Predict, Prevent and Manage Severe Hyperbilirubinemia in Term and Late Preterm Newborns

- Executive summary

A practical guideline for Prediction, Prevention and Management of Severe Hyperbilirubinemia in Term and Late Preterm Newborns has been adapted to fit the Egyptian healthcare system. This process of customizing existing evidence-based clinical practice guidelines for local contexts offers a practical alternative to creating new ones from scratch, potentially enhancing their usefulness while conserving resources. This guideline aims to provide practical guidance for Prediction, Prevention and Management of Severe Hyperbilirubinemia in Term and Late Preterm Newborns in Egypt, as well as the adaptation methods employed to create Egyptian National Guideline for Prediction, Prevention and Management of Severe Hyperbilirubinemia in Term and Late Preterm Newborns using the Adapted ADAPTE method. The entire adaptation process, encompassing the setup, adaptation, and finalization phases, is thoroughly described. This involved a guideline adaptation group (GAG) and an external review group by experts in clinical content.

The finalized adapted CPG provides pediatricians and healthcare workers in the field of neonatology in Egypt with practical, evidence-based guidance for Prediction, Prevention and Management of Severe Hyperbilirubinemia in Term and Late Preterm Newborns. This initiative underscores the effectiveness of the Adapted ADAPTE method and emphasizes the significance of collaboration between clinical and methodological experts in adapting national guidelines.

Guideline’s development and methods:

·       After reviewing all the inclusion and exclusion criteria and quality appraisal results, the GDG/ GAG recommended using the following source original clinical practice guidelines (CPGs):

Clinical practice guideline revision: Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. AAP 2022.

·       We conducted Adolopment for these guidelines: (Adoption and Development):

Ø Adoption for most of the guideline recommendations.

Ø Development of Good Practice Statements.

Guideline registration:

Will be registered in: http://www.guidelines-registry.org.

 Recommendations and Good Practice Statements (GPS):

·   All pregnant women should be tested to determine their ABO blood group and Rh (D) type and receive an antibody screen to determine the need for Rh (D) immunoglobulin (RhIG) and to assess the potential for isoimmune hemolytic disease of the fetus or newborn. SoR: GPS

·   If the maternal antibody screen is positive or unknown because the mother did not have prenatal antibody screening, the infant should have a direct antiglobulin test (DAT) and the infant’s blood type should be determined as soon as possible using either cord or peripheral blood. SoR: Strong

· If the maternal blood group is unknown, testing for maternal and infant blood group as well as DAT is essential in any case of early jaundice. SoR: GPS

·       Clinicians should promote frequent breastfeeding on demand and recommend starting  within the first hour after birth and should provide breastfeeding support for all mothers. SoR: GPS

·       Oral supplementation with water or dextrose water should NOT be provided to prevent hyperbilirubinemia or decrease bilirubin concentrations. SoR: Strong

·       All infants should be visually assessed for jaundice at least every 12 hours following delivery until discharge. TSB or TcB should be measured as soon as possible for infants noted to be jaundiced < 24 hours after birth. SoR: GPS

·       TcB or TSB should be measured for ALL babies between 24 and 48 hours after birth or before discharge if that occurs earlier. SoR: Conditional

·       If appropriate follow up cannot be arranged for an infant recommended to have an outpatient follow up bilirubin measure, discharge may be delayed. SoR: Conditional

·       Before discharge, all families should receive WRITTEN and VERBAL EDUCATION about neonatal jaundice. SoR: GPS

·       Beginning at least 12 hours after birth, if discharge is being considered, the difference between the bilirubin concentration measured closest to discharge and the phototherapy threshold at the time of the bilirubin measurement should be calculated and used to determine follow-up appointments. SoR: conditional

·       Infants with risk factors for hyperbilirubinemia (Table-8) as determined by history of risk factors, family history, examination and laboratory results require closer monitoring than infants without risk factors. SoR: GPS

·       Elevated TSB in a formula fed infant or late onset jaundice should raise the possibility of G6PD. SoR: GPS

·       Use TSB as the definitive test to guide phototherapy and escalation-of-care decisions, including exchange transfusion. SoR: GPS

·       Decisions to initiate phototherapy or escalate care are guided by the gestational age, the TSB, and the presence of risk factors for bilirubin neurotoxicity (Table-9). SoR: GPS

·       A TSB measurement should be performed on every infant who is jaundiced in the first 24 hours after birth. SoR: Strong

