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Neonatal Hyperbilirubinemia: Risk Assessment and Management
SHEENA BHAVSAR, PA-CBAYLOR COLLEGE OF MEDICINETEXAS CHILDREN’S HOSPITAL: PAVILION FOR WOMEN
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Objectives
Importance and Impact on infant health
Physiologic and Pathologic causes of hyperbilirubinemia in newborns
Guide to a systematic risk assessment
Management
Follow up
Common parent/provider questions
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Hyperbilirubinemia
Elevated levels of bilirubin in the blood, >95th percentile based to the hour specific nomogram.
Severe hyperbilirubinemia is defined as > 25mg/dL
One of the primary causes of hospital readmission of neonates
Usually peaks between 3-5 days of life
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Bilirubin Encephalopathy
- highly neurotoxic substance- can bind to brain tissue and cause neurologic dysfunction
ACUTE (hypotonia, lethargy, poor suck irritability, high pitched cry, intermittent hypertonia , seizures, fever, apnea, coma)
VS CHRONIC (movement disorders, auditory neuropathy,
oculomotor dysfunction, GI concerns) KERNICTERUS
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Causes?
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INCREASED ERYTHROCYTE BREAKDOWN
Physiologic Jaundice
Trauma
Blood Incompatibility
Infection
Enzyme Deficiency
Globin Synthesis Defect
Membrane conditions
DECREASED BILIRUBIN CLEARANCE
Physiologic Jaundice
Breastmilk Jaundice
Anatomic Obstruction
Liver enzyme defect
Drug Induced
Liver Disease
Metabolic
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INCREASED ERYTHROCYTE BREAKDOWN
Physiologic Jaundice
Trauma
Blood Incompatibility
Infection
Enzyme Deficiency
Globin Synthesis Defect
Membrane conditions
DECREASED BILIRUBIN CLEARANCE
Physiologic Jaundice
Breastmilk Jaundice
Anatomic Obstruction
Liver enzyme defect
Drug Induced
Liver Disease
Metabolic
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INCREASED BREAKDOWN
increased breakdown of red blood cells – 2-3x more than adults
birth trauma
DECREASE CLEARANCE
Gestational age-dependent physiologic deficiency of glucuronyl transferase enzyme -
• 0.1% of adult activity at 30 weeks.
• 1% of activity at 40 weeks.
Physiologic Jaundice
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How to simplify etiology and importance of early follow up for parents?
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Causes of Exaggerated Physiologic Jaundice
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BREASTFEEDING/BREASTMILK Jaundice Breastfeeding jaundice
- 1st week of life
- exaggerates physiological jaundice
- mild dehydration, delayed passage of meconium
Breast milk jaundice
- 6-14 days of life, can continue for over 1 month
- ↑ β glucuronidase and fatty acids that inhibit enzymes involved in conjugation and intestinal absorption, ↑ enterohepatic circulation
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TRAUMA/BRUISING
More RBCs that go through hemolysis--> more bilirubin production
Examples:
-nuchal cord
-cephalohematoma
-bone/vascular injury
Assisted delivery – vacuum or forceps
*often bilirubin peaks will be later for these infants ~5-7days
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PATHOLOGIC CAUSES: Blood Type Incompatibility
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Antibody Screen Maternal and fetal blood can mix during the pregnancy
and delivery process. Maternal antibodies in the form of IgG can cross the placenta (both Rh and ABO antibodies).
Indirect Coombs Test (aka antibody screen) tests the mother’s blood for potential antibodies that could affect the newborn
Direct Coombs Test identifies the presence of "foreign" antibodies that have adhered to the infant's rbcs, which is a potential cause of hemolysis - using a reagent.
A positive test does not mean the infant will have hyperbilirubinemia but places the baby at higher risk. *Evidence shows that an infant with ABO incompatibility but with a coombs negative test does NOT place the infant at higher risk due to the ABO incompatibility alone
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Unconjugated HyperbilirubinemiaABO incompatibility
the most common cause of hemolytic disease in newborn 0.3 - 2.2% most commonly O/A Hydrops very rare milder than Rh, severity can not be predicted
Fetal RBCs express less ABO antigen compared to adult RBCs. Also in contrast to Rh Antigens, ABO Antigens are expressed by a variety of tissues(in both fetus and adult) reducing the chance of these antibodies binding to RBCs.
