infant including plans for follow

up if the infant is being discharged

• List three factors that contribute significantly to the efficacy of phototherapy


Neonatal Hyperbilirubinemia

• Patient Study #1:

BA is a 3100 gram, 36-37 gestational age male born to a 29 year

old, 0+, Gr 1 P0000 female whose pregnancy was uncomplicated.

The infant’s course in the hospital was unremarkable except for

the mother needing help to establish breast feeding. He was

noted to be jaundiced at 34 hours of age; total serum bilirubin

(TSB) was 8.5mg/dL. He was discharged at 40 hours of age with

follow up at 2 days of age when he was noted to be very

jaundiced (to his feet). The TSB was 19mg/dL (0.3 directconjugated).

His blood type is A+. He is active, pink, alert, with a

normal cry and normal tone.

• What would you do?


»GENERAL


Neonatal Indirect-Unconjugated

Hyperbilirubinemia

• Enhanced production (2.5 times adult)-load:

– Shortened RBC life span

– Higher RBC Volume (higher hematocrit)

• Reduced hepatic cell entry (clearance) of bilirubin (ligandin)—

Uptake

• Reduced uridine diphosphate glucuronosyl transferase

(UDPGT) activity (1% of adult activity)—Conjugation

• Enhanced enterohepatic circulation—increased load

– Decreased oral intake-decreased intestinal motility

– High concentration of beta-glucuronidase activity (intestinal mucosa)resultant

hydrolysis of conjugated bilirubin and reabsorption of

unconjugated (indirect) bilirubin.

– Low amounts of bacteria


Neonatal Jaundice

Physiologic → Developmental or Physiologic

Jaundice Jaundice Bilirubinemia

(Cause of Jaundice in 95% of

newborn infants)

Defined as occurrence of jaundice in a newborn in whom the

bilirubin rate of rise does NOT cross percentile curves and in

whom the peak bilirubin level is below the 95 th percentile for

age.

NOTE: About 60-67% of full term and late preterm newborn

infants become jaundiced.


Neonatal Hyperbilirubinemia

Bilirubin

• INDIRECT (UNCONJUGATED)

– Fat Soluble

– Bound to albumin-non toxic

– Crosses Blood Brain Barrier, Placenta if UNBOUND to albumin

– Total Serum Bilirubin = TSB = INDIRECT BILIRUBIN level unless abnormal

direct (see below)

• Direct (conjugated)

– Water soluble

– Excreted in stool, urine

Does NOT cross Blood Brain Barrier, Placenta

• >1mg/dL if TSB ≤5mg/dL-Abnormal

• >15-20% of TSB if TSB ≥5mg/dL-Abnormal

Do NOT subtract direct level from TSB unless abnormal-rely usually on

TSB =Indirect Level


Neonatal Hyperbilirubinemia

• General

– Bilirubin production in newborn infants: 6-10mg/kg/day (2.5

times higher load than adults)

• Hemoglobin is the major heme containing protein (1g produces 34mg of

bilirubin)

– Total Serum Bilirubin (TSB): Indirect (unconjugated) Bilirubin bound to

albumin (most) plus free, indirect bilirubin (toxic) plus direct (conjugated)

bilirubin (usually very low in newborn infants)

One gram of albumin binds 8.5mg/dL of indirect (unconjugated) bilirubin

somewhat tightly

• Bilirubin bound to albumin is nontoxic

• Free, indirect (unconjugated) bilirubin, which is POTENTIALLY TOXIC to the

CNS, is very difficult to measure and NOT done in most laboratories.

• Direct or conjugated bilirubin is non toxic (water soluble)

– Early discharge (


Neonatal Hyperbilirubinemia

• General (Continued)

– Usually detect jaundice at bilirubin levels of 5-8mg/dL in newborn

infants (2mg/dL in adults), range 2-12 mg/dL

• Visual estimation of TSB is NOT RELIABLE to determine level

– At least 60-67% of full-term, late preterm infants develop jaundice

by 7 days of age

• Most common clinical sign in neonatal period-primarily indirect

(unconjugated) bilirubin = TSB

– Indirect (unconjugated) bilirubin will NOT harm most full term

infants unless TSB levels at or above 25-30 mg/dL (extremehazardous)

or risk factors exist with TSB levels at or above 20-25

mg/dL (severe-extreme)

TSB: Total Serum Bilirubin


Neonatal Hyperbilirubinemia

• General (Continued)

– Peak total serum bilirubin (TSB) levels (indirect bilirubin) occur at

3-7 days postnatal age in full term infants

• Later, higher TSB levels: 4-10 days, often 10-14 mg/dL or higher in:

– Preterm infants (including late preterm) infants

– Exclusively breast fed infants

– East Asian infants

– Peak indirect (unconjugated) bilirubin levels (TSB) should be under

12-13 mg/dL (< 15-17 mg/dL?)

