Neonatal Jaundice

Alan Gill MD 1/2/03

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Objectives
Understand

etiology and pathophysiology of neonatal jaundice and kernicterus Identify high risk conditions Understand limits of clinical exam Describe appropriate evaluation Apply appropriate treatment to term and near term infants

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Epidemiology

Clinical Jaundice (> 5mg%)

65% full-term infants (> 37 weeks in AAP guideline)

peak 3-5 days

80% preterm infants

peak 5-7 days

Exaggerated Hyperbilirubinemia (>12.8mg%) 4% African-Americans 6-10% Caucasian 25% Asian (>20mg% in 2%) WWW.SMSO.NET

Effect of Type of Feeding

2/3 of breastfeeding infants will have chemical jaundice for 2-3 weeks TSB > 12mg% in 12% BF vs. 4% FF TSB > 15mg% in 2% BF vs. 0.3% FF

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The hyperbili pendulum swings

AAP

currently revising its 1994 guideline JACHO alert due to several case reports of kernicterus in healthy newborns Especially near term 35-38 weeks, dehydrated breastfeeding, and with extremely high bilirubin levels

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Incidence and Cause of Severe Hyperbilirubinemia in term newborns

73/51,387 newborns > 2,000 grams birth weight and >36 week gestation reached 25mg/dl total bili = 1.4/1,000 306 readmitted for hyperbili, (ave 18.5, range 12.5-29.1)

94.8 % of unknown cause or breast feeding 3.6% ABO hemolytic disease 1.0% cephalohematoma/birth trauma 0 cases of sepsis

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Kernicterus Registry for term and near-term infants

90 total since 1992 61with full data and readmitted in one week

20/61 jaundice noted by parent and nurse but not measured until readmitted Predischarge total bili measured in only 16/61 10/16 95%, 15/16 40%, 1/16 < 40% bili/age Peak total bili values median 38, range 21.5-50 mg/dl No early F/U appoint (within 48 hours) in 44/61,instead come back in 1-2 weeks, Early appointments, 14 appointments made and kept, 7 early and measured, 7 early and not measured, 3 appointments not kept
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Kernicterus

Acute

First 1-2 days, poor feeding, stupor, hypotonia, seizures 3-7 days irritability, hypertonia of extensor muscles, fever > 1 week hypertonia (opisthotonus, retrocollis), stupor or coma, shrill cry

Chronic

1st year limited upward gaze, movement disorders (chorea, ballismus, tremor), hearing loss > 1 year old CP, movement disorders, hearing loss, MR, gaze paresis
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Kernicterus Risk Factors

TSB

level > 25-30 mg/dl Acidosis Increased free bilirubin

low albumin, drug displacement

Blood-brain

barrier disruption

prematurity, sepsis, ischemia

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Kernicterus cases potentially correctable causes

Early discharge (<48hrs) without f/u within 48 hrs Failure to check bili level if onset in first 24 hours Failure to note risk factors Visual assessment underestimate of severity Delay in testing jaundiced newborns or treating elevated levels Lack of concern for presence of jaundice or parental concern
Pediatrics 2001; 108:763-765
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Common Clinical Risk Factors for Severe Hyper-bilirubinemia

Jaundice in the first 24 hours Visible jaundice at discharge Previous jaundiced sibling Near term gestation 35-38 weeks Exclusive breastfeeding East Asian (4), Mediterranean (1), African origin (12) (G6PD deficiency), 19/61 kernicterus cases = G6PD Bruising, cephalohematoma, birth trauma Hemolysis risk, O + maternal blood type, sepsis
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Overproduction

Inherited RBC enzymes

Infection

Viral hepatitis TORCH Sepsis DIC Rh isoimmunization Atypical Antibody isoimmune

G6PD deficiency Pyruvate kinase deficiency

Thallesemias, sickle cell (rare due to fetal Hgb protection) Infant of diabetic mother Polycythemia Birth trauma

Hemoglobinopathies

Immune Hemolysis

Other

Inherited RBC membrane defects

Spherocytosis,Elliptocytosis Stomatocytosis,pyknocytosi s
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Glucose 6 Phosphate Deficiency

Most frequent inherited RBC disorder

X linked recessive, more likely in boys Can be triggered by infection, medications Class 1-5 depending on level of deficiency Present in 10% of African American male newborns but not expressed, needs another yet to be defined cofactor

Lab testing: Smear hemolysis, Coombs neg, RBC assay for G6PD

High levels = normal Normal levels = normal unless high retic count which may be deficiency falsely covered by high retic count, normal is 10.816.2 u/g Hb Low levels = low
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Decreased Clearance

