INTRODUCTION — Newborn infants are at risk for elevated total serum or plasma bilirubin (TB) levels. Term and late preterm infants (gestational age ≥35 weeks) with a TB >25 mg/dL (428 micromol/L) or "severe" hyperbilirubinemia are at risk for developing bilirubin-induced neurologic dysfunction (BIND), which occurs when bilirubin crosses the blood-brain barrier and binds to brain tissue resulting in neurologic injury if not treated appropriately or in a timely fashion (figure 1). (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Epidemiology and clinical manifestations", section on 'Bilirubin-induced neurologic dysfunction (BIND)'.)

An overview of the management of unconjugated hyperbilirubinemia, including prevention and treatment of severe hyperbilirubinemia in term and late preterm infants is reviewed here. The clinical manifestations, evaluation, pathogenesis, and etiology of this disorder are discussed separately. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Epidemiology and clinical manifestations" and "Unconjugated hyperbilirubinemia in term and late preterm infants: Screening" and "Unconjugated hyperbilirubinemia in the newborn: Pathogenesis and etiology".)

DEFINITIONS — Although there is no consensus amongst experts in the field in defining the clinical significance of varying total serum or plasma bilirubin (TB) levels for term and late preterm infants, the authors use the following definitions in this topic based on their experience.

●Benign neonatal hyperbilirubinemia is a transient and normal increase in TB levels occurring in almost all newborn infants, which is also referred to as "physiologic jaundice."

●Significant hyperbilirubinemia in infants ≥35 weeks gestational age (GA) is defined as a TB >95^th percentile on the hour-specific Bhutani nomogram (figure 2) [1].

●Severe neonatal hyperbilirubinemia is defined as a TB >25 mg/dL (428 micromol/L). It is associated with an increased risk for developing bilirubin-induced neurologic dysfunction (BIND).

●Extreme hyperbilirubinemia is defined as a TB >30 mg/dL (513 micromol/L). It is associated with a higher risk for developing bilirubin-induced neurologic dysfunction (BIND).

●Bilirubin-induced neurologic dysfunction is due to brain damage from free (unbound) bilirubin that crosses the blood-brain barrier and binds to brain tissue, as evidenced by both molecular and cytological injuries of brain cells (figure 1). Clinical observational data in neonates have reported a spectrum of neurologic conditions among vulnerable neonates who have experienced an exposure to bilirubin of a lesser degree than generally associated with acute and chronic bilirubin encephalopathy (ABE and CBE, respectively). This syndrome of BIND is a major complication of an elevated TB level (generally <25 mg/dL [428 micromol/L]). These subtle clinical neuromotor manifestations include processing disorders with objective perturbations of visuomotor, auditory, speech, cognition, and language. Risk factors include prematurity, presence of hemolysis, perinatal-neonatal complications, altered bilirubin-albumin binding, and severity and duration of bilirubin exposure. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Epidemiology and clinical manifestations", section on 'Clinical manifestations'.)

•Acute bilirubin encephalopathy (ABE) is used to describe the acute manifestations of bilirubin neurotoxicity. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Epidemiology and clinical manifestations", section on 'Acute bilirubin encephalopathy'.)

•Chronic bilirubin encephalopathy (CBE), previously referred to as kernicterus, is used to describe the chronic and permanent sequelae of bilirubin neurotoxicity. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Epidemiology and clinical manifestations", section on 'Chronic bilirubin encephalopathy (kernicterus)'.)

MANAGEMENT GOAL AND OVERALL APPROACH — An association between severe hyperbilirubinemia (total serum or plasma bilirubin [TB] >25 mg/dL [428 micromol/L]) and chronic bilirubin encephalopathy (CBE), previously referred to as kernicterus, the chronic and permanent sequelae of bilirubin-induced neurologic dysfunction (BIND), was first identified in infants with extreme hyperbilirubinemia TB >30 mg/dL (513 micromol/L) due to erythroblastosis fetalis in the 1950s [2-4].