• 4-6% of full term infants with TSB >13mg/dL

• 3% of full term infants with TSB >15mg/dL (95 th percentile, 15-

17mg/dL), 1-2% with TSB > 20 mg/dL

• 10-20% of breast fed infants with TSB levels >13-14 mg/dL


Neonatal Hyperbilirubminemia

TSB LEVEL-95 th Percentile

for Age in Hours

Developmental or Physiologic 12-15 mg/dL

Higher, more prolonged in: 15-17 mg/dL

– Premature (includes late preterm)

– Breast fed infants (exclusive)

– East Asian Race

Moderate Hyperbilirubinemia > 12-17 mg/dL

Significant Hyperbilirubinemia ≥ 17 mg/dL

Severe Hyperbilirubinemia ≥ 20 mg/dL

Extreme Hyperbilirubinemia ≥ 25 mg/dL

Hazardous Hyperbilirubinemia > 30 mg/dL

Prolonged Jaundice (Indirect)- 3 weeks-3 months

Breast Milk Jaundice?


RISK FACTORS – NEONATAL

HYPERBILIRUBINEMIA


Important Risk Factors-Significant Hyperbilirubinemia

• Predischarge TSB* or TcB* level: High-intermediate (>75th) (under

38 weeks or other high risk factors) or High Risk (>95th) (full-term,

no risk factors) zone on hour specific nomogram (Bhutani,VK et al

Pediatrics, 1999; 103: 6)

• Lower gestational age or prematurity including late preterm infants

(34 0/7-36 6/7 weeks)-two fold increased risk

• Exclusive breastfeeding (particularly if difficulties with nursing,

excessive weight loss(> 7-10%) and/or first time mother with little

family support)

Jaundice in first 24 hours

• Early Hospital discharge-less than 24/48 hours of age and/or,

excessive weight loss (>7-10%)


Treatment Guidelines-Hour Specific

Nomogram

16


Breastfeeding versus Breast Milk Jaundice

Breast feeding*

(Nonfeeding)

Breast Milk+

Time of Onset 2-4 days 4-7 days

Usual time to peak

bilirubin

3-6 days 5-15 days

Peak TSB >12mg/dL >5-10mg/dL (at 3 wks)

occasionally 15-20mg/dL

Mean age for TSB


Risk Factors for Breastfeeding Problems

• Maternal-need for lactation consultant

– Medical illness

– C-section

– Lack of breast enlargement (prenatal, postnatal)

– Flat or inverted nipples

– Previous breast surgery

– Sore nipples, breast enlargement postnatally

• Infant-need for lactation consultant

– Oral cleft, microagnathia

– Multiples

– Latch on difficulties

– Respiratory, cardiac, or neurologic disorders; anomalies

– Sleepy, lethargic

Jaundice


Adequacy of Breast Feeding

• Adequacy of Intake

• “Latching On

• 4-6 wet diapers per day

• Weight loss less than 7-10% by day 3, 4

• Breast feeding 8-12 times per day

• 3-4 stools per day

– Mustard yellow, mushy by day 3, 4

• Supplementation if necessary: Formula, NOT

glucose water/ water


Important Risk Factors-Significant

Hyperbilirubinemia (Continued)

• Isoimmune hemolytic disorder (e.g., ABO or Rh incompatibility,

other)-Direct Antiglobulin Test (+) (most)

• Other hemolytic disorder

– Membrane or structural disorder- (e.g.,spherocytosis)

– Enzyme deficiency (e.g.,G6PD deficiency, pyruvate kinase)

• Previous sibling who required phototherapy

• Cephalohematoma or significant ecchymoses

• Polycythemia

• East Asian Race

*TSB/TcB: Total Serum Bilirubin/Transcutaneous Bilirubin

Maisels, MJ et al

Pediatrics 2009; 124: 1193


Neonatal Hyperbilirubinemia:

ABO Incompatibility

• MOther’s blood type O, BABy A or B

PLUS

– Positive Direct Antiglobulin Test (DAT, Direct Coombs Test)—Common

• B antigen stronger than A antigen of infants born to O mothers

• 33% of A or B infants born to O mothers have anti A or B antibodies (IgG) attached

to RBC (20% of these with significant hyperbilirubinemia)

• ABO Hemolytic disease may occur with negative Coombs or DAT

Jaundice often present first 24 hours, but uncommon reason for readmission

– Gilbert Syndrome genotype (?) if prolonged jaundice (breast milk?)

– Rare late anemia (in contrast to Rh isoimmunization)

– High risk factor-use hour specific nomogram (Bhutani, VK et al Pediatrics 1999:

103:6) + phototherapy/exchange transfusion nomogram

• Start phototherapy 2-5mg/dL lower than for usual patient


Neurotoxicity Risk Factors-- Lowers the Threshold

for Treatment of Hyperbilirubinemia

• Any illness (e.g. RDS)

• Prematurity including Late Preterm Infants (34 0/7-36

6/7 weeks)

• Isoimmune hemolytic disease (e.g.,ABO

incompatability (?), Rh, Other)

• G6PD deficiency

• Asphyxia

• Acidosis

• Sepsis

• Serum albumin < 3gm/dL-not routinely measured


» EVALUATION-NEONATAL JAUNDICE


Neonatal Jaundice

• General

– Bilirubin deposits in skin, subcutaneous tissues as total serum bilirubin (TSB)

rises

• At least 60-67% of healthy full term infants appear jaundiced during the

first postnatal week

• Somewhat (?) direct relationship between TSB and intensity of

jaundice(?)-cephalocaudal progression:

– Face to trunk to abdomen to extremities progression

Jaundice can be noted with TSB levels


2

3

1

4

5

Neonatal Jaundice

Dermal Zone Indirect Bilirubin

Mean Range Risk

0 (none) 15-20 High

Visual Assessment: Fraught with Hazards!