Impaired excretion in the enterohepatic circuit

Impaired metabolism

Endocrine
Hypothyroid Hypopituitary

Prematurity Breast Milk Jaundice

Late onset enzyme competition

Inherited Metabolic
Inborn errors of metab

Structural
Bowel obstruction Pyloric stenosis Meconium ileus Biliary atresia

galactosemia Tyrosinosis Hypermethioninemia Crigler-Nijjar syndrome Gilbert syndrome Rotor syndrome

Albumin Displacement

Drug induced
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Cystic fibrosis Alpha-1 antitrypsin

Medications increasing bilirubin

Sulfisoxazole (displacement or G6PD hemolysis) Ceftriaxone (displacement from albumin) Nitrofurantoin (capable of inducing G6PD hemolysis, manufacturer warns against use at term, no reported case of hemolytic anemia in an in-utero exposed newborn) Streptomycin, Benzyl alcohol, Chloramphenicol
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Breast feeding and Jaundice Two peaks

Early days 2-5 Associated with inadequate volume and calories Do not treat with dextrose water Supplement with formula, cup or nipple attached butterfly tubing Late, persisting for weeks, Mothers milk contains 5-pregnane-3, 20--diol, or nonesterified long chain fatty acids that competitively inhibit glucuronyl transferase Contains a glucuronidase Will diagnostically decline rapidly if breast milk not given for 12-24 hrs, bili declining by up to 2 mg/dl/12 WWW.SMSO.NET hr

Breast feeding and Jaundice

Watch for weight loss and urine output

dehydration in first 3-5 days of life,

10% weight loss, < 5 wet diapers per day by day 3 of life

supplement if dehydration

Approximately one third of healthy breast fed newborns will have persistent jaundice after 2 weeks should not be direct bilirubin (dark urine or light stools) do not have to interrupt breast feeding investigate those lasting beyond 3 weeks
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Questions for Jaundice

Term

healthy physiologic vs. pathologic or preterm or ill? How high is the total serum bilirubin? What treatment is indicated? What follow-up is needed?

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Neonatal Jaundice Physiologic or Pathologic?

Physiologic

Pathologic

Term 37 weeks Healthy Higher red cell turnover Shorter red cell lifespan Decreased ability to excrete Average full term newborn peaks at 5-6 mg/dl total bili Peak at 3-5th day of life, onset after 24 hours Peaks 7 days in Asian and preterm Hematocrit drops in 1st month
Average term 51 to 44 @1mo 2 SD term 42 to 33 @1mo

Onset in first 24 hours direct bili >1.5 mg/dl

dark urine, pale stool

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rate of rise > 0.5 mg/dl/hour ill neonate with sepsis or asphyxia, or symptomatic Prematurity + Family hx of G6PD, hemolysis hemolytic disease such as ABO incompatibility poor response to rx persistence > 3 weeks

Direct hyperbilirubinemia: Pathologic

Direct

Bilirubin 1.5 mg/dl

hepatitis biliary obstruction, atresia infection: viral (TORCH) or sepsis inborn errors of metabolism, galactosemia, tyrosinosis, cystic fibrosis, alpha 1 antitrypsin hyperalimentation hypothyroidism
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Clinical Signs of Neonatal Jaundice as a Symptom of Other Disease

Vomiting Lethargy Poor feeding Hepatosplenomegal y Excessive weight loss Apnea

Tachypnea Pallor Rubor Temperature instability Birth injury

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Clinical Factors Suggesting Hemolytic Disease

Family history of significant hemolytic disease Sibling with severe neonatal jaundice Ethnicity suggestive of inherited disease

Asians Greeks Sardinians Sephardic Jews Black

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Clinical Exam: Unreliable

Zone 1 Zone 2 Zone 3 Zone 4 Zone 5 head - clavicle 5

clavicle-umbilicus 6-8 umbilicus-knees knees-ankles palms + soles 9-12 13-15 15

Clinical Exam: Unreliable

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Clinical Exam: Unreliable

Poor

correlation inter-observer and with serum bilirubin Best cut appears to be jaundice to nipples

for bili > 12.0 mg/dl

97% sensitive

SnOut (negative high sensitivity test helps rule out disease) Arch Pediatr Adolesc Med. 2000; 154:391-4

19% specific

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Measurements

Estimates of serum bilirubin concentrations that are based solely on clinical examination are not reliable

Serum bilirubin Transcutaneous bilirubin

Older devices affected by skin pigmentation Newer multi-wavelength spectral reflectance correlate 0.88 with the serum value,
example SpectRx, 3 mg/dl