As a result, prevention of CBE has been focused on eliminating severe neonatal hyperbilirubinemia by using the following measures:

●Prevention of significant hyperbilirubinemia (TB >95^th percentile on the hour-specific Bhutani nomogram (figure 2)) by identifying at-risk infants and initiating preventive therapeutic interventions as needed. In our center, universal screening of all term and late-preterm infants identifies at-risk neonates for hyperbilirubinemia. In these patients, phototherapy is initiated to prevent hyperbilirubinemia when TB exceeds a threshold level based upon hour-specific TB levels dependent upon the infant's age-in-hours and gestational age (GA), and the presence or absence of additional risk factors (algorithm 1 and figure 3 and table 1) (calculator 1) [1,5]. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Screening", section on 'Screening approach'.)

●Reduction of TB in infants with hyperbilirubinemia using the following interventions:

•Enhanced enteral nutrition as a component of general supportive care for all infants to enhance bilirubin excretion. This includes promotion of human milk feeding, prevention of significant body weight loss (defined as more than 10 percent of birth weight 48 hours after delivery) and enhancing maternal milk production [6]. (See "Initiation of breastfeeding".)

•Interventions used to reduce TB levels for infants at risk for severe hyperbilirubinemia include (see "Unconjugated hyperbilirubinemia in the newborn: Interventions"):

-Phototherapy ‒ Phototherapy is the initial intervention used to reduce TB levels.

-Exchange transfusion ‒ Exchange transfusion is an increasingly rarely used intervention that is typically reserved for infants who are symptomatic, have severe hyperbilirubinemia with increasing TB, have rapidly-rising TB levels (rate of raise >0.2 mg/dL per hour [3.4 micromol/L]), or at risk for severe hyperbilirubinemia with failure to respond adequately to intensive phototherapy.

Infants who are close or meet the criteria for exchange transfusion should be directly admitted or transferred to a neonatal intensive care unit (NICU). Referral should not be made to an emergency department (ED) if the infants is being readmitted because this will delay the initiation of treatment [7]. Urgent and intensive phototherapy (referred to as "crash-cart" phototherapy) is provided during the interim time period needed to set up for the procedure. On admission, a type and crossmatch of the infant's blood and placement of an umbilical catheter are performed promptly, so that exchange transfusion, if needed, can be started as quickly as possible. (See "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Phototherapy' and "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Exchange transfusion'.)

The indications for when to intervene and for which intervention to use are discussed in the following section and are consistent with the 2004 American Academy of Pediatrics (AAP) guideline [8]. Details regarding phototherapy and exchange transfusion are discussed separately. (See "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Phototherapy' and "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Exchange transfusion'.)

ASSESSMENT OF RISK SEVERITY — The decision of when to initiate therapy and the choice of intervention are based on an infant's probability of developing severe hyperbilirubinemia (defined as total serum or plasma bilirubin [TB] >25 mg/dL [428 micromol/L]). The risk severity assessment uses hour-specific TB values and the presence or absence of additional risk factors (including gestational age [GA] <38 weeks), which increase the risk of developing bilirubin-induced neurologic dysfunction (BIND) (figure 3 and figure 4 and algorithm 1). Factors that increase the risk of unconjugated hyperbilirubinemia include isoimmune hemolytic disease and other hemolytic red blood cell disorders (eg, glucose-6-phosphate dehydrogenase deficiency [G6PD]), asphyxia, lethargy, temperature instability, sepsis, acidosis, hypoalbuminemia (albumin <3 g/dL), East Asian ethnicity, and inadequate fluid intake with excessive weight loss (table 1) [5]. This approach of assessing risk severity is consistent with the practice guidelines developed by the American Academy of Pediatrics (AAP) [1] and the United Kingdom's National Institute for Health and Clinical Excellence (NICE guideline for neonatal jaundice). Similar national guidelines have also been developed in Norway, which are based on TB values, birth weight, and postnatal age [9]. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Screening", section on 'Risk assessment' and "Unconjugated hyperbilirubinemia in term and late preterm infants: Screening", section on 'Additional evaluation'.)

The risk for severe hyperbilirubinemia and the threshold for intervention either with phototherapy or exchange transfusion may be determined using the newborn hyperbilirubinemia assessment calculator based on TB values and the presence of concomitant risk factors (calculator 1).