From Kramer, LI Am J Dis Child 1969

118:454

Keren, R et al Arch Dis Child

Fetal Neonatal Ed 2009; 94: F317


Neonatal Hyperbilirubinemia-Pathologic

When to evaluate pathologic jaundice (laboratory tests):

Jaundice in first 24 hours (TcB*/TSB*)

• Excessive production usually-hemolysis

– TcB/TSB above 75 th percentile (high intermediate or high risk

zone) or rapidly rising (i.e. crossing percentiles) on hourly

nomogram (Bhutani, VK et al, 1999: 103: 6)

• Cord TSB > 4-5 mg/dL or TSB > 5 mg/dL at 24 hours

• TSB crossing lines (of concern) or rising more than 0.2-0.5

mg/dL/hr for 4-8 hours(?)

• TSB crossing lines (of concern) or increasing more than 5

mg/dL per 24 hours

• TSB over 13(?),15-17 ml/dL in full term infant

*TcB/TSB-Transcutaneous Bilirubin/Total Serum Bilirubin


Neonatal Hyperbilirubinemia-Pathologic

(Continued)

When to evaluate (laboratory tests):

– Cannot explain jaundice/high TSB by history, physical

exam

– TSB approaching exchange level or not responding to

phototherapy

Jaundice at or beyond 3 weeks of age or infant is ill

(total, direct)

– Elevated direct (conjugated) bilirubin level

• At or Above 1 with TSB ≤5mg/dL

• At or Above 15-20% of total TSB when TSB is >5mg/dL

• Dark urine, light colored stools

*TcB/TSB-Transcutaneous Bilirubin/Total Serum Bilirubin


Initial Evaluation--Neonatal Hyperbilirubinemia

• LABORATORY TESTS:

– TSB*-TOTAL: Indirect (uncojugated) plus Direct

(conjugated)

• Repeat TSB in 4-24 hours depending on TSB level, postnatal

age, risk factors

– Blood type, Rh (maternal, infant for both); Direct Antiglobulin

or Coombs test (DAT)

• Save cord blood when maternal blood type is O or Rh(-)

• CBC, reticulocyte count, smear (?)

– Consider albumin level, G6PD level for G6PD deficiency (family

history, ethnicity)

*Total Serum Bilirubin


Additional Evaluation of Neonatal Hyperbilirubinemia

(Contd)

• LABORATORY TESTS:

– Consider bacterial or viral infection (blood, urinary tract

infection) if indicated— most with both elevated indirect

and direct bilirubin levels

– T 4/TSH--state screen results for prolonged

hyperbilirubinemia (over 2-3 weeks of age)

– Consider tests for other metabolic disorders (state

screen)—often with both indirect (unconjugated) and

direct (conjugated) hyperbilirubinemia including

galactosemia for prolonged jaundice

*Total Serum Bilirubin


Transcutaneous Bilirubin (TcB) Measurements

• Instantaneous, non-invasive, safe, reliable, easy, cost effective (fewer TSBs)

• Measures tissue bilirubin, not TSB--yellow color of blanched skin, subcutaneous tissue

– Chest (most accurate)

– Forehead (usual site-ease)

– Much more accurate than visual estimation of TSB

• Valid screening test for hyperbilirubinemia with good correlation with Total Serum

Bilirubin(TSB)-may underestimate TSB by 2-3mg/dL

• Compare with TSB measurements (laboratory)-quality control

• May use for all races and for preterm (at least > 29 weeks), full term infants

• TcB results NOT reliable under phototherapy (ok if >24 hours off phototherapy? or covered

area?), marked hirsutism (e.g. Hispanic), dark skinned? or >15mg/dL

• Always obtain TSB if to initiate therapy or if TcB >13-15 mg/dL

– TcB value is at 70% of value to start phototherapy

– TcB at or above the 75 th percentile on hour specific nomogram (high intermediate or

high risk zone)


Monitoring with Transcutaneous Bilirubinometry (TcB)

(Continued)

• Screening tool—“Worry about infant”, then “obtain TSB”?

– Obtain TSB if TcB at or above 75 th percentile (high intermediate or high risk

zone) on hour specific nomogram (Bhutani VK et al. Pediatrics 1999; 103: 6)

• Factor in age in hours, risk factor(s)

– Obtain TSB before implementing therapy (TcB at 70-75% of TSB level for

phototherapy)

– Obtain TSB if TcB is > 13-15 ml/dL in full term or preterm infant

– Superior to visual estimate and reduces likelihood of missing clinically

significant TSB

NOTE: TcB: NOT a substitute for TSB measurement, NOT to be used alone

TSB/TcB: Total Serum Bilirubin/Transcutaneous bilirubin


Transcutaneous Screening for

Bilirubinemia (TcB)

• Transcutaneous Measurements

– JM-103 (Konica Minolta)

• Overestimate bilirubin level in dark-skinned infants (?)

– Bili Check (Respironics)

• Underestimate bilirubin levels in Hispanic infants (?)

– Sternum more accurate than forehead (exposure to

light in latter)

– Obtain Total Serum Bilirubin (TSB)-laboratory-:

• Under phototherapy

• Total bilirubin ≥ 15mg/dL

• Rapidly rising bilirubin levels (crossing lines)


Transcutaneous Bilirubinometry Screening

Program and Resource Utilization

• Significant Reduction:

– Total serum bilirubin levels (capillary sticks)

– Phototherapy utilization

– Age at readmission for therapy

– Duration of re-hospitalization stay

• Improved laboratory utilization, patient care, patient

convenience, patient safety.

