Neonatal jaundice affects more than 80% of newborns and is the most common cause of readmission after discharge from the nursery. From the day of discharge to day 5 after birth is critical because the bilirubin level peaks during this period for most neonates. In 2022, the American Academy of Pediatrics (AAP) updated its 2004 clinical practice guideline and 2009 commentary that included clarification and modifications for the postnursery management of healthy neonates. Based on evaluation of evidence published since 2004, the AAP clinical practice committee raised the phototherapy thresholds by a narrow range that the committee considered to be safe, revised the risk assessment approach based on the hour-specific bilirubin concentration, and defined an “escalation of care” approach to rapidly address elevated bilirubin concentrations. The primary aim of postdischarge jaundice evaluation is to avoid severe hyperbilirubinemia, which can impose a risk of bilirubin toxicity to the central nervous system.

The 2022 AAP clinical guideline provides specific recommendations and evidence-based “key action statements” focused on 1) prevention of hyperbilirubinemia, 2) assessment and monitoring for hyperbilirubinemia, 3) treatment of hyperbilirubinemia, 4) postdischarge follow-up, and 5) hospital policies and procedures (Table). Prevention begins with identification and treatment of pregnant people at risk for developing antibodies to red blood cell antigens, which can lead to hemolytic disease in the newborn. Providing feeding support during the birth hospitalization is paramount because exclusive breastfeeding and hyperbilirubinemia are strongly associated. Every neonate should be screened 24 to 48 hours after birth, or before discharge if that occurs earlier, with either a transcutaneous bilirubin (TcB) or a total serum bilirubin (TSB) level. The same approach is recommended for infants born at home.

Table.

Strategies in the Management of Neonatal Hyperbilirubinemia of Infants ≥35 Weeks’ Gestation

PREVENTION OF HYPERBILIRUBINEMIAASSESSMENT AND MONITORING FOR HYPERBILIRUBINEMIATREATMENT OF HYPERBILIRUBINEMIAPOSTDISCHARGE FOLLOW-UPHOSPITAL POLICIES AND PROCEDURES
Prevent hyperbilirubinemia associated with isoimmune hemolytic disease Identifying risk factors for hyperbilirubinemia Providing phototherapy Timing of follow-up after discharge Clinician documentation 
Providing feeding support Identifying the need for treatment Prolonged indirect hyperbilirubinemia Use the difference between the bilirubin concentration and the phototherapy threshold at the time of measurement to determine the interval between discharge and follow-up and the need for additional total serum bilirubin or transcutaneous bilirubin screening Nursing protocols with standing orders for assessment and bilirubin testing in the first 24 h 
 Visual estimation of total serum bilirubin concentrations Monitoring infants receiving phototherapy Incorporate gestational age and other hyperbilirubinemia neurotoxicity risk factors (postnatal age, assessment of breastfeeding, weight loss from birth, assessment of infant and parental well-being) into the decision-making process Written and verbal education for families in their preferred language and appropriate information about newborn jaundice, warning signs, and required postdischarge testing and follow-up care 
 Transcutaneous bilirubin levels Discontinuing phototherapy   
 Evaluating elevated direct-reacting or conjugated bilirubin concentrations Follow-up after phototherapy   
  Escalation of care and providing an exchange transfusion   
PREVENTION OF HYPERBILIRUBINEMIAASSESSMENT AND MONITORING FOR HYPERBILIRUBINEMIATREATMENT OF HYPERBILIRUBINEMIAPOSTDISCHARGE FOLLOW-UPHOSPITAL POLICIES AND PROCEDURES
Prevent hyperbilirubinemia associated with isoimmune hemolytic disease Identifying risk factors for hyperbilirubinemia Providing phototherapy Timing of follow-up after discharge Clinician documentation 
Providing feeding support Identifying the need for treatment Prolonged indirect hyperbilirubinemia Use the difference between the bilirubin concentration and the phototherapy threshold at the time of measurement to determine the interval between discharge and follow-up and the need for additional total serum bilirubin or transcutaneous bilirubin screening Nursing protocols with standing orders for assessment and bilirubin testing in the first 24 h 
 Visual estimation of total serum bilirubin concentrations Monitoring infants receiving phototherapy Incorporate gestational age and other hyperbilirubinemia neurotoxicity risk factors (postnatal age, assessment of breastfeeding, weight loss from birth, assessment of infant and parental well-being) into the decision-making process Written and verbal education for families in their preferred language and appropriate information about newborn jaundice, warning signs, and required postdischarge testing and follow-up care 
 Transcutaneous bilirubin levels Discontinuing phototherapy   
 Evaluating elevated direct-reacting or conjugated bilirubin concentrations Follow-up after phototherapy   
  Escalation of care and providing an exchange transfusion   