? Confirm values > 40% per age

Carbon monoxide exhaled

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Transcutaneous Accuracy

Data of 99 measurements within 30 min of serum total bili

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Practice Parameter: Management of Hyperbilirubinemia in the Healthy Term Newborn Pediatrics 1994;94:558-565 & 1995;95:458-461 AAP Provisional Committee for Quality Improvement Subcommittee on Hyperbilirubinemia Comprehensive literature review Retrospective Epidemiologic data The recommendations that follow....are based on evidence when appropriate data exist and derived from consensus when data is lacking. In these guidelines, the AAP has attempted to describe a range of acceptable practices, recognizing that adequate data are not available from the scientific literature to provide more precise recommendations.
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Guideline Recommendations: Evaluation

Maternal prenatal testing

ABO & Rh(D) typing Antibody screen for isoimmune antibodies

Save cord blood for direct Coombs, blood type, and Rh whenever:

mother has not had any prenatal care mother is Rh negative mothers blood type is Group O

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Laboratory Testing
Bilirubin,

total and direct

clinical suspicion

Type,

Rh, direct coombs, CBC, retic, smear

O positive mother, (1 in 5 coombs + with significant hyperbili) Onset jaundice in < 24 hours, Total bili 95% for age Hct < 40, or suspicion of hemolysis Family history hemolytic anemia, severe neonatal jaundice, Ethnic origin for G6PD

G6PD for bili > 15 + appropriate ethnic group

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Increased Indirect Bilirubin

Positive Coombs

Negative Coombs

Isoimmunization Rh ABO Other

Direct Coombs Testing

Strongly positive:

Rh Kell Kidd Duffy

Negative or weakly positive:

Anti-A

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Set-up
Mothers blood type = O Infants blood type = A or B

15% of all pregnancies in the U.S.

3% develop clinically significant jaundice 50% occur in the first born

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ABO Incompatibility
Hemolysis

consider present if

Hct < 45% Abnormal blood smear with 3-4+ spherocytes Reticulocyte count is 4.5% in the first 72 hrs, or Reticulocyte count is >1-2% in the first 1-2 wks.

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Increased Indirect Bilirubin

Positive Coombs

Negative Coombs

Isoimmunization Rh ABO Other

Hematocrit
High Twin transfusion Maternal fetal transfusion Delayed cord clamping SGA infant Normal or Low

Increased Indirect Bilirubin

Positive Coombs

Negative Coombs

Isoimmunization Rh ABO Other

Hematocrit
High Twin transfusion Maternal fetal transfusion Delayed cord clamping SGA infant Normal or Low

Normal or Low Hematocrit

Reticulocyte Count D1=7 D3=3 D7=1

Normal or Low Hematocrit

Reticulocyte Count D1=7 D3=3 D7=1

Increased

Normal

RBC Morphology

Normal or Low Hematocrit

Reticulocyte Count D1=7 D3=3 D7=1

Increased

Normal

RBC Morphology

Characteristic Spherocytosis Eliptocytosis Stomatocytosis

Non-specific G6PD deficiency Pyruvate kinase deficiency Other hereditary enzyme deficiency DIC

Normal or Low Hematocrit

Reticulocyte Count D1=7 D3=3 D7=1

Increased

Normal Extravascular Blood Cephalohematoma Other hemorrhage

RBC Morphology

Characteristic Spherocytosis Eliptocytosis Stomatocytosis

Non-specific G6PD def. PK def. Other hered. enzyme def. DIC

Normal or Low Hematocrit

Reticulocyte Count D1=7 D3=3 D7=1

Increased

RBC Morphology

Characteristic Spherocytosis Eliptocytosis Stomatocytosis

Non-specific G6PD def. PK def. Other hered. enzyme def. DIC

Normal Extravascular Blood Cephalohematoma Other hemorrhage Increased EHC Breastfeeding Pyloric stenosis SBO or LBO Swallowed blood

Normal or Low Hematocrit

Reticulocyte Count D1=7 D3=3 D7=1

Increased

RBC Morphology

Characteristic Spherocytosis Eliptocytosis Stomatocytosis

Non-specific G6PD def. PK def. Other hered. enzyme def. DIC

Normal Extravascular Blood Cephalohematoma Other hemorrhage Increased EHC Breastfeeding Pyloric stenosis SBO or LBO Swallowed blood Metabolic-Endocrine Cong. glucuronyl trans. deficiency Galactosemia Hypothyroidism Infants of DM mothers

Pre-discharge bilirubin
% pre-discharge bilirubin >95% 76-95% 40-75% <40% Probability of subsequent high bili 2/5 1/8 1/46 0/1,756

Subsequent high bili = reaching 95% for age

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Pre-discharge bilirubin
Hours of life 24 hours 48 hours 72 hours 96 hours 40% 5 mg/dl 7.5 mg/dl 11 mg/dl 12 mg/dl 75% 6.5 mg/dl 11 mg/dl 13.5 mg/dl 15 mg/dl 95% 8 mg/dl 13 mg/dl 16 mg/dl 17 mg/dl