• Consider Integration with a public health nurse newborn

follow-up program

• From Wainer, Setal

Pediatrics 2012; 129: 77-86;


Hour Specific Nomogram for Transcutaneous Bilirubin

(TcB) Measurements in Healthy Newborns ≥35 Weeks

Gestation


Common Causes of Prolonged (3 weeks or longer) or

Recurrent, Indirect Hyperbilirubinemia

• Hemolytic disorders (may develop anemia)

– Blood group incompatibility-ABO (?); Rh, Kell, Duffy, c, C, E

– RBC membrane abnormality (e.g. spherocytosis)

– RBC enzymatic defect (e.g. G6PD deficiency)

– Disorders of hemoglobin synthesis (rare)

• Extravascular Blood (e.g., cephalohematoma, ecchymoses)

• Congenital Hypothyroidism (T 4, TSH)-state screen results

• Galactosemia (state screen results-often has both indirect and

direct bilirubin components)

• Urinary tract infection(may have direct bilirubin component)

• Pyloric Stenosis

• Constipation

• Crigler Najjar syndrome (I, II), Gilbert syndrome

• Breast Milk Jaundice (role of Gilbert Syndrome?)


» MANAGEMENT-NEONATAL HYPERBILIRUBINEMIA


Neonatal Hyperbilirubinemia

• Patient Study #1:

BA is a 3100 gram, 36-37 gestational age male born to a

29 year old, 0+, Gr 1 P0000 female whose pregnancy

was uncomplicated. The infant’s course in the hospital

was unremarkable except for the mother needing help

to establish breast feeding. He was noted to be

jaundiced at 34 hours of age; total bilirubin (TSB) was

8.5mg/dL. He was discharged at 40 hours of age with

follow up at 2 days of age when he was noted to be very

jaundiced (to his feet). The TSB was 19mg/dL (0.3

direct-conjugated). His blood type is A+. He is active,

pink, alert, with a normal cry and normal tone.

• What would you do?


Neonatal Hyperbilirubinemia

• Patient Study #1-Management:

– Hospitalize

– Start Intensive phototherapy-- special blue overhead lights with Bili-Blanket

or double bank(?)—irradiance>30-35 microwatts/cm2/nm

– Breast feeding (frequent) with IV fluids and/or formula supplementation if

indicated (150-180 ml/kg/d)-see how feedings progress

– Monitor TSB every 4-6 hours until declining, intake/output, daily weights

– CBC with differential/platelet count, reticulocyte count, Direct Coombs test

(DAT-positive); consider blood/urine/CSF(?) cultures, CRP; albumin, smear?,

G6PD ?

– IVIG (0.5-1 gm/kg over 4 hours) for DAT (+) hemolytic disorder (ABO

incompatability, Rh)-infusion every 12 hours for 3 doses

– Exchange transfusion?


Maisels MJ, Mcdonagh AF.

Mechanism of Phototherapy

N Engl J Med 2008; 358:920-928


Phototherapy for Neonatal Hyperbilirubinemia

• Effectively reduces indirect (unconjugated) bilirubin levels and has

dramatically reduced need for exchange transfusions; 30-40%

decline in 24 hours

• “Pumps” bilirubin (converts to structural and configurational

photoisomers) from skin-”bleaches” skin

– Degradation products more easily excreted in urine, bile

• Transcutaneous bilirubin (TcB), Visual inspection:

NEITHER RELIABLE UNDER PHOTOTHERAPY

• Total Serum Bilirubin (TSB) Levels-Laboratory

– Indirect equals total serum bilirubin (TSB) level unless direct over 20% of TSB

level >5 mg/dL

– Note: Direct bilirubin may reduce albumin binding capacity


Factors Related to Efficacy of Phototherapy

Maisels MJ, Mcdonagh AF.

N Engl J Med 2008; 358:920-928


Management Under Phototherapy

– Increase fluid intake (increased insensible loss—less with LED lights)

• Breast feeding--supplementation with formula (NOT water or glucose

water) to reduce enterohepatic circulation

• IV fluid if needed

• Monitor weight, intake/output

– Overheating—burns if halogen (spotlight) light too close (use

manufacturer’s recommendation for distance); does NOT occur with LED

lights

– Cover eyes with patches, genitalia with diaper

Do NOT always need eye patches with bili-blanket

– Monitor TSB (NOT TcB) every 4-24 hours depending on TSB level, postnatal

age, and risk factors


Mangement Under Phototherapy

(Continued)

– Discontinue phototherapy when TSB is below the level

phototherapy was initiated (12-14mg/dL)

– Rebound in TSB may occur (1-5mg/dL) particularly in preterm

infants and those with hemolysis

– Monitor intake/output, weight

– Monitor for diarrhea, rash

– Monitor for later melanocytic nevi?

