Approach
The main goal of treatment for unconjugated hyperbilirubinemia is to prevent bilirubin toxicity, specifically bilirubin encephalopathy and kernicterus.[7][33][34][35][36][47] Infants with risk factors for significant hyperbilirubinemia require closer monitoring and escalation of care.[7] Decisions regarding management are guided by the gestational age, the hour-specific total serum bilirubin (TSB), and the presence of risk factors for bilirubin neurotoxicity (gestational age <38 weeks, albumin <3.0 g/dL, serious illness in the newborn infant, [e.g., sepsis or significant clinical instability in the previous 24 hours], or isoimmune hemolytic disease, glucose-6-phosphate deficiency or other hemolytic conditions).[7]
Unconjugated hyperbilirubinemia
Phototherapy
Phototherapy is recommended based on TSB thresholds in correlation with gestational age, hyperbilirubinemia neurotoxicity risk factors, and age of the infant in hours.Thresholds are provided in the American Academy of Pediatrics guidelines. Phototherapy should be initiated if the TSB level is above or at the threshold.[7] Clinicians should consult local guidelines for treatment thresholds.
Phototherapy uses light energy to cause photochemical reactions to transform bilirubin into isomers that are less lipophilic and more easily excretable, and make breakdown products that do not require conjugation in the liver. Bilirubin absorbs visible light most strongly in the blue region of the spectrum (around 460 nm) and the most effective phototherapy wavelengths are from 425 nm to 490 nm.[48][49]
Double-light phototherapy is often considered to be more effective than single-light or fiberoptic phototherapy.[50][51][52] Fiberoptic and light-emitting diode (LED) phototherapy units are alternatives to conventional phototherapy in term neonates.[53][54][55][56] [
]
LED phototherapy is as efficacious as conventional therapy, and overhead use (versus illumination from beneath the infant) shortened the mean duration of phototherapy and increased the rate of decrease in total serum bilirubin (TSB).[55][56][57][58][59]
[ ]
Special blue compact fluorescent lamp phototherapy had no superiority over special blue standard length tube light phototherapy in terms of efficacy and adverse effects on the neonate and effects on nursing staff.[60]
The risk/benefit profile is excellent, with immediate onset of action on switching on the phototherapy light. Adverse effects are generally mild and include insensible water loss, loose stools, skin rash, and potential retinal damage. These can be prevented by maintaining adequate hydration and ensuring the baby wears eye shields during phototherapy; however, there is no evidence to support this recommendation.[49] It is important that a clinician monitors and maintains adequate hydration, nutrition and temperature control during phototherapy.[49] While there is limited information, it has been suggested that phototherapy may limit familial bonding. Hence, it would be advisable to balance the benefit versus adverse effects of treatment threshold of phototherapy treatment in the management of hyperbilirubinemia in infants ≥35 weeks of gestational age.[7][61]
Two large retrospective studies showed an association between neonatal phototherapy and childhood epilepsy, but not febrile seizures.[62][63] In both studies, the effect was seen only in boys. While the sex difference may be attributed to the known increased susceptibility of male infants to perinatal injury, how phototherapy increases the risk of childhood seizures is not known. These data are limited for several reasons, including lack of information about the dose or type of phototherapy used and reliance on International Classification of Diseases (ICD)-11 codes for some of the covariate data. Nevertheless, it may be prudent to initiate phototherapy strictly at threshold values (i.e., avoiding prophylactic treatment) and to terminate it once serum bilirubin falls below these levels.
One randomized controlled trial reported that aggressive phototherapy did not impact on the outcome of neurodevelopmental impairment or death in extremely low birth weight (ELBW) infants (birth weight <1000 g), compared with conservative phototherapy.[64] However, a systematic review of 9 studies showed that prophylactic phototherapy may reduce long-term neurodevelopmental impairment.[65] [
]
While aggressive phototherapy did reduce the rate of neurodevelopmental impairment alone, there was an increase in mortality among infants with birth weights 500 g to 750 g.[64] Hence, an aggressive phototherapy approach is not recommended for ELBW infants.One Cochrane review found that the use of reflective curtains during phototherapy resulted in the reduction of serum bilirubin.[66] [
]
[Evidence B]For hospitalized infants, TSB should be measured within 12 hours after starting phototherapy - the timing of this measurement and frequency of TSB monitoring during phototherapy is based on the age of the child, presence of hyperbilirubinemia neurotoxicity risk factors, and the level and rate of rise of the TSB.[7]
Home LED-based phototherapy may be considered in patients who are already discharged who meet specific criteria and the TSB should be measured daily.[7] Monitor closely for the need to have inpatient phototherapy.