The updated guideline emphasizes identification of risk factors for hyperbilirubinemia. These risk factors include lower gestational age, jaundice in the first 12 hours after birth, predischarge TcB or TsB concentration close to the phototherapy threshold, hemolysis, rapid rise of TcB or TsB level greater than 0.2 mg/dL (3.42 µmol/L) per hour after the first 24 hours of age, phototherapy before nursery discharge, family history of need for phototherapy, exchange transfusion or inherited blood disorders (glucose-6-phosphate dehydrogenase [G6PD] deficiency), exclusive breastfeeding with suboptimal intake or excessive weight loss, scalp hematoma or significant bruising, trisomy 21, or macrosomic infant of a diabetic mother. Decisions to initiate phototherapy or escalate care are informed by the infant’s gestational age, hour-specific TsB level, and the presence of neurotoxicity risk factors. Neurotoxicity risk factors include the degree of prematurity, serum albumin level less than 3 g/dL (<30 g/L), isoimmune hemolytic disease, G6PD deficiency, sepsis, and clinical instability. Nomograms detailing the phototherapy thresholds extending through 336 hours of age (14 days) have been constructed by gestational age and age in hours for infants with and without recognized hyperbilirubinemia neurotoxicity risk factors other than gestational age.

The 2022 guideline recommends that the timing of pediatric primary care follow-up be based on the difference between the bilirubin concentration and the phototherapy threshold at the time of bilirubin measurement to determine the interval between discharge and follow-up and the need for additional TSB or TcB measurements. This approach incorporates both gestational age and other hyperbilirubinemia neurotoxicity risk factors, the presence of other hyperbilirubinemia risk factors as described previously herein with special consideration of postnatal age, assessment of breastfeeding, weight loss from birthweight, and assessment of the well-being of the infant and parents. Nursery discharge should be delayed up to 72 to 96 hours of age for families who cannot ensure follow-up appointments.

For infants who required phototherapy before nursery discharge, the timing of follow-up bilirubin testing after discontinuing phototherapy should be based on the risk of rebound hyperbilirubinemia. In most instances, a follow-up bilirubin concentration should be obtained at least 12 hours, and preferably 24 hours, after phototherapy is discontinued to allow for sufficient time for rebound hyperbilirubinemia. A repeated bilirubin level should be measured the day after phototherapy is discontinued in infants who received phototherapy before 48 hours of age, had a positive direct antiglobulin test, or have known or suspected hemolytic disease, including G6PD deficiency, as well as infants treated with phototherapy during the birth hospitalization and readmitted for exceeding the phototherapy threshold for their age. Infants readmitted because they exceeded the phototherapy threshold after nursery discharge but who did not receive phototherapy during the birth hospitalization and infants treated with home phototherapy who exceeded the phototherapy threshold should have bilirubin measured 1 to 2 days after phototherapy discontinuation or clinical follow-up 1 to 2 days after phototherapy to determine whether bilirubin measurement is warranted. Rebound hyperbilirubinemia should be treated according to guideline recommendations for the initiation of phototherapy.