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Coombs positive due to true sensitization
vs Maternal administration of Rh
immunoglobulin?
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Important to look at mother’s antibody testing for active Anti D titers
Infant is still considered on the more conservative risk curve though likely due to maternal RhIg administration
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* Once mother is sensitized, even if Rh immunoglobulin is given during subsequent
pregnancies, there is a higher risk of antibody mediated hemolysis
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Unconjugated hyperbilirubinemiaG6PD deficiency
G6PD is needed to clear free radicals that cause oxidative damage. G6PD deficiency causes increased risk of hemolytic anemia in states of oxidative stress (infection certain chemical exposure and certain foods , e.g. fava beans)
most common cause of non-immune hemolytic anemia gene located on X chromosome, > 400 mutations described 12.2% of AA males, 4.1% AA females, 4.3% Asian males newborn screening 21% (26/125) of cases with kernicterus G6PD level recommended for any infant receiving phototherapy with an
appropriate genetic/geographic background, and for any neonate who does not respond well to phototherapy
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Risk FACTORS
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Risk Factors for Development of Severe Hyperbilirubinemia _________________________________________________________________________________Major Risk Factors Predischarge TSB or TcB level in the high-risk zone Jaundice observed in the first 24 hours Blood group incompatibility with + Coombs test, other known
hemolytic disease (i.e. G6PD). Gestational age 35 – 36 weeks Cephalohematoma or significant bruising Exclusive breastfeeding, particularly if nursing is not going well
and weight loss is excessive East Asian race Previous sibling received phototherapy
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Family history of need for phototherapy
East Asian Race – polymorphisms in UGT gene causing lower levels of functioning gene expression. Can be in other familial subgroups also
Family history of Gilbert Syndrome – can predispose infants to exaggerated physiologic jaundice. Affects 9% of the general population
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Other causes: INCREASED ERYTHROCYTE
BREAKDOWN
Physiologic Jaundice
Trauma
Blood Incompatibility
Infection
Enzyme Deficiency
Globin Synthesis Defect
Membrane conditions
DECREASED BILIRUBIN CLEARANCE
Physiologic Jaundice
Breastmilk Jaundice
Anatomic Obstruction
Liver enzyme defect
Drug Induced
Liver Disease
Metabolic
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35-36 weeks 36-37 weeks 37-38 weeks
Likelihood of need for readmission for PTX.
13.2 x 7.7 x 7.2 x
Retrospective Study:
Prevalence of significant jaundice requiring re-admissionto hospital for phototherapy.Compared to neonates > 40 weeks
Maisels MJ, Kring E. Length of stay, jaundice, and hospital readmission. Pediatrics.1998
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Risk Factors for Development of Severe Hyperbilirubinemia in Infants________________________________________________________
Minor Risk Factors Predischarge TSB or TcB level in the high intermediate-risk
zone Gestational age 37-37w6d weeks Jaundice observed before discharge Previous sibling with jaundice Macrosomic, infant of a diabetic mother Maternal age > 25 yr Male gender
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Infant of diabetic mothers
Mother with elevated blood glucose
infant with elevated blood glucose
Hyperinsulinemia
higher metabolic rate
polycythemia
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Risk Factors for Development of Severe Hyperbilirubinemia in Infants __________________________________________________________________
Decreased Risk
TSB or TcB level in the low-risk-zone Gestational age > 41 weeks Exclusive formula feeding Discharge from hospital after 72 hours Black race **
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Management
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Routine Protocol: Mother and baby blood type and coombs test
Risk factors assessment
Serum bilirubin at 24-48 hours of life
Appropriate early follow up
* remember visual assessment is not a good predictor at 1-3 days
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Visual estimation….
Zone 1 2 3 4 5
µmol/L ~mg/dL
100 6
1509
20012
25015
>250>15
Department of Neonatal Medicine Protocol Book; Royal Prince Alfred Hospital www.cs.nsw.gov.au/rpa/neonatal/ html/newprot/jaund2.htm after Kramer LI Advancement of dermal icterus in the jaundiced newborn. Arch J Dis Child 1969;118:454
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Interpret all bilirubin levels according to the infant’s age in hours.