– Interrupt phototherapy for feeding, parental visits to enhance

parent-infant bonding, even when under intensive (reduce

disruption) phototherapy if infant isresponding to therapy


Guidelines for Phototherapy for Infants

≥35 weeks Gestation


Bili Tool

• Risk for development of hyperbilirubinemia

Risk Zone

http://bilitool.org/

Age (hours) 18-168 hours

Total Bilirubin _________

Start Phototherapy-yes/no-alerts to risk factors


Management of Hyperbilirubinemia in Apparently Healthy Full Term/

Late Preterm Infants

TSB Levels: Initiate Phototherapy and Exchange Transfusion

Age (hours) Consider PT* PT* , ET o if Intensive PT fails** ET o and PT

≤24—-----------------------NOT NORMAL

25-48 ≥10-12 ≥15 ≥20-22 ≥25

49-72 ≥12-15 ≥18 ≥22-25 ≥30

>72 ≥12-18 ≥18-20 ≥22-25 ≥30

TSB: Total Serum Bilirubin, mg/dL

*PT: Phototherapy; use lower (“Consider PT” values) TSB levels for late preterm infants or those with risk

factors as hemolysis (e.g.,ABO, Rh, G6PD) or rapidly rising bilirubin values.

o ET: Exchange Transfusion (>20-25 if one or more risk factors)

**Administer IVIG if ABO, Rh or other isomimmune hemolytic disease exists

Note: Start phototherapy when TSB levels are 5-8mg/dL below exchange

transfusion levels


Phototherapy-Hospital, Home

• Bili Blanket

– Overhead phototherapy lights ?

• Monitor Total Serum Bilirubin (TSB) levels, intake/output, neurologic exam at least

every 24 hours-initial 30-40% decline in TSB in 24 h, most in first 4-6 h

Do NOT use home phototherapy in presence of high risk factors (e.g., poor feeding,

lethargy, excessive weight loss, isoimmune hemolytic disorder, poor temperature

control)

Do NOT use home phototherapy if TSB approaching exchange transfusion levels

• Can NOT use Transcutaneous bilirubinometry (TcB) monitoring if under

phototherapy

• Reduced cost, improved parental satisfaction/bonding.


Treatment with Phototherapy

Best Practice Recommendations for

Phototherapy Equipment Capability

– Blue/green light spectrum: 450-470

– irradiance spectrum

– Greater than 30 µW/CM 2 /nm

– LED bulb preferred


– Maximize surface area exposure ( e.g., bank

plus blanket)

50


PREVENTION - SEVERE HYPERBILIRUBINEMIA


Patient Study # 2

BH was the 4054 gram, early term infant born to an O+, 24 yo

Gr 4 P2103, Hispanic female with insulin dependent diabetes

mellitus. She was GBS positive and was treated during labor. The

infant had a NSVD with Agpars of 9 and 9.

At 2 days of age, the infant’s TSB was 13.7 and phototherapy

was initiated. At 3 days of age when discharged home, the infant’s

bilirubin was 16.7 and home phototherapy was utilized and

continued. The infant was breast feeding well. The infant was A+,

DAT (2+) and had a sibling who required phototherapy. The mother,

who spoke English and Spanish fluently, was instructed to have the

infant seen the next day in clinic. However, no appointment was

available until one week later. During the next 5 days, the infant

had frequent “spit ups” and became more lethargic with decreased

intake. Vomiting was more frequent on day 9 of age when the infant

was taken to the ER.


Patient 2 (Continued)

In the ER, the infant’s bilirubin was 33 (2 direct) and the

infant was admitted to the NICU where the bilirubin was

38 (3 direct). Other liver function tests were normal with

an albumin of 4.8. UA had 44 WBC (culture was negative)

and CRP was


Three Phases of Bilirubin Encephalopathy

• Acute—Initial Phase

– Lethargy, sleepiness

– Hypotonia

– Poor suck/feeding

• Acute-Intermediate

– Hypertonia--Opisthotonus, retrocollis, arching

– Fever

– High pitched cry

– Poor suck/ feeding

• Advanced or Chronic-Kernicterus

– Stupor, Coma, Seizures

– Athetosis, dystonia, chorea, ballismus, tremor-MOTOR

– Paresis of vertical gaze (oculomotor nuclei)-sunsetting sign

– Sensorineural hearing loss (auditory neuropathy)

– Enamel dysplasia of deciduous teeth

– Minority with cognitive delay

“Bright Mind Trapped in an Uncontrollable Body”


Kernicterus

• Can occur in healthy infants (including those being breast fed) with extremely

elevated TSB levels (>25-30 mg/dL, >20-25 mg/dL if hemolysis or other

neurotoxicity high risk factors)-still happens

• Exclusive breast feeding, early discharge (


Neonatal Hyperbilirubinemia-Bilirubin

Encephalopathy* (2008)

• Major neurotoxicity risk factors

– Rh Isoimmunization

• (NOT ABO incompatibility)

