2022 Hyperbilirubinemia

Update to 2004 Guidelines

Kemper AR, Newman TB, Slaughter JL, et al. Clinical practice guideline revision: Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2022;150(3)

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Background

• Current evidence base is not sufficient to quantitatively derive the exact treatment threshold at which phototherapy should be started to prevent kernicterus.
• Guidelines depend on expert opinion.
• Guideline is being revised based on:
• Recent large cohort studies show higher thresholds below which kernicterus does not happen
• Large cohort studies suggest that phototherapy may be harmful
• Aim of this revision is to continue to safely reduce the risk of kernicterus while reducing the risk of unnecessary treatment

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Multiple studies show that kernicterus does not happen at lower treatment thresholds

• Kuzniewicz MW, Wickremasinghe AC, Wu YW, et al. Incidence, etiology, and outcomes of hazardous hyperbilirubinemia in newborns. Pediatrics. 2014;134(3):504–509
• Wickremasinghe AC, Risley RJ, Kuzniewicz MW, et al. Risk of sensorineural hearing loss and bilirubin exchange transfusion thresholds. Pediatrics. 2015;136(3):505–512
• Wu YW, Kuzniewicz MW, Wickremasinghe AC, et al. Risk for cerebral palsy in infants with total serum bilirubin levels at or above the exchange transfusion threshold: a population-based study. JAMA Pediatr. 2015;169(3):239–246
• Newman TB, Liljestrand P, Jeremy RJ,et al; Jaundice and Infant Feeding Study Team. Outcomes among newborns with total serum bilirubin levels of 25 mg per deciliter or more. N Engl J Med. 2006;354(18):1889–1900
• Gamaleldin R, Iskander I, Seoud I, et al. Risk factors for neurotoxicity in newborns with severe neonatal hyperbilirubinemia. Pediatrics. 2011;128(4):e925–e931
• Vandborg PK, Hansen BM, Greisen G, Mathiasen R, Kasper F, Ebbesen F. Follow-up of extreme neonatal hyper- bilirubinaemia in 5- to 10-year-old children: a Danish population-based study. Dev Med Child Neurol. 2015; 57(4):378–384
• Ebbesen F, Bjerre JV, Vandborg PK. Relation between serum bilirubin levels >=450 lmol/L and bilirubin encephalopathy; a Danish population- based study. Acta Paediatr. 2012; 101(4):384–389

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Slaughter JL, Kemper AR, Newman TB. Technical Report: Diagnosis and Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation. Pediatrics. 2022;150(3)

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Large cohort studies suggest that phototherapy may be harmful

• Newman TB, Wu YW, Kuzniewicz MW, Grimes BA, McCulloch CE. Childhood seizures after phototherapy. Pediatrics. 2018;142(4):e20180648
• 496632 infants total followed for development of seizure disorder > 60 days after birth who also received phototherapy. Phototherapy found to be associated with a slight risk in childhood seizures diagnosed after 60 days of life. Boys were more likely than girls to be both treated with phototherapy and receive a diagnosis of childhood seizure
• Wickremasinghe AC, Kuzniewicz MW, Grimes BA, McCulloch CE, Newman TB. Neonatal phototherapy and infantile cancer. Pediatrics. 2016;137(6): e20151353
• Increased propensity score adjusted odds ratio for all cancer 1.4, myeloid leukemia 2.6 and renal cancer 2.5. Large population study > 5 million infants from CA vital statistics

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Overview of Major Changes

• Prevention of hyperbilirubinemia
• Emphasis on Neurotoxicity Risk Factors
• Increased treatment thresholds
• Treatment thresholds based on weeks gestational age and presence or absence of treatment thresholds
• More explicit guidance for escalation of care
• Change in guidance for monitoring bilirubin levels and follow-up care
• More explicit guidance on outpatient management and readmission

Prevention of Hyperbilirubinemia: HDN

• If maternal antibody screen is + or unknown in pregnancy or at the time of admission, infant should have Blood type and DAT from cord blood or peripheral blood.
• If mom received RhIG (Rhogam) antibody screen on mom and baby can be positive.
• If mom is DAT+ (our lab will typically identify antibodies as passive anti-Rh(D) in lab results) received RhiG in pregnancy and was antibody negative prior to receiving RhIG the infant should be considered DAT negative.
• If maternal and infant antibodies are not passively acquired anti-Rh(D) this is a neurotoxicity risk and infant should have TcB or TSB immediately, every 4 hours x 2, then every 12 hours x 3.