·       TSB should be measured if TCB exceeds or is within 3 mg /dl of phototherapy treatment threshold or if TcB is ≥ 15mg/dL. SoR: Conditional

·       If more than 1 TcB or TSB measure is available, the rate of increase of bilirubin may be used to identify infants at higher risk of subsequent hyperbilirubinemia.  A rapid rate of increase (≥ 0.3 mg/dL per hour in the first 24 hours or ≥ 0.2 mg/dL per hour thereafter) is exceptional and suggests hemolysis. In this case, a DAT should be performed if not previously done. SoR: Conditional

·       The formal assessment of babies with gestational age ≥35 weeks presenting with indirect neonatal hyperbilirubinemia:

-   History and family history (risk factors for hyperbilirubinemia and risk factors for neurotoxicity)

-   Clinical examination (general / signs of neurotoxicity (BIND score).

-   Laboratory assessment:

-  Complete blood count and reticulocyte count.

-  TSB

-  Maternal and child blood group and Rh.

-  DAT test.

-  Further investigations as required. SoR: GPS

·  - Assessment for acute bilirubin encephalopathy should be done in every jaundiced baby with risk factors for neurotoxicity (Table-9) or any severely jaundiced baby using modified BIND score. SoR: Conditional

·  For breastfed infants who are still jaundiced at 3-4 weeks of age and for formula fed infants who are still jaundiced at 2 weeks of age, the total and direct reacting or (conjugated) bilirubin concentration should be measured to identify possible pathologic cholestasis. SoR: Conditional

·   Infants who have an elevation of direct reacting or conjugated bilirubin should have a urine analysis and culture. Additional laboratory evaluation for sepsis should be performed if indicated by history and physical examination (Table-11). SoR: Stong

·       All nurseries and NICUs treating infants should have the necessary equipment to provide intensive phototherapy (Table-12). SoR: Conditional

·       Intensive phototherapy is recommended at the TSB threshold in (Figures-4 & 5) on the basis of gestational age, hyperbilirubinemia neurotoxicity risk factors and age of infant in hours. SoR: GPS

·       The direct reacting or conjugated bilirubin value should not be subtracted from the total bilirubin value when determining management. SoR: GPS

·       In breastfed infants on conventional phototherapy, it is recommended that, if possible, breastfeeding should be continued while withholding phototherapy for the duration of the feed (max 20 minutes). If TSB is approaching escalation of care level, the infant should not come out of phototherapy to feed, as this is a medical emergency. SoR: Strong

·       In breastfed infants receiving phototherapy, supplementation with expressed breast milk or formula is appropriate if the infant’s intake seems inadequate, weight loss is excessive, or the infant is dehydrated. SoR: Strong

·       Routine intravenous fluids are NOT necessary for term or near-term infants receiving phototherapy unless there is evidence of dehydration or if TSB is approaching escalation of care threshold. SoR: Strong

·       For hospitalized infants, TSB should be measured within 12 hours after starting phototherapy. The timing of the initial TSB measurement after starting phototherapy and the frequency of monitoring during phototherapy should be guided by the age of the child, the presence of hyperbilirubinemia neurotoxicity risk factors, the TSB concentration and TSB trajectory. SoR: GPS

·       For infant requiring phototherapy measure the hemoglobin concentration, hematocrit, or complete blood count to assess the presence of anemia and to provide a base line in case subsequent anemia develops. SoR: GPS

·       Evaluate the underlying cause or causes of hyperbilirubinemia:

-  In infants who require phototherapy by obtaining a DAT.

-   In infants whose mother had a positive antibody screen.

-   Or whose mother is blood group O, regardless of Rh status.

-   Or whose mother is Rh (D) negative. SoR: GPS

·       G6PD activity should be measured in:

·        Any infant with jaundice of unknown cause whose TSB:

-  increases despite intensive phototherapy.

-  increases suddenly

-  increases after an initial decline or who requires escalation of care.

·       Any infant who requires escalation of care. SoR: GPS

·       Monitoring TSB for infants receiving intensive phototherapy without signs of ABE:

·       If TSB ≥ 25 mg/dL, repeat TSB within 2–3 h.

·       If TSB 20–25 mg/dL, repeat within 3–4 h.

·       If TSB <20 mg/dL repeat in 4–6 h.

·       If TSB continues to fall, repeat in 8–12 h.