The bilirubin/albumin (B/A) molar ratio can be used as an additional factor in determining the need for exchange transfusion; it should not be used alone, but in conjunction with TB values [1,10]. In term neonates, a B/A molar ratio >7 (bilirubin mg/dL to albumin g/dL) indicates that all bilirubin binding sites on albumin are occupied. Any further increases in bilirubin can lead to elevated levels of free (unbound) bilirubin, which can cross the blood-barrier result in a higher (unmeasured) risk of neurotoxicity (figure 1) [11]. In preterm infants, additional confounding factors may affect the ability of albumin to bind bilirubin, making it more challenging to predict their bilirubin binding capacity (BBC) [12]. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Screening", section on 'Additional evaluation' and "Unconjugated hyperbilirubinemia in the preterm infant (less than 35 weeks gestational age)", section on 'Other tests'.)

CRITERIA FOR INTERVENTION BASED ON RISK SEVERITY ASSESSMENT

Term infants without risk factors

●Phototherapy indications (figure 3) – For well infants ≥38 weeks gestational age (GA), phototherapy is started at the following total serum or plasma bilirubin (TB) values based on the age of the patient:

•24 hours of age – >12 mg/dL (205 micromol/L)

•48 hours of age – >15 mg/dL (257 micromol/L)

•72 hours of age – >18 mg/dL (308 micromol/L)

●Exchange transfusion indications (figure 4) – For well infants ≥38 weeks GA, exchange transfusion is indicated at the following TB values based on the age of the patient in infants who have not responded to intensive phototherapy:

•24 hours of age – >19 mg/dL (325 micromol/L)

•48 hours of age – >22 mg/dL (376 micromol/L)

•72 hours of age – >24 mg/dL (410 micromol/L)

•Any age greater than 72 hours – ≥25 mg/dL (428 micromol/L)

In our practice, we consider exchange transfusion for asymptomatic term (≥38 weeks GA) infants <48 hours of age with TB >20 mg/dL (342 micromol/L) if their serum albumin is <3 g/dL only if they have failed to respond adequately to phototherapy or have signs of acute bilirubin encephalopathy (ABE). In our experience, these infants typically will have hemolytic disease and require intensive medical care. The risk of neurotoxicity is greater in these infants than in older infants over four days of age. If used, a calculated bilirubin/albumin (B/A) molar ratio >7 to 8 mg/g (indicating >70 percent of albumin binding sites occupied by bilirubin) in conjunction with TB values may be useful to indicate when to perform an exchange transfusion.

Term infants without risk factors who are readmitted with TB >25 mg/dL (428 micromol/L) are monitored closely for neurologic findings (eg, using bilirubin-induced neurologic dysfunction [BIND] scores [13]). In these patients, an exchange transfusion is indicated if they do not respond to intensive (crash-cart) phototherapy or they become symptomatic. (See 'Exchange transfusion' below and 'Symptomatic patients' below and "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Exchange transfusion' and "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Intensive phototherapy ("crash-cart" phototherapy)'.)

Term infants with risk factors or late preterm infants without risk factors

●Phototherapy indications – For term infants (≥38 weeks GA) with risk factors for hyperbilirubinemia (table 1) or late preterm infants (35 to 37 6/7 weeks GA) without risk factors, phototherapy is started at the following TB values based on the age of the patient:

•24 hours of age – >10 mg/dL (171 micromol/L)

•48 hours of age – >13 mg/dL (222 micromol/L)

•72 hours of age – >15 mg/dL (257 micromol/L)

The threshold for intervention may be lowered for infants closer to 35 weeks GA and raised for those closer to 37 6/7 weeks GA.

●Exchange transfusion indications – For term infants (≥38 weeks GA) with risk factors for hyperbilirubinemia (table 1) or late preterm infants (35 to 37 6/7 weeks GA) without risk factors, exchange transfusion is indicated at the following TB values based on the age of the patient:

•24 hours of age – >16.5 mg/dL (282 micromol/L)

•48 hours of age – >19 mg/dL (325 micromol/L)

•≥72 hours of age – >21 mg/dL (359 micromol/L)

The threshold for intervention may be lowered for infants closer to 35 weeks GA and raised for those closer to 37 6/7 weeks GA.

In our practice, neonates with TB >17 mg/dL (291 micromol/L; 95^th percentile) should be considered for an exchange transfusion at age <48 hours if their serum albumin is <3 g/dL and have failed to respond adequately to intensive ("crash-cart") phototherapy. In addition, when used, B/A molar ratio >7 to 8 mg/g/dL in conjunction with TB values may guide a decision to prepare for an exchange transfusion. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Screening" and "Unconjugated hyperbilirubinemia in term and late preterm infants: Screening", section on 'Additional evaluation' and "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Intensive phototherapy ("crash-cart" phototherapy)'.)