When documenting bilirubin levels ALWAYS note phototherapy level for infant based on risk
e.g. 13.6/0.2 @ 83 HOL Low intermediate risk Ptx level: 18.8 low risk curve
Vs 13.6/0.2 @ 83 HOL Low intermediate risk
Ptx Level: 16.5 on middle curve for age
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Hour Specific Bilirubin Nomogram
from Bhutani, et. al. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy-term and near-term newborns, Pediatrics 1999.
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Factors that affect Phototherapy Level
+ Coombs TestAge: <38weeks
+ Symptomatic SepsisAsphyxia requiring NICU admission
+ G6PD Deficency risk
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Guidelines for phototherapy in hospitalizedinfants of 35 or more weeks’ gestation
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For infants <2500g or <35wks :*use the low birth weight tabLE OR* use the highest risk curve up to 96
hours of life
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Provide appropriate follow-up based on the time of discharge and the risk
assessment.
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Low risk
Term babies with normal weight loss and no other risk factors do not require repeat bilirubin value if performed at 24-48 hours of age
* consider Coombs positive?
* family history
* significant bruising
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Low intermediate risk
Will require close follow up (in 24-48 hours) if:
Less than 38 weeks
Excess weight loss >7%
Breastfeeding exclusively
Significant bruising or Cephalohematoma
Sibling history of requiring phototherapy
Hemolytic disease risk
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High intermediate risk
Requires follow up in 24-48 hours:
All babies regardless of gestational age
If baby is coombs positive or has major risk factors may be advisable to obtain repeat bilirubin value to assess rate of rise while inpatient if value is <2 away from phototherapy level
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High risk
Require repeat bilirubin in 6-24 hours with close assessment of risk factors and age
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Considering Rate of Rise?
While inpatient (assuming <72 hours old) a rate of rise of >0.2mg/dL/hr has significant potential to raise a HIR bili over phototherapy within 24 hours
* After 72 hours – a lower rate of rise can also be significant as the curve begins to plateau. An average rate of rise can be calculated for age ranges using the bhutani curve to assess risk
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Hour Specific Bilirubin Nomogram
from Bhutani, et. al. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy-term and near-term newborns, Pediatrics 1999.
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When to start Phototherapy?
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Guidelines for phototherapy in hospitalized infants of 35 or more weeks’ gestation_______________________________________________
Phototherapy includes double bank lights and a biliblanket It is an option to provide conventional phototherapy in
hospital at TSB levels 1-2 mg/dL below general rule: 1 or less with term baby no risk factors
2 or less with <38 wks or + risk factors If value is above phototherapy level * always look at the
exchange transfusion level
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What to consider in an outpatient setting when thinking about readmission?
Within 1mg/dL below phototherapy level
Rate of rise: >5mg/dL/per day
At risk of lost to follow up
Poor feeding despite adequate supply
Signs of Acute Bilirubin Encephalopathy
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When to check next bilirubin once phototherapy is started?
If term infant with no other risk factors and below phototherapy level – appropriate to check in 24 hours
If coombs positive – appropriate to check in 6-12 hours
If above phototherapy level – appropriate to check in 6-12 hours
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If the bilirubin level continues to increase while under phototherapy,
consider?
Check intensity How much time is the baby
actually received therapy Consider hemolysis Feeding assessment
Blood type with Coombs test H/H reticulocyte count Peripheral smear G6PD deficiency?
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Considering IV IG, exchange transfusion….
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Guidelines for phototherapy in hospitalized infants of 35 or more weeks’ gestation
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When to stop phototherapy?
- Bilirubin level has shown some decrease
- Bilirubin level is a safe distance from phototherapy level
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Phototherapy case: 3320g 39w0d female born via SVD to a 22y.o G2P1->2 mother.
Mother O+/ Baby A-/coombs positive . No other risk factors known at this time.
T bili at 6 hours of life= 6.6. --> started phototherapy
@ 12 HOL =9.8 H/H 16.4/48.8, retic 5.8%.
@ 15 HOL =10
@ 48 HOL =12.8
@ 66 HOL =13.0, LUL: 15.1mg/dL MRC
* phototherapy discontinued
6 hour Rebound T bili 13.4
Infant discharged with follow up in 24 hours....
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Case 2 continued …
Infant arrives at follow up clinic.