·       Consider exchange transfusion if TSB is not decreasing or is moving closer to the level for exchange transfusion. SoR: Strong

·      Discontinuing phototherapy is an option when TSB has decreased by at least 2 mg / dL below the hour specific threshold at the initiation of phototherapy. A longer period of phototherapy is an option if there are risk factors for rebound hyperbilirubinemia (e.g. Gestational age < 38 weeks, age < 48 hours at the start of phototherapy, hemolytic disease. SoR: Conditional

·       Repeat bilirubin measurement after phototherapy is based on the risk of rebound hyperbilirubinemia. Risk factors are:

·       Infants who received phototherapy before 48 hours.

·       Infants who had a positive DAT.

·       Infants who had known or suspected hemolytic disease.

·       Infants with risk for hyperbilirubinemia and hyperbilirubinemia neurotoxicity risk factors (Table-8 and 9). SoR: GPS

·       In the presence of one of the above risk factors: TSB should be measured for rebound at 6-12 hours after phototherapy discontinuation. All other infants should be followed up for TSB after 24 hours of discontinuation of phototherapy. SoR: GPS

·      Care should be escalated when an infant’s TSB reaches or exceeds the escalation of care threshold defined as 2 mg /dl below the exchange transfusion threshold. The direct reacting or conjugated bilirubin value should not be subtracted from the total bilirubin value when determining management. SoR: GPS

·       For infants requiring escalation of care, blood should be sent STAT for total and direct reacting serum bilirubin, a complete blood count, serum albumin, serum chemistries and blood type and cross match. SoR: GPS

·       Infants requiring escalation of care should receive intravenous hydration and emergent intensive phototherapy. A neonatologist should be consulted about urgent transfer to a NICU that can perform an exchange transfusion. SoR: Conditional

·       TSB should be measured at least every 2 hours during the escalation period. Once the TSB is lower than the escalation of care threshold, continue phototherapy according to the bilirubin level. SoR: GPS

·       Intravenous immunoglobulin (IVIG) (0.5-1 g/kg over 2 hours) may be provided to infants with isoimmune hemolytic disease (i.e., positive DAT) whose TSB reaches or exceeds the escalation of care threshold.  This dose can be repeated in 12 hours. SoR: Conditional

·       Urgent exchange transfusion should be performed for infants with signs of intermediate or advanced stages of acute bilirubin encephalopathy (Table-10). SoR: Conditional

·       An urgent exchange transfusion should be performed for infants if the TSB ≥ the exchange transfusion threshold (Figure-7 and 8). If while preparing for exchange transfusion but before starting the exchange transfusions, a TSB concentration is below the exchange transfusion threshold and the infant does NOT show signs or intermediate or advanced stages of ABE, then the exchange transfusion may be deferred while continuing intensive phototherapy and following TSB every 2 hours until the TSB is below the escalation of care threshold. SoR: Conditional

·       Use the following medications with caution in a baby with hyper-bilirubinemia as they may cause bilirubin to be displaced from albumin binding sites and increase the risk of ABE:

·       Konakion.

·       Digoxin.

·       Diazepam.

·       Salicylates.

·       Diuretics e.g., furosemide and hydrochlorothiazide.

·       Ceftriaxone.

·       Ibuprofen.

·       Sulfamethoxazole such as in trimethoprim/sulfamethoxazole (cotrimoxazole). SoR: Conditional

·       The use of any of the following medications for the treatment of hyperbilirubinemia is NOT RECOMMENDED (Phenobarbitone, Agar, Clofibrate, albumin, charcoal, cholestyramine, D penicillamine, glycerine, riboflavin, homeopathy, and metalloporphyrins). SoR: Conditional

·       Any infant with severe neonatal hyperbilirubinemia should receive a hearing screen including brainstem auditory evoked potentials (ABR) for the early diagnosis of auditory dys-synchrony or sensory neural hearing loss and timely intervention. SoR: Conditional

·       Infants who required exchange transfusion or those who exhibit neurological abnormalities with history of neonatal jaundice require regular neurological follow up. SoR: Conditional

·       Infants with isoimmunization are at risk of severe anemia after several weeks (up to 8-12 weeks of age); Repeat hemoglobin measurement should be performed at two weeks if it was low at discharge and at four weeks if it was normal. SoR: Conditional

·       Infants suspected to have G6PD deficiency (elevated TSB in formula infants or late onset jaundice) should be tested at 3 months of age. SoR: Conditional