– Sepsis

– Prematurity

• No Risk Factors

*34-36 weeks Gestational Age

TSB ≥ 25mg/dL

TSB ≥ 30-31 mg/dL

Note: Biological factors besides bilirubin level are important in

pathogenesis of bilirubin encephalopathy

From Gamaleidin, R etal

Pediatrics 2011; 128;e925-e931


Kernicterus

• Can NOT associate a specific risk of CNS

damage with a particular Total Serum Bilirubin

level (TSB) in the full term or late preterm

infant

• Kernicterus has been well described in

extremely premature infants at very low TSB

levels


Prevention of Kernicterus

• Can likely prevent kernicterus in most healthy, full term infants

by ensuring adequate feeding, monitoring of TSB/TcB,

education of parents, identifying infants at risk for severe

hyperbilirubinemia and timely outpatient follow up within 24-

48 hours of discharge

• However, kernicterus may occur, despite appropriate

monitoring and management, in an infant with prematurity,

G6PD deficiency, sepsis, asphyxia, genetic predisposition or

other unknown neurotoxicity factors

• “Sentinel event” ? YES, TSB of 30 mg/dL or higher


Predictive Ability of a

Pre Discharge Hour-Specific Serum

Bilirubin for Subsequent Significant

Hyperbilirubinemia in Healthy Term

and Near-Term Newborns

Bhutani VK et al. Pediatrics 1999; 103: 6-14


Hour-Specific Bilirubin Nomogram


Predischarge Risk Zone Bilirubin Level as a

Predictor of Significant Hyperbilirubinemia

Zone Newborns Newborns who developed

(n=2840) TSB level >95 th percentile (%)

High Risk (>95 th percentile) 6% 40%

High Intermediate (76 th -95 th ) 13% 13%

Low Intermediate (40 th -75 th ) 20% 2%

Low Risk (


American Academy of Pediatrics

Clinical Practice Guideline

Subcommittee on Hyperbilirubinemia

Management of Hyperbilirubinemia

in the Newborn Infant

35 or More Weeks of Gestation

Pediatrics 2004; 114: 297-316


Hyperbilirubinemia in the Newborn

Infant ≥ 35 Weeks Gestation:

An Update with Clarification

Maisels MJ, et al. Pediatrics 2009; 124:

1193-1198


Routine transcutaneous bilirubin

measurements combined with

clinical risk factors improve the

prediction of subsequent

hyperbilirubinemia

Maisels MJ et al, Journal of Perinatology 2009;

29: 612-617

Noninvasive Measurements of Bilirubin

Maisels MJ Pediatrics 2012; 129, 779


Commentary on Hyperbilirubinemia in the Newborn

Infant ≥35 weeks (Pediatrics, October, 2009)

• Update with clarification of the AAP 2004 hyperbilirubinemia practice

guideline

• Consideration for universal predischarge bilirubin screening using TSB/TcB

to assess risk of subsequent hyperbilirubinemia

• More structured approach to management and follow up

– Predischarge TSB/TcB (75-95(high intermediate) or >95 th percentile

(high risk zone)

– Gestational age (


Universal Bilirubin Screening-Predischarge

• Excellent Idea

– Plot on hour specific nomogram (Bhutani VK et al. Pediatrics

1999; 103: 6)-high or high intermediate risk zones

• Need to combine TSB/TcB level with clinical (breast feeding, gestational

age) and NEUROTOXICITY risk factors (prematurity, asphyxia, acidosis,

illness, lethargy, G6PD deficiency, isoimmune hemolysis (ABO, Rh),

sepsis, low albumin


Screening of Infants for

Hyperbilirubinemia to Prevent

Chronic Bilirubin Encaphalopathy:

US Preventive Services

Recommendation Statement

US Preventive Services Task Force. Pediatrics 2009;

1124: 1172-1177


Universal Bilirubin Screening Predischarge

(Continued)

• US Preventive Services Task Force: Insufficient evidence to recommend

screening for hyperbilirubinemia

– Evidence about benefits and harms of screening to prevent kernicterus

(chronic bilirubin encephalopathy) is lacking

– No evidence screening is associated with improved outcomes or use of

hour specific nomogram reduces incidence of kernicterus

– Insufficient evidence about potential harms and efficacy of phototherapy

• Screening may lead to earlier, excessive use

of phototherapy


» SUMMARY


Neonatal Hyperbilirubinemia

• Summary

– Most common condition affecting newborn infants (60-70% become

jaundiced) requiring evaluation and management

– Represents imbalance between bilirubin production and hepatic/enteric

clearance

– Visual estimation of TSB is fraught with hazard

– Most frequent reason for re-hospitalization of infants during first 7 to 10

days post birth (particularly if breast fed)

– Benign transitional phenomenon of no overt clinical impact for great

majority of infants, but can be catastrophic very rarely

– New evidence suggests combining a predischarge, hour specific TSB/TcB

level (nomogram) with TWO risk factors, Gestational Age


Ten Key Recommendations for Preventing and

Managing Neonatal Hyperbilirubinemia

• Promote and support successful breast feeding

• Establish nursery protocols for the jaundiced infant including

TcB measurements, TSB determinations, and physician

contact

• Interpret TcB/TSB levels by age in HOURS, NOT DAYS

• Measure TcB/TSB in infants jaundiced ≤24 hours of age

• Remember, visual assessment of bilirubin level is NOT

reliable, particularly in darkly pigmented infants and/or if

under phototherapy

• Late preterm infants must NOT be treated as full term infants;

they are more prone to higher bilirubin levels that remain

high longer


Ten Key Recommendations for Preventing and

Managing Neonatal Hyperbilirubinemia

(Continued)