Severe neonatal hyperbilirubinemia is more common among preterm and small-for-gestational-age infants, infants of diabetic mothers, infants who are hypothyroid, and infants affected by breastfeeding jaundice or breast milk jaundice. Unconjugated hyperbilirubinemia in neonates may reflect increased bilirubin production from hemolysis (immune mediated from ABO or Rh incompatibility; nonimmune from G6PD deficiency, pyruvate kinase deficiency, or cephalohematoma) or from decreased bilirubin clearance (Crigler-Najjar or Gilbert syndrome).

Severe hyperbilirubinemia requires urgent evaluation, and the neonate should be assessed for the need for phototherapy or exchange transfusion. The threshold for phototherapy and exchange transfusion is lower for preterm neonates and for neonates with high-risk factors. A detailed evaluation is needed for severe hyperbilirubinemia or persistent jaundice, including total and direct (conjugated) bilirubin, complete blood cell count, reticulocyte count, peripheral smear, review of maternal and infant blood types, and direct antiglobulin and G6PD deficiency testing. Many health care systems do not perform routine newborn blood typing if the mother is not type O. Blood and urine cultures may be considered if the neonate exhibits signs of sepsis, such as fever, lethargy, respiratory difficulties including apnea, changes in behavioral state, and/or feeding intolerance. Note that the 2022 clinical guideline identifies that infants 7 days or older with a persistently elevated TSB level within 2 mg/dL (34.21 µmol/L) of the phototherapy threshold may have prolonged indirect hyperbilirubinemia. In the 2004 clinical guideline, persistent jaundice was categorized as duration longer than 2 weeks in term infants and longer than 3 weeks in preterm infants.

Infants whose postdischarge bilirubin level is elevated to 2 mg/dL (34.21 µmol/L) below the gestational age and age-in-hours specific exchange transfusion threshold assessed on the appropriate exchange transfusion nomogram (with no, or with any, recognized hyperbilirubinemia neurotoxicity risk factors) require escalation of care. This entails admission to a pediatric hospital unit capable of providing intensive phototherapy, providing intravenous therapy, and performing a neonatal exchange transfusion. If the infant shows signs of acute bilirubin encephalopathy (feeding difficulty, lethargy, hypertonia), an exchange transfusion is required. The severity of the infant’s symptoms can be quantified using the bilirubin-induced neurologic dysfunction score, a tool that assesses clinical signs (mental status, muscle tone, cry, suck, feeding, visible jaundice) associated with bilirubin toxicity (hypotonia followed by hypertonia, and/or opisthotonos or retrocollis).

Specific parent counseling and instructions should be included in the discharge summary about the importance of follow-up appointments in assessing jaundice and the dangers of severe hyperbilirubinemia for a neonate. On the day of discharge, written instructions should be given in the parents’ preferred language, and information should be communicated verbally to them by the nurse and clinician, with assistance of a medical interpreter as needed. Useful resources for parent counseling are provided by the AAP (https://www.healthychildren.org/English/ages-stages/baby/Pages/Jaundice.aspx) and the Centers for Disease Control and Prevention (CDC) (https://www.cdc.gov/ncbddd/jaundice/facts.html).

During postdischarge follow-up visits, adequacy of the infant’s intake and elimination patterns should be evaluated, and the infant’s weight should be measured and percentage weight loss from birthweight calculated. A helpful decision tool that calculates an infant’s weight loss is the Newborn Weight Tool nomogram (https://www.newbornweight.org). Healthy infants typically lose weight during the first 3 to 5 days after birth; then they begin to gain 15 to 30 g daily, regaining birthweight by 10 to 14 days of age. A detailed feeding history is important, with risk factors including breastfeeding problems, low milk supply, use of any maternal medications or herbal remedies, early pacifier use, and infant formula supplementation. Breastfeeding should be encouraged, with a recommendation to feed 8 to 12 times per 24 hours during the first week after birth. Formula-fed neonates should be fed 1 to 2 oz every 2 to 3 hours during the first week. Parents should be discouraged from giving water supplements.