A decision to discontinue phototherapy can be considered when the TSB has decreased by at least 2 mg/dL below the hour-specific threshold at the initiation of phototherapy. If there are risk factors for rebound hyperbilirubinemia (gestational age <38 weeks, age <48 hours at the start of phototherapy, hemolytic disease), then a longer period of treatment is an option.[7]
A follow-up bilirubin test is required after discontinuing phototherapy after at least 12 hours, and preferably 24 hours to allow time to demonstrate any rebound hyperbilirubinemia.[7]
Breast-feeding/bottle-feeding can be continued in most circumstances while on phototherapy. Oral supplementation with water or glucose is not recommended.[7] Temporary interruption of breast-feeding is very rarely needed, but it may be considered for specific clinical scenarios in which rapid reduction in TSB is urgently needed or if phototherapy is unavailable.[7]
Escalation of care
Some infants with elevated or rapidly increasing bilirubin concentrations require escalation of care, with optimal management in a neonatal intensive care unit, to prevent the need for an exchange transfusion and possibly to prevent kernicterus.
Exchange thresholds are outlined by the American Academy of Pediatrics by gestational age for infants with or without recognized hyperbilirubinemia neurotoxicity factors other than gestational age.[7]
Escalation of care should be initiated when an infant’s TSB reaches or exceeds the escalation-of-care threshold which is defined as 2 mg/dL below the exchange transfusion threshold.[7]
Supportive management includes intravenous hydration and intensive phototherapy.[7][67][68]
TSB should be measured at least every 2 hours from the start of the escalation-of-care period.[7]
Exchange transfusion
A decision to undertake an urgent exchange transfusion is made when an infant’s TSB is at or above the exchange transfusion threshold.[7]
Immediate exchange transfusion is also indicated if there are clinical signs of acute bilirubin encephalopathy such as hypertonia, arching, retrocollis, opisthotonos, high-pitched cry, or recurrent apnea, even if the TSB is falling.[7]
The risk of acute bilirubin encephalopathy is also high when lower bilirubin levels are associated with additional risk factors, such as isoimmune hemolytic disease, glucose-6-phosphate dehydrogenase deficiency, temperature instability, significant lethargy, perinatal asphyxia, sepsis, acidosis, and albumin level <3 g/dL (if measured).[7]
Exchange transfusion should also be considered if the jaundice is refractory to phototherapy (e.g., bilirubin not decreasing after 4-6 hours of phototherapy).
Albumin transfusion can be considered prior to exchange transfusion, though the efficacy of these interventions has not been shown to be consistently useful.[69][70][71]
Phototherapy should be continued while preparing for the exchange transfusion and continued after the procedure as necessary while repeating TSB measurements on the relevant nomograms in order to assess the requirement for continuing phototherapy or repeat exchange transfusions.
Cross-matched washed packed red blood cells mixed with thawed adult fresh-frozen plasma to a hematocrit approximating 40% is preferred for exchange transfusions.[7]
In addition to the above criteria, a bilirubin to albumin ratio (along with gestational age and risk) can be used in conjunction with the TSB level in determining the need for exchange transfusion.[7]
Intravenous immune globulin (IVIG)
Use of IVIG in neonatal unconjugated hyperbilirubinemia secondary to hemolytic disease is controversial. IVIG has been shown to significantly reduce the need for exchange transfusions, but there are no definitive data proving its efficacy.[72][73] The reasons for this discrepancy remain unexplained. One 2018 Cochrane review of 9 studies with 658 term and preterm infants with rhesus or ABO (or both) incompatibility, concluded that further studies are needed before the use of IVIG for the treatment of alloimmune hemolytic disease of the newborn can be recommended.[74] [
]
Based on current evidence, it is recommended that IVIG treatment in infants ≥35 weeks of gestational age with a positive direct antiglobulin test be limited to those in whom the TSB is rising despite intensive phototherapy or is near the exchange level (within 2-3 mg/dL) and there is concern that an exchange transfusion may not occur in a timely manner.[7][61]
Conjugated hyperbilirubinemia
Conjugated bilirubin measured within the first 24-48 hours of life and even after, should be normal (i.e., <95%). Neonates being investigated for conjugated hyperbilirubinemia should have prompt follow-up to rule out cholestasis and biliary atresia in a timely fashion.[75] The management of conjugated hyperbilirubinemia is dependent on its etiology. Phototherapy is contraindicated in these patients as it may lead to "bronze baby" syndrome. Simple or exchange transfusions are not indicated. Consultation with an appropriate specialist may be required for further management, depending on the etiology.
Physiologic jaundice
No treatment is required for physiologic jaundice.
Breast-feeding-associated jaundice
“Suboptimal intake hyperbilirubinemia” associated with inadequate breast milk intake typically peaks on days 3-5 after birth and is frequently associated with excess weight loss. Decreased stool frequency leads to an increased enterohepatic circulation of bilirubin. Early optimizing of breast-feeding and consideration of additional enteral intake if there is clinical or laboratory evidence that breast-feeding is compromised may help to mitigate the risk of subsequent hyperbilirubinemia.[76]
“Breast milk jaundice” or the “breast milk jaundice syndrome,” in contrast, persists up to 3 months despite adequate human milk intake and optimal weight gain, and is almost always nonpathologic.[7][76] Breastfed infants who are adequately hydrated should not routinely receive supplementation. Temporary supplementation with infant formula and temporary interruption of breast-feeding is very rarely indicated, and should be made jointly with the infant’s parents, when possible, after discussion of risks and benefits.[7]
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