Term infants with risk factors or late preterm infants who are readmitted with TB >25 mg/dL (428 micromol/L) are monitored closely for neurologic findings (eg, using BIND scores [13]). In these patients, an exchange transfusion is indicated if they do not respond to intensive ("crash-cart") phototherapy or they become symptomatic. (See 'Exchange transfusion' below and 'Symptomatic patients' below and "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Exchange transfusion' and "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Intensive phototherapy ("crash-cart" phototherapy)'.)

Late preterm infants with risk factors

●Phototherapy indications – For late preterm infants (35 to <38 weeks GA) with risk factors (table 1), phototherapy is started at the following TB values based on the age of the patient:

•24 hours of age – >8 mg/dL (137 micromol/L)

•48 hours of age – >11 mg/dL (188 micromol/L)

•72 hours of age – >13.5 mg/dL (231 micromol/L)

●Exchange transfusion indications – For late preterm infants (35 to <38 weeks GA) with risk factors (table 1), exchange transfusion is indicated at the following TB values based on the age of the patient:

•24 hours of age – >15 mg/dL (257 micromol/L)

•48 hours of age – >17 mg/dL (291 micromol/L)

•≥72 hours of age – >18.5 mg/dL (316 micromol/L)

In our practice, neonates with TB >15 mg/dL (257 micromol/L; 75^th percentile) should be considered for an exchange transfusion at age <48 hours if their serum albumin is <3 g/dL and they have failed to respond adequately to intensive ("crash-cart") phototherapy. In addition, when used, B/A molar ratio is >5.8 mg/g/dL in conjunction with TB values, an exchange transfusion may be considered.

Late preterm infants with risk factors who are readmitted with TB >18 mg/dL (308 micromol/L) are monitored closely for neurologic findings (eg, using BIND scores [13]). In these patients, an exchange transfusion is indicated if they do not respond to intensive (crash-cart) phototherapy or they become symptomatic. (See 'Exchange transfusion' below and 'Symptomatic patients' below and "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Exchange transfusion' and "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Intensive phototherapy ("crash-cart" phototherapy)'.)

Preterm infants: <35 weeks GA — The management of preterm infants <35 weeks gestational age (GA) is discussed separately. (See "Unconjugated hyperbilirubinemia in the preterm infant (less than 35 weeks gestational age)", section on 'Management approach'.)

Symptomatic patients — Exchange transfusion is indicated in infants with signs of acute bilirubin encephalopathy (ABE, significant lethargy, hypotonia, poor sucking, high-pitched cry, opisthotonos, retrocollis, or seizures) irrespective of the TB level (table 2). The procedure for exchange transfusion should be set up as soon as possible with the need to obtain matched irradiated cytomegalovirus-safe red blood cell products and vascular access. Intensive phototherapy should be provided in the interim time period. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Epidemiology and clinical manifestations", section on 'Acute bilirubin encephalopathy' and "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Exchange transfusion'.)

Rhesus isoimmune hemolytic disease refractory to phototherapy — In infants with Rhesus (Rh) isoimmune hemolytic disease, administration of intravenous immune globulin (IVIG; dose 0.5 to 1 g/kg over two hours) is suggested if the TB level is rising despite phototherapy or is within 2 or 3 mg/dL (34 to 51 micromol/L) of the threshold for exchange transfusion [1,14]. The dose may be repeated in 12 hours if necessary [1]. (See 'Intravenous immune globulin (IVIG)' below.)

Infants greater than one week of age with acute rise of TB — Infants who have acute rates of rise in total serum and plasma bilirubin (TB) levels (>0.2 mg/dL/hour, [3.42 micromol/L/hour]) who are greater than one week of age, often have glucose-6-phosphate dehydrogenase (G6PD) deficiency causing hemolysis or other intrinsic hemolytic diseases (see "Overview of hemolytic anemias in children", section on 'Intrinsic hemolytic anemias'). These infants require more urgent and aggressive interventions and are best managed in a critical setting for close monitoring of neurologic signs (eg, using BIND scores) [13], intensive ("crash-cart") phototherapy, and preparation for an exchange transfusion. Timing is critical, as delay in intervention may have deleterious effects. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Treatment of neonatal jaundice and chronic hemolysis' and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Treatment of acute hemolytic episodes'.)