T/D Bili: 19.1/0.4 @ @ 100 HOL PTx level: 17.7
-readmitted for phototherapy. Received another 36 hours of phototherapy, discontinued at 138 HOL.
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Things to consider when treating with phototherapy It is NOT mandatory to check H&H and retic% on every
baby – when is it beneficial?
Bilirubin value should decrease during phototherapy treatment before discontinuing lights
Consider age of baby and risk factors to assess safe range to stop phototherapy to decrease risk of readmission
If initial bilirubin is above phototherapy level always check exchange transfusion level. If coombs positive and within 1-2 of exchange level consider IVIG
How important are rebound bilirubin levels?
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When to follow up after phototherapy treatment: Within 24-48 hours of discharge – rebound
bilirubin needed BUT NOT NECESSARY PRIOR TO DISCHARGE.
If infant has significant risk factors consider a rebound bili prior to discharge
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Provide parents with written and verbal information about newborn jaundice.
Call PCP or bring infant to the ER if over the weekend with poor feeding, increased sleepiness or no urine output in >8 hours.
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Transcutaneous bilirubin checks
PROS: Accurate across different skin color variations, gestational
age Accurate within 1-2mg/dL if value below 11mg/dL
(insufficient data on values over 11 to be significant) Less invasive – good screen tool CONS: Consider cost based on population and need for
confirmatory serum bilirubin levels Does not measure conjugated bilirubin levels
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Why is conjugated bilirubin important? Elevated conjugated bilirubin levels help differentiate the
etiology of hyperbilirubinemia, detected other serious diseases such as
- Biliary atresia, Alagille Syndrome, Alpha 1 antitrypsin deficiency +
Should not begin phototherapy without a normal baseline conjugated bilirubin as this may exacerbate other conditions and possibly cause more liver/biliary damage
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Commonly asked questions?
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Will sunlight help? Evidence shows: Yes sunlight is just as effective 2015 – study in Nigeria showed sunlight using a filter
canopy that removed harmful UV rays was just as effective as conventional phototherapy
However is NOT TO BE ADVISED as the risk of sunburn, overheating, dehydration, hypothermia all outweigh the benefits. There are also safer and more reliable alternative interventions
Slusher TM, Vreman HJ, Olusanya BO, et al. Safety and efficacy of filtered sunlight in treatment of jaundice in African neonates. Pediatrics. 2014;133(6):e1568–e1574. doi:10.1542/peds.2013-3500
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Will supplementing formula help? Evidence shows: Yes. Breastmilk vs formula does have different
growths in gut flora which then change how effectively bilirubin is broken down. Larger volumes of supplement also benefit in infant who have low intake jaundice
However the benefits of breastmilk on gut health including decreasing overall inflammation outweighs the risk of higher bilirubin levels and should be weighed against risk and benefits of interruption
What about fluids: The mechanism of action proposed includes direct dilution for IV fluids and enhancement of peristalsis to reduce enterohepatic circulation by oral fluids. No significant evidence to show oral or IV fluid supplementation will significantly decrease bilirubin levels
Tuzun F, Kumral A, Duman N, et al. Breast milk jaundice: Effect of bacteria present in breast milk and infant feces. J Pediatr Gastroenterol Nutr 2013;56:328–332.
Lai NM, Ahmad Kamar A, Choo YM, Kong JY, Ngim CF. Fluid supplementation for neonatal unconjugated hyperbilirubinaemia. Cochrane Database Syst Rev. 2017;8(8):CD011891. Published 2017 Aug 1. doi:10.1002/14651858.CD011891.pub2
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Are we being too conservative?
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Incidence rate Globally stable in western countries ~ 8 in 100,000 diagnosed
with severe hyperbilirubinemia (>25mg/dL) Kernicterus rates of ~ 2004 0.44-1.5 in 100,000 newborns
previously: 1994 1.5 in 100,000 newborns1988 5.1 in 100,000 newborns
Incidence rates remain low due to the early monitoring, identifying at risk infants and timely interventions
Key concept is there is not defined bilirubin level at which kernicterus begins – the range remains the same for those with acute signs that resolve and those with chronic sequelae
Obstacles in obtaining reliable data: - absence of a population based data reporting system - variable timeliness to intervention and follow up - admitting at variable stages of acute encephalitis signs
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THE END
QUESTIONS ??
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