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Lui Freeze Thaw Elution Test

• If mom is O negative DAT + with passive anti-D antibodies and baby is A or B+ and DAT+ it is an option to determine if DAT+ in baby is due to passive antiD antibodies or ABO incompatibility

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• Lui Freeze Thaw Eleution Test Order Code LAB1281
• Can be done on cord blood
• Requires about 3 ml cord blood
• Results in about 2 hours
• Cannot be done reflexively – must be ordered

Prevention of Hyperbilirubinemia: Feeding

• Adequate feeding is an important component of preventing neonatal hyperbilirubinemia
• Breastfeeding should be promoted according to AAP guidelines including breastfeeding in the first hour of life, frequent breastfeeding on demand at least eight times in 24 hours, and assessment of infant for adequate latch, suck and transfer of milk
• Oral supplementation with water or dextrose water should not be done
• Decisions about temporary supplementation with DHM or formula should be made jointly with infant’s parents
• “Breastfeeding Jaundice” is better called “suboptimal intake jaundice”, is associated with excess weight loss, and peaks at 3-5 days

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Assessment for Hyperbilirubinemia

• All infants should be visually assessed for jaundice at least every 12 hours following delivery until discharge.
• Assessment takes place in an adequately lit room or in bright natural light
• TSB or TcB should be measured as soon as possible for infants noted to be jaundiced < 24 hours after birth
• Risk factor for developing jaundice should be identified and charted in EMR
• Neurotoxicity risk factors that place baby at higher risk for neurotoxicity should be identified and charted in EMR
• All newborns should have a screening TSB or TcB measured between 24-48 hours of life or prior to discharge whichever comes first

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Risk Factors for Jaundice

• These risk factors place newborns at higher risk for developing jaundice.
• Lower gestational age
• Jaundice in the first 24 hours of life
• Predischarge TcB or TSB concentration close to the phototherapy threshold
• Hemolysis from any cause, if known or suspected based on a rapid rate of rise in TSB or TcB > 0.3 mg/dl/hr. in first 24 hours or >0.2 mg/dl after 24 hours
• Phototherapy before discharge
• Parent or sibling requiring phototherapy or exchange transfusion
• Family history of or suggesting inherited RBC disorders including G6PD, spherocytosis, elliptocytosis
• Exclusive breastfeeding with suboptimal intake
• Scalp hematoma or significant bruising
• Down Syndrome
• Macrosomia Infants of diabetic mothers

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Neurotoxicity Risk Factors for Jaundice

• These risk factors place newborns at higher risk for neurotoxicity and are specifically used to guide treatment and follow up care for infants with jaundice
• Gestational age < 38 weeks and risk increases with degree of prematurity (Phototherapy thresholds based on Neurotoxicity risk factors other than gestational age)
• Albumin < 3.0 g/dl
• Isoimmune hemolytic disease (positive DAT), G6PD deficiency or other hemolytic condition
• Sepsis
• Significant clinical instability in the previous 24 hours

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A note about G6PD

• One of the most important causes of hazardous hyperbilirubinemia leading to kernicterus in the US and around the world.
• Overall, 13% of AA males and 4% of AA females have G6PD deficiency.
• G6PD deficiency can be difficult to recognize
• Infants with G6PD deficiency are more likely to receive phototherapy prior to discharge.
• Measuring G6PD enzyme levels at time of hemolysis can result in false negatives.
• If G6PD is strongly suspected level should be repeated in 3 months
• G6PD activity should be measured in any infant with jaundice of unknown cause whose TSB increases despite intensive phototherapy, whose TSN increases suddenly or increases after an initial decline, or who requires escalations of care

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Assess for risk of hemolytic disease

• Rapid rate of increase suggests hemolysis. It is recommended to check a DAT if not already done

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• Rapid rate of rise is defined as:
• >=0.3 mg/dl/hr in the first 24 hours of life
• >=0.2 mg/dl/hr after 24 hours of life

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• Consider DAT if Delta-TSB <3.5 and mom is O+

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A note about TcB

• TcB can be used to screen for hyperbilirubinemia but should not be used for treatment decisions or escalation of care
• TcB levels are valid and reliable as screening tools
• TcB levels that are within 3 mg/dl of phototherapy threshold or >15 should be confirmed with TSB