Subthreshold (prophylactic) phototherapy — There is no indication to use subthreshold phototherapy (also referred to as prophylactic phototherapy). Clinicians have initiated phototherapy at subthreshold levels of TB during the birth hospitalization as a means to avoid subsequent readmission. Although the use of subthreshold phototherapy may reduce the risk of readmission, its use would result in unnecessary exposure of phototherapy, impede infant-maternal bonding, and prolong birth hospitalization [15] (see "Unconjugated hyperbilirubinemia in term and late preterm infants: Screening", section on 'Follow-up'). As a result, we suggest subthreshold phototherapy not be used in the routine care of newborns when good follow-up is arranged, as it unnecessarily exposes many infants to phototherapy (and its potential adverse effects), prolongs birth hospitalization, and increases hospital costs.

INTERVENTIONS USED TO PREVENT AND TREAT SEVERE HYPERBILIRUBINEMIA

Phototherapy — Phototherapy is the most commonly used intervention to treat and prevent severe hyperbilirubinemia. It is an effective intervention to lower total serum or plasma bilirubin (TB) and has been considered a safe intervention based upon its extensive use in millions of infants and only infrequent reports of significant adverse effects and long-term neurologic complications.

The efficacy, dosing (including selection of light sources and devices), and adverse effects of phototherapy, as well as monitoring response to and discontinuation of therapy, are discussed in detail separately. (See "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Phototherapy'.)

Exchange transfusion — Although exchange transfusion is an increasingly rare, expensive, time-consuming procedure, which requires clinical expertise; it is a potentially life-saving emergency procedure that is the most effective method for removing bilirubin rapidly. It is primarily used for symptomatic infants with moderate or advanced clinical signs of bilirubin-induced neurologic dysfunction (BIND) (table 2) when intensive phototherapy fails to prevent severe hyperbilirubinemia. Exchange transfusion is also useful for infants with increased bilirubin production resulting from Rhesus isoimmune hemolysis because circulating antibodies and sensitized red blood cells also are removed. (See "Postnatal diagnosis and management of hemolytic disease of the fetus and newborn", section on 'Hyperbilirubinemia'.)

Exchange transfusions should be performed only by trained personnel in a neonatal intensive care unit (NICU) equipped with full monitoring and resuscitation capabilities. Patients who are admitted after birth hospitalization should be admitted to the NICU to expedite the initiation of phototherapy and exchange transfusion, bypassing the emergency department and avoiding unnecessary delay of therapy [1]. During the time interval needed to set up an exchange transfusion, infants should receive intensive phototherapy ("crash-cart" phototherapy). In some cases, effective phototherapy may effectively reduce TB so that exchange transfusion can be avoided. (See "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Intensive phototherapy ("crash-cart" phototherapy)'.)

The efficacy and complications of the exchange transfusion as well as the procedure and postprocedural management are discussed separately. (See "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Exchange transfusion'.)

Intravenous immune globulin (IVIG) — Evidence is inconclusive on the benefit of IVIG in the management of neonates with severe hemolytic disease of the newborn. In our practice, we reserve the use of IVIG for infants with Rhesus isoimmune hemolytic disease who fail to adequately respond to intensive phototherapy. Data regarding the efficacy of IVIG are reviewed separately. (See 'Rhesus isoimmune hemolytic disease refractory to phototherapy' above and "Postnatal diagnosis and management of hemolytic disease of the fetus and newborn", section on 'Immune globulin therapy'.)

Unproven pharmacologic agents — Pharmacologic agents, including phenobarbital, ursodeoxycholic acid (UDCA), metalloporphyrins, and clofibrate have been used as agents that may inhibit hemolysis, increase conjugation and excretion of bilirubin, increase bile flow, or inhibit the formation of bilirubin, respectively. However, there is little evidence that these drugs are useful in the management of neonatal hyperbilirubinemia and they are not used in our center for the management of neonatal unconjugated hyperbilirubinemia.