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Follow-up
Farnoff

has shown that babies discharged at 48-72 hours have same risk of severe hyperbili as those discharged <48 hours Any baby discharged < 72 hours should be seen in 1-2 days

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The Rate of Rise

Newborns are not once a day modules, bilirubin is rising until peak at day 3-5 In first 24 hours if jaundiced recheck in 4 hours and calculate rate of rise 24-48 hours consider calculate rate of rise in 812 hours with second total bilirubin >48 hours if is < 75% for age can check in 24 hours Rate of rise of 0.5mg/dl/hour is too fast and should be investigated
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Treatments

Food and stooling

Removes via enterohepatic elimination

forms lumirubin a water soluble compound effectiveness depends on spectrum and dose
Blue light 450nm most effective, green penetrates deepest Standard 8 tubes of florescent white bulbs = 6-12 microwatts/cm2 Fiber-optic blankets = up to 50 microwatts/cm2 Distance 15-20 cm

Phototherapy

Exchange transfusion

2% mortality, 12% severe complications

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Effective Phototherapy

Infant in bassinette not incubator needs to be within 15-20cm distance for blue or white florescent bulbs Halogen bulbs can burn, use manufacturers recs Fiberoptic pads to give double phototherapy Twice as effective as single in low birth weight 50% better than single in term newborns Naked Eye covers Hydration Breast milk or formula if not dehydrated Milk plus IV hydration if dehydrated
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Guideline Recommendations: Treatment

No evidence to support excess IV fluids Phototherapy may be discontinued:

Term infant TSB < 14mg/dL Preterm infant (34-37weeks) > 5-6 days old TSB @ 12 < 5 days old TSB @ 10

Ave. TSB rebound after PT stopped = 1 mg/dL

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1994 AAP Guidelines For Healthy Term Physiologic

Age in hours Consider Photo Phototherap Therapy Exchange if Photo fails 20 25 25 Exchange and photo 25 30 30

25-48 49-72 >72

12 15 17

15 18 20

Intensive phototherapy should yield 1-2 mg/dl drop in 4-6 hr

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ABO incompatibility hemolysis

Generally phototherapy interventions are instituted 3mg/dl lower than those for non-hemolytic healthy term in the 1994 guidelines 87.7% (202/230) did not require phototherapy never were greater than total bili of 12 mg/dl Phototherapy for term healthy ABO coombs+ <24 hours = >5mg/dl 24-48 hours = >10mg/dl Exchange transfuse for >20mg/dl F/u Hct All at 6 week Earlier, one week if t bili > 15 mg/dl
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Management of Hyperbilirubinemia in the Sick Term Newborn: TSB levels mg/dL

Age (hrs) Up to 24
25-48

Phototherapy
7-10 10-12

Exchange Transfusion
18 20

49-72
> 72

12-15
12-15

20
20

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Harriet Lane Preterm Phototherapy Guidelines < 1 week old

Weight (kg) Phototherapy
500-1,000 gms 1000-1500 gms 1500-2500 gms >2500 gms 2000 edition 5-7 mg/dl 7-10 10-15 >15

Consider Exchange Transfusion 12-15 mg/dl

15-18 18-20 >20

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in the Sick Preterm Newborn (< 37 weeks) : TSB levels mg/dL

Weight (gm)
Up to 1000

Phototherapy
4-6

Exchange Transfusion 8-10 10-12

15 17

1001-1500
1501-2000 > 2000

6-8
8-10 10

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Conclusions

Neonatal Jaundice is common (> 50% of newborns) Family history, maternal blood type and newborn clinical setting help to define higher risk groups Unreliable clinical exam requires low threshold for serum bilirubin Nomograms of pre-discharge total bili per age help prognostication/follow up testing plan Early followup of all newborns discharged with
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References

Johnson, L et al, System-based approach to management of neonatal jaundice and prevention of kernicterus, J Pediatr 2002, 140:396-403 Subcommittee on Neonatal Hyperbili, Neonatal Jaundice and Kernicterus, Pediatrics, 2001, p 763 AAP Practice Parameter: Management of Hyperbilirubinemia in the Healthy Term Newborn, Pediatrics 1994, 94:588-565 Bhutani, V et al, Predictive Ability of a Predischarge hour specific Serum Bilirubin for Subsequent Significant Hyperbilirubinemia in Healthy Term and Near-term Newborns, Pediatrics, Vol 103, #1, January 99, p 6-14 Moyer VA et al, Accuracy of Clinical Judgement in Neonatal Jaundice, Arch Pediatr Adolesc Med, 2000; 154:391-394 www.cdc.gov/ncbddd/dd/kernicterus2.htm

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