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• Use TSB as the definitive test to guide phototherapy and escalation of care decisions, including exchange transfusions

A note about Direct Bilirubin

• Direct bilirubin >1 mg/dl Is considered abnormal
• If direct bilirubin is elevated, repeat in a few day to 2 weeks. Any increase requires further evaluation
• A direct bilirubin concentration of >20% of the total is no longer regarded as necessary for the diagnosis of cholestasis
• If Direct bilirubin is >50% of total bilirubin consult GI or NICU
• Consider causes of neonatal direct hyperbilirubinemia other than biliary atresia that require early treatment
• UTI, isoimmune hemolytic disease, sepsis and some inborn errors of metabolism
• Measure total and direct bilirubin in breastfeeding infant who are till jaundiced at 3-4 weeks and formula feeding infants who are still jaundiced at 2 weeks

Treatment of Hyperbilirubinemia

• Use TSB along with presence or absence of neurotoxicity risk factors and gestational age to guide phototherapy and escalation of care decisions including exchange transfusions
• If more than one TcB or TSB is available, the rate of increase can be used to identify infants at risk for subsequent hyperbilirubinemia.
• Rate of rise is elevated if > 3 mg/dl in first 24 hours and >2 mg/dl after 24 hours
• Not yet in epic – being worked on right now
• www.peditools/bili2022

Phototherapy Treatment Threshold WITH Neurotoxicity Risk Factors

Phototherapy Treatment Threshold WITHOUT Neurotoxicity Risk Factors

Phototherapy

• The general approach is to provide intensive phototherapy to as much of the infant’s surface area as possible.
• The goal is to decrease the likelihood of further increases in TSB that would lead to escalation of care
• Intensive phototherapy requires a narrow-spectrum LED blue light with irradiance of at least 30 microwatts/cm2 at a wavelength around 475nm.
• Light outside the 460-490 nm range provides unnecessary heat and potentially harmful wavelengths.

Phototherapy

• Clinicians and families may choose to treat at lower levels based on individual circumstances and preferences
• Consider risk of overtreatment on infant and family
• If phototherapy is required, measure HGB, HCT or CBC or assess for anemia.
• If phototherapy is required, evaluate for underlying cause
• Obtain a DAT if mom has + antibodies or if mom is blood type O or if mom is Rh negative
• TSB should be measured within 12 hours after starting phototherapy. Timing of bilirubin measurement and frequency of measurements should be guided by age, presence of neurotoxicity risk factors, the TSB and rate of rise

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Phototherapy and Fluid/Feeding

• Feeding should be maintained during inpatient or home phototherapy to promote bilirubin clearance and avoid dehydration.
• Interrupting phototherapy for breastfeeding does not impact the overall effectiveness of phototherapy if it is otherwise appropriately used
• These interruptions should be minimalized if the bilirubin concentration is approaching the need to escalate care
• Although breastfeeding and human milk have many benefits, brief use of formula might lead to a more rapid decline in TSB concentration and reduce the risk of readmission for phototherapy
• Use of IV Fluids is not recommended unless there is evidence of dehydration that cannot be corrected enterally or if the TSB exceeds the escalation of care threshold

“Escalation of Care”

• Escalation of care = intensive care that some infants with elevated or rapidly increasing bilirubin concentrations need to prevent the need for exchange transfusion
• Escalation of care threshold is 2 mg/dl below the exchange transfusion threshold
• Escalation of care period starts from the time the TSM reaches the escalation of care threshold and ends when the TSB is below the escalation of care threshold
• Infants meeting criteria for escalation of care should be admitted to the NICU
• Initiating escalation of care is a medical emergency
• Infants requiring escalation of care should have STAT labs including total and direct bilirubin, CBC, albumen, serum chemistries and type and crossmatch
• Infants requiring escalation of care should receive IV hydration and emergent intensive phototherapy
• During escalation of care period TSB should be measured at least every 2 hours until the escalation of care period ends
• IVIG over 2 hours may be provided to infants with isoimmune hemolytic disease during the escalation of care period

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“Escalation of Care”