●Ursodeoxycholic acid (UCDA) – UDCA enables the emulsification of bile in the biliary ducts. It increases bile flow, bile elimination into the gut, and helps to lower TB levels [16]. It is useful in the treatment of cholestatic jaundice (direct bilirubin >2 mg/dL). As a result, we use UCDA in infants with combined unconjugated and conjugated hyperbilirubinemia in addition to phototherapy, and those with conjugated hyperbilirubinemia alone. (See "Causes of cholestasis in neonates and young infants" and "Biliary atresia", section on 'Choleretics'.)

●Phenobarbital – Phenobarbital increases the conjugation and excretion of bilirubin and decreases postnatal TB levels when given to pregnant women or infants. However, prenatal administration of phenobarbital may adversely affect cognitive development and reproduction [17,18]. As a result, we do not recommend phenobarbital be used routinely used to treat neonatal unconjugated hyperbilirubinemia because of its clinically significant adverse effects.

●Metalloporphyrins – There are studies showing that synthetic metalloporphyrins (SnMP), such as tin mesoporphyrin, reduce bilirubin production by competitive inhibition of heme oxygenase [19-27]. However, SnMP (or other metalloporphyrins) are not approved in the United States to treat neonatal hyperbilirubinemia and is not available for general use.

●Fibrates – Fibrates including clofibrate and fenofibrate are a class of phenoxyisobutyric acid derivatives, which are peroxisome proliferator-activated receptor alpha agonists. Although they have been used in term neonates with ABO incompatibility, their efficacy and safety have not been proven [28-30]. As a result, fibrates should not be routinely used in the management of neonatal hyperbilirubinemia.

OUTCOME — When infants with hyperbilirubinemia are identified and treated appropriately, the outcome is excellent with minimal or no additional risk for adverse neurodevelopmental sequelae [31-33].

This was best illustrated in a prospective study of 140 infants with total serum or plasma bilirubin (TB) levels ≥25 mg/dL (428 micromol/L) including 10 infants with TB ≥30 mg/dL (513 micromol/L) identified from a cohort of 106,627 term or late preterm infants [31]. Treatment included phototherapy in 136 cases and exchange transfusions in five cases. The hyperbilirubinemic infants compared with the control group had a greater proportion of infants who were born <38 weeks gestational age (GA), East Asian ancestry, and exclusively breastfed during birth hospitalization. At two-year follow-up, results were as follows:

●There were no reports of kernicterus in either the severely hyperbilirubinemic or control group.

●Formal cognitive testing was performed in 82 children with neonatal severe hyperbilirubinemia and 168 control children at two and six years of age. There was no difference between patients with severe hyperbilirubinemia and matched controls in cognitive testing, reported behavioral problems, and frequency of parental/caregivers concerns.

●On physical examination, patients with severe hyperbilirubinemia (TB ≥25 mg/dL [428 micromol/L]) compared with control patients had a lower prevalence of abnormal neurologic findings (17 versus 29 percent). The degree and duration of hyperbilirubinemia had no effect on these outcomes.

●In a subset analysis, nine patients with severe hyperbilirubinemia (TB ≥25 mg/dL [428 micromol/L]) and a positive direct antiglobulin test (DAT, also referred to as Coombs test) had lower scores on cognitive testing than other patients with hyperbilirubinemia with a negative DAT. There was no difference between these two hyperbilirubinemic groups regarding the presence of an abnormal neurologic finding.

Similar findings were noted in a follow-up study from the Collaborative Perinatal Project of children (n = 46,872) at seven and eight years of age who were born ≥36 weeks GA with a birth weight (BW) ≥2000 g between 1959 and 1966 [32]. An adverse effect on cognitive testing was only seen in children who had a TB ≥25 mg/dL (428 micromol/L) and a positive DAT result as neonates. TB in the absence of a positive DAT had no effect on cognitive testing.

Population-based studies have also reported observing no or limited chronic neurologic effects of hyperbilirubinemia in countries that have implemented national or regional guidelines for management of neonatal hyperbilirubinemia:

●In a report of all live-born births in Denmark from 2004 to 2007, results based on parental survey demonstrated no difference in development at one to five years of age between infants with at least one neonatal measurement of TB ≥25 mg/dL (428 micromol/L) from controls matched by sex, age, GA, and municipality of residency [34].