Visual inspection of the infant is a tool that has efficacy in discriminating mild from significant jaundice that can guide the need for bilirubin testing. In the community setting, visual estimation is routinely used to guide decisions about obtaining TcB or TSB measurements in term infants 3 or more days old, for whom treatment thresholds are high enough that distinguishing between milder degrees of jaundice is not important. Clinicians should assess jaundice with the awareness that visual estimate of bilirubin level is often inaccurate, particularly for darker-pigmented neonates. Assessment for jaundice should be in a well-lit room or preferably in daylight near a window by blanching the skin with digital pressure; jaundice usually progresses in a cephalocaudal direction. If a neonate has a high risk of severe hyperbilirubinemia or if clinical assessment shows increasing jaundice, TcB or TSB screening should be considered. Many studies have validated the accuracy of noninvasive TcB, providing levels within 1 to 2 mg/dL (17.10–34.21 µmol/L) of TSB levels; but TcB levels greater than 15 mg/dL (>256.56 µmol/L) need confirmation with a TSB screen because high values are unreliable. If a portable bilimeter is used for follow-up, be aware of significant variability among devices on the market: an infant should be tested using the same device for serial screening.

Breastfeeding jaundice usually occurs in the first week after birth from inadequate feeding. Intestinal hypomotility and poor elimination of bilirubin in stool are underlying causes for breastfeeding jaundice. Affected neonates with evidence of significant weight loss need supplementation with expressed breast milk or formula.

Breast milk jaundice occurs after the first week and can persist for up to 3 weeks. Inhibition of uridine diphosphate glucuronosyltransferase by pregnanediol and deconjugation of conjugated bilirubin by β-glucuronidase in breast milk are possible underlying causes. Affected neonates usually exhibit adequate feeding and good weight gain. It is not recommended to withhold breast milk in infants with breast milk jaundice.

A conjugated or direct bilirubin level greater than 1 mg/dL (>17.10 µmol/L) when the TSB level is less than 5 mg/dL (<85.52 µmol/L) or 20% of TSB if the TSB level is greater than 5 mg/dL (>85.52 µmol/L) is significant and needs evaluation for the cause of the neonatal cholestasis, including alkaline phosphatase, γ-glutamyl transpeptidase, aminotransferase, and albumin levels; coagulation tests; TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus infection, and herpes simplex) serology; urine test for cytomegalovirus; and blood and urine cultures. Fasting abdominal ultrasonography should be considered to evaluate for evidence of biliary atresia or a choledochal cyst. The clinician should also check the infant’s newborn screening for galactosemia, and repeat testing for galactosemia and thyroid function, and perform metabolic studies (glucose, lactate, ammonia, ferritin, and serum amino acid levels). A pediatric gastroenterology consultation is required for neonates with conjugated hyperbilirubinemia without apparent cause.

Adhering to the universal postdischarge follow-up guidelines ensures the early detection of severe hyperbilirubinemia and, thereby, prevention of acute bilirubin encephalopathy. Also, early detection of neonatal cholestasis is possible only with appropriate postdischarge follow-up visits.

Several factors make neonates particularly susceptible to the development of bilirubin-induced neurotoxicity, marked by the yellow staining of brain gray matter we know as kernicterus. The postbirth transition from fetal to adult hemoglobin puts stress on a liver that is not yet fully functioning to metabolize a heavy load of breakdown bilirubin, a burden worsened if there is mother-infant ABO incompatibility or other cause of hemolysis. For unconjugated bilirubin to become water soluble, allowing it more readily to be eliminated through urine, it must undergo glucuronidation in the liver, a process that is not fully operational in the weeks after birth. The blood-brain barrier that should be a protective shield against accumulating bilirubin does not reach full integrity early in infancy, allowing bilirubin to cross more easily into the central nervous system, where it attaches to gray matter and induces the encephalopathy we are trying to prevent.

–Henry M. Adam, MD

Associate Editor, In Brief

AUTHOR DISCLOSURE:

Drs Balasundaram and Campbell have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.

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