• Perform a pre discharge assessment (TcB screen?) for risk

of severe hyperbilirubinemia

• Provide information, education to parents on newborn

jaundice

• Provide follow up (24-48 hours) based on time of discharge

and the risk assessment

• Treat with phototherapy or exchange transfusion if

indicated

Modified from: American Academy of Pediatrics, Clinical Practice

Guideline, Subcommittee on Hyperbilirubinemia. Management of

hyperbilirubinemia in the newborn infant 35 or more weeks

gestation. Pediatrics 2004; 114:297


Maroon and Gold Summary Points

• The two most common risk factors for development of significant hyperbilirubinemia in

newborn infants are Prematurity (includes late preterm infants) and Exclusive Breast

Feeding. Neurotoxicity factors increase risk of CNS damage: any illness, prematurity

(including late preterm), hemolysis (ABO ?, Rh),, asphyxia, acidosis, sepsis, low albumin

level

• Visual estimation of neonatal bilirubin levels is NOT reliable

• Transcutaneous bilirubin levels (TcB) are similar or 2-3 mg/dL lower than Total Serum

Bilirubin (TSB) levels and are very useful in following patients in the hospital and clinic

setting but can NOT be used if under phototherapy


Maroon and Gold Summary Points (Cont’d)

• Measurement of TcB, TSB and plotting on Bhutani’s hour specific nomogram (Pediatrics

1999; 103:6) is useful in identifying infants at high risk for developing severe

hyperbilirubinemia necessitating phototherapy. Does this prevent kernicterus?

• Neonates who are discharged before 36-48 hours and those with high risk factors for

hyperbilirubinemia should definitely be seen within 24-48 hours of discharge for a

TcB/TSB particularly if jaundice is present (MD, Public Health Nurse) or if in high risk or

high intermediate risk zone on nomogram

Jaundice in breast fed babies may be present up to 3 months of age although a direct

bilirubin level with a TSB level along with the state screening results for T4/ TSH

(hypothyroidism) and galactosemia should be checked in those infants with jaundice

persisting beyond 3 weeks of age


References: General

American Academy of Pediatrics, Subcommittee on Hyperbilirubinemia.

Management of hyperbilirubinemia in the newborn infant 35 or more

weeks gestation. Clinical Practice Guideline. Pediatrics 2004; 114:297-316

(Published correction in Pediatrics 2004; 114:1138).

Bili Tool: http://bilitool.org

Hammerman C, Kaplan M. Recent developments in the management of

neonatal hyperbilirubinemia. NeoReviews 2000; 1: e19-e24.

Kaplan M, Hammerman C. American Academy of Pediatrics guidelines for

detecting neonatal hyperbilirubinemia and preventing kernicterus. Arch

Dis Child Fetal Neonatal Ed 2005; 90: F448-F449.

Keren R, et al. Visual assessment of jaundice in term and late preterm infants.

Arch Dis Child Fetal Neonatal Ed. 2009; 94: F312-F322.

Maisels MJ. Neonatal jaundice. Pediatrics in Review 2006; 27: 443-454.

Maisels MJ, et al. Hyperbilirubinemia in the newborn infant ≥ 35 weeks’

gestation:

An update with clarifications. Pediatrics 2009; 124: 1193-1198.

Maisels MJ. “Neonatal Hyperbilirubinemia”. Care of the High Risk Neonate.

Ed. Klaus MH, Fanaroff AA. Philadelphia, PA: WB Saunders; 2001, 324-362.


References: General (Continued)

Maisels MJ. What’s in a name? Physiologic and pathologic jaundice: The

conundrum defining normal bilirubin levels in the newborn. Pediatrics 2006;

118: 805-807.

McDonagh AF, Maisels MJ. Bilirubin unbound: Déjà vu all over again? Pediatrics

2006; 117:523-525.

Moerschel SK, et al. A practical approach to neonatal jaundice. American Family

Physician 2008; 77: 1255-1262.

Newman TB, et al. Infants with bilirubin levels of 30mg/dL or more in a large

managed care organization. Pediatrics 2003; 111: 1303-1311

Newman TB, et al. Outcomes among newborns with total serum bilirubin levels of

25mg/dL or more. New Engl J Med 2006; 354: 1889-1900.

Wong RJ, et al. “Neonatal Jaundice and Liver Disease”. Neonatal-Perinatal

Medicine, 8th Edition. Ed. Martin RJ, Fanaroff AA, Walsh MC. St. Louis, MO:

Mosby; 2006, 1419-1465.

Wong RJ, et al. Tin mesoporphyrin for the prevention of severe neonatal

hyperbilirubinemia. NeoReviews 2007; 8: e77-e83.


References: Breast Feeding

de Almeida MFB, Draque CM. Neonatal jaundice and

breast feeding. NeoReviews 2007; 8: e282-e288.

Gourley GR. Breastfeeding, diet, and neonatal

hyperbilirubinemia, NeoReviews 2000; 1: e25-e30.

References: Phototherapy

Maisels MJ, McDonagh AF. Phototherapy for neonatal

jaundice. N Engl J Med 2008; 358: 920-928.

Newman TB, et al. Numbers needed to treat with

phototherapy according to the American Academy of

Pediatrics guidelines. Pediatrics 2009; 123: 1352-

1359.


References

Bilirubin Predischarge Screening- Includes Transcutaneous

Bilirubin Measurements

Bhutani VK, et al. Predictive ability of a predischarge hour-specific serum bilirubin for

subsequent significant hyperbilirubinemia in ealthy term and near-term newborns.