Exchange Transfusion Thresholds WITH Neurotoxicity Risk Factors

Exchange Transfusion Threshold WITHOUT Neurotoxicity Risk Factors

Exchange Transfusion

• An urgent exchange transfusion should be performed for infants with signs of intermediate or advanced stages of acute bilirubin encephalopathy
• Hypertonia, arching, retrocollis, opisthotonos, high pitched cry or recurrent apnea
• An urgent exchange transfusion should be performed for infants if the TSB is at or above the exchange transfusion threshold
• Defer if the bilirubin falls below the exchange transfusion threshold and there are np signs of encephalopathy while preparing for exchange transfusion

Bilirubin to Albumin Ratio

• The bilirubin to albumin ratio can also be used with the TSB in in determining need tor exchange transfusion
• >=8.0 if the gestational age is >=38 weeks’ gestation and there are no hyperbilirubinemia neuro- toxicity risk factors, or
• >=7.2 if the gestational age is >=38 weeks’ gestation and there is at least 1 hyperbilirubinemia neurotoxicity risk factor, or
• >=7.2 if the gestational age is 35 through 37 weeks’ gestation with no hyperbilirubinemia neurotoxicity risk factor, or
• >=6.8 if the gestational age is 35 through 37 weeks’ gestation and at least 1 hyperbilirubinemia neurotoxicity risk factor.

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Changes to Follow-Up and Discharge Planning

• If appropriate follow up for outpatient repeat bilirubin cannot be arranged, discharge may be delayed
• Use of the Bhutani nomogram is no longer recommended.
• Post-discharge follow-up will be determined by calculating the delta-TSB. Delta-TSB is the difference between the last measured bilirubin concentration and the phototherapy threshold at the time of measurement.
• EPIC still contains 2004 guideline recommendations
• www.peditools/bili2022

*Only appropriate for infants > 12 hours old and infants who have not received phototherapy before discharge

�Kuzniewicz MW, Li SX, McCulloch CE, et al. Predicting the Need for Phototherapy After Discharge: Update for 2022 Phototherapy Guidelines. Pediatrics. 2022;150(3)�

• Purpose: To quantify how well predischarge delta-TSB predicts post discharge TSB exceeding the new 2022 AAP phototherapy thresholds
• Method: Retrospective cohort
• Population: N=146,679 >35 weeks universally screened for TSB.
• Measure: delta-TSB = difference between the measured bilirubin and the age specific treatment threshold at the time bilirubin was measured
• Outcomes – TSB level above the 2022 AAP Phototherapy threshold at <24 hours, <48 hours or < 30 days from the predischarge TSB

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Kuzniewicz MW, Li SX, McCulloch CE, et al. Predicting the Need for Phototherapy After Discharge: Update for 2022 Phototherapy Guidelines. Pediatrics. 2022;150(3)

Home Phototherapy

• Newborns with TSB above treatment threshold after discharge from birth hospitalization can be treated at home with an LED based phototherapy device if they meet the following criteria:
• Gestational age >= 38 weeks
• >= 48 hour old
• Clinically well with adequate feeding
• No neurotoxicity risk factors
• No previous phototherapy
• TSB <= 1mg/dl above phototherapy treatment threshold
• LED based phototherapy device available in the home with no delay
• TSB can be measured daily
• It is an option to start home phototherapy at a lower threshold (2 mg/dl below phototherapy threshold) to reduce readmission risk

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Home Phototherapy

• Effectiveness depends on the the quality of the home phototherapy device and the ability of the family to use it
• Not recommended for infants with neurotoxicity risk factors
• Feeding should be maintained. Interrupting phototherapy for breastfeeding dies not impact the overall effectiveness of treatment.
• Minimize interruptions if bilirubin level is approaching escalation of care
• For infants receiving home phototherapy the TSB should be measured daily
• Infants should be readmitted if the TSB increases and the delta TSB narrows or if the TSB is >1 mg/dl above the phototherapy threshold

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Discontinuing Phototherapy

• Consider when TSB has decreased by at least 2 mg/dl below treatment threshold at the initiation of phototherapy
• Rebound hyperbilirubinemia = TSB that reaches the phototherapy threshold for the infants age within 72-96 hours of discontinuing phototherapy
• Gestational age < 38 week, age < 48 hours at the start of phototherapy and hemolytic disease are risks for rebound hyperbilirubinemia
• Follow up testing after discontinuing phototherapy should take place at least 12 hours and preferably 24 hours after stopping phototherapy

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