Pediatrics 1999; 103: 6-14

Burgos, AE et al Screening and follow-up for neonatal hyperbilirubinemia: A review. Clin

Pediatrics 2012; 51:7-16

Dalal SS, et al. Does measuring the changes in TcB value offer better prediction of

hyperbilirubinemia in healthy neonates? Pediatrics 2009; 124: e851-e857.

De Luca D, et al. Transcutaneous bilirubin nomograms. Arch Pediatr Adolesc Med 2009;

163: 1054-1059.

Fay DL, et al. Bilirubin screening for all newborns: A critique of the hour specific bilirubin

nomogram. Pediatrics 2009; 124: 1203-1205.

Keren R, et al. A comparison of alternative risk-assessment strategies for predicting

significant hyperbilirubinemia in term and near-term infants. Pediatrics 2008; 121:

e170-e179.

Keren R, Bhutani VK. Predischarge risk assessment for severe neonatal hyperbilirubinemia.

NeoReviews 2007; 8: e68-e76.

Maisels MJ, et al. Hyperbilirubinemia in the newborn infant ≥ 35 weeks’ gestation:

An update with clarifications. Pediatrics 2009; 124: 1193-1198.

Maisels MJ, et al. Routine transcutaneous bilirubin measurements combined with clinical

risk factors improve the prediction of subsequent hyperbilirubinemia. J Perinatol 2009;

29: 612-617.


References

Bilirubin Predischarge Screening Includes

Transcutaneous Bilirubin Measurements (Continued)

Newman TB, et al. Combined clinical risk factors with bilirubin levels to predict

hyperbilirubinemia in newborns. Arch. Pediatr Adolesc Med 2005; 159:113-119.

Newman TB, et al. Prediction and prevention of extreme neonatal hyperbilirubinemia in

a mature health maintenance organization. Arch Pediatr Adolesc Med 2000; 154:

1140-1147.

Newman TB. Universal bilirubin screening, guidelines, and evidence. Pediatrics 2009;

124: 1199-1202.

Sarici SU, et al. Incidence, course, and prediction of hyperbilirubinemia in near-term

and term newborns. Pediatrics 2004; 113: 775-780.

Trikalinos T, et al. Systematic Review of screening for bilirubin encephalopathy in

neonates. Pediatrics 2009; 124: 1162-1171.

US Preventive Services Task Force. Screening of infants for hyperbilirubinemia to

prevent chronic bilirubin encaphalopathy: US Preventive Services Task Force

Recommendation Statement. Pediatrics 2009; 124: 1172-1177.

Varvarigou A, et al. Transcutaneous bilirubin nomogram for prediction of significant

neonatal hyperbilirubinemia. Pediatrics 2009; 124: 1052-1059.


References:

Transcutaneous Bilirubinometry

Bosschaart, N et al. Limitations and oportuniies of transcutaneous bilirubin

measurements. Pediatrics 2012; 129: 689-694

Fonseca, R et al. Covered skin transcutaneous bilirubin estimation is

comparable with serum bilirubin during and after phototherapy.J.

Perinatology 2012; 32:129-131

Maisels MJ. Transcutaneous bilirubinometry. NeoReviews 2006; 7: e217e225.

Maisels MJ, Kring E. Transcutaneous bilirubin levels in the first 96 hours in a

normal newborn population of ≥ 35 weeks’ gestation. Pediatrics 2006;

117: 1169-1173.

Maisels MG. Noninvasive measurements of bilirubin. 2012; 129: 779-781

Schmidt ET, et al. Evaluation of transcutaneous bilirubinometry in neonates.J

Perinatol 2009;29:564-569

Wainer, S et al. Impact of a transcutaneous bilirubinometry program on

resource utilization and severe hyperbilirubinemia. Pediatrics 2012; 129:

77-86


References: Kernicterus

Davidson L, Thilo TH. How to make kernicterus a “never event”. NeoReviews 2003; 4:

e308-e313.

Gamaleidin,R et al. Risk factors for neurotoxicityh in newborns with severe neonatal

hyperbilirubinemia. Pediatrics 2011; 128: e925-e931

Johnson L, Bhutani VK. Editors Bilirubin Supplement. Need for a safer management of

newborn jaundice: A Report from the US Kernicterus Registry. J Perinatol 2009; 29: s1s67

(Supplement 1 February-Multiple Articles).

MMWR. Kerincterus in full term infants-United States, 1994-1998. 2001; 50: 491-494.

Newman TB, et al. Infants with bilirubin levels of 30mg/dL or more in a large managed care

organization. Pediatrics 2003; 111: 1303-1311

Newman TB, et al. Outcomes among newborns with total serum bilirubin levels of

25mg/dL or more. New Engl J Med 2006; 354: 1889-1900.

Sentinel Event Alert: Kerincterus threatens healthy babies. Issue 18. April, 2001.

Shapiro SM, et al. Hyperbilirubinemia and kernicterus. Clin Perinatol 2006; 33: 387-410

Vandborg, PK et al. Follow-up of neonates with total serum bilirubin levels_> 25 mg/dL: A

Danish population-based study. Pediatrics 2012. 130: 61-66

Watchko JF. Hyperbilirubinemia and bilirubin toxicity in late preterm infants. Clin Perinatol

2006; 33: 839-852.

Watchko JF. Neonatal hyperbilirubinemia-What are the risks? New Engl J Med 2006;

354:1947-1949.

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