●In a study from Nova Scotia of 61,238 infants born between 1994 and 2000, there were no reported cases of kernicterus after implementation of treatment guidelines [33]. There were no differences in the overall neurologic composite outcome (cerebral palsy [CP], developmental delay, hearing and vision abnormalities, attention-deficit disorder [ADD], and autism) in infants with hyperbilirubinemia with TB ≥19 mg/dL (325 micromol/L) compared with those with lower TB levels. However, subset analysis for each neurologic outcome suggested that some neurologic impairment might be associated with hyperbilirubinemia. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Epidemiology and clinical manifestations", section on 'Hyperbilirubinemia and autism'.)

●A retrospective study of 525,409 births from 1995 to 2011 delivered at 15 Kaiser Permanente Northern California hospitals failed to demonstrate an independent associated risk of autism spectrum disorder with either hyperbilirubinemia or phototherapy [35].

These results support the American Academy of Pediatrics (AAP) guideline for the management of hyperbilirubinemia in term and late preterm infants, especially the use of lower threshold values for intervention in infants with a positive DAT and evidence for ongoing hemolysis [1].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neonatal jaundice".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Jaundice in babies (The Basics)")

●Beyond the Basics topics (see "Patient education: Jaundice in newborn infants (Beyond the Basics)")

A list of frequently asked questions and answers for parents/caregivers is available through the American Academy of Pediatrics (AAP): www.healthychildren.org/English/ages-stages/baby/Pages/Jaundice.aspx

SUMMARY AND RECOMMENDATIONS

●Management goal – The management goal is to prevent kernicterus (chronic and permanent sequelae of bilirubin-induced neurologic dysfunction [BIND]). Management is focused on eliminating severe hyperbilirubinemia defined as a total serum or plasma bilirubin (TB) >25 mg/dL (428 micromol/L) by preventing neonatal hyperbilirubinemia (figure 2), and reducing TB in infants with hyperbilirubinemia. (See 'Management goal and overall approach' above and "Unconjugated hyperbilirubinemia in term and late preterm infants: Screening", section on 'Screening for hyperbilirubinemia'.)

●Risk assessment – Prevention of hyperbilirubinemia is based on identifying at-risk infants and using interventions to reduce TB as needed. The decision of when to initiate therapy and the choice of intervention are based on assessment of the probability of developing severe hyperbilirubinemia using hour-specific TB values, and the presence or absence of additional risk factors including gestational age (GA) <38 weeks (figure 3 and figure 4 and table 1 and algorithm 1). (See 'Assessment of risk severity' above.)

●Criteria for intervention – Threshold hour-specific TB values for management including initiating interventions varies for the following risk categories:

•Term infants without additional risk factors. (See 'Term infants without risk factors' above.)

•Term infants with additional risk factors or late preterm infants (35 to 37 6/7 weeks GA) without risk factors. (See 'Term infants with risk factors or late preterm infants without risk factors' above.)

•Late preterm infants with risk factors.

•Preterm infants <35 weeks GA. (See "Unconjugated hyperbilirubinemia in the preterm infant (less than 35 weeks gestational age)".)

The risk for severe hyperbilirubinemia (TB >25 mg/dL [428 micromol/L]) and the threshold for intervention based upon the hour-specific bilirubin value and presence of additional risk factors can be determined using the newborn hyperbilirubinemia assessment calculator (calculator 1). (See 'Management goal and overall approach' above and "Unconjugated hyperbilirubinemia in term and late preterm infants: Screening".)

●Interventions – Interventions used to lower TB include phototherapy, the most commonly used intervention to treat and prevent severe hyperbilirubinemia, and exchange transfusion, increasing rarely used intervention, typically reserved for infants who are symptomatic, or have severe hyperbilirubinemia or are at-risk for severe hyperbilirubinemia despite intensive phototherapy. (See 'Management goal and overall approach' above and 'Interventions used to prevent and treat severe hyperbilirubinemia' above.)

•We recommend phototherapy as the initial therapy to prevent and treat severe hyperbilirubinemia in asymptomatic term and late preterm infants (Grade 1B) (picture 1). (See 'Phototherapy' above and "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Phototherapy'.)

•We recommend exchange transfusions in symptomatic infants who exhibit moderate to advanced BIND based on clinical assessment (table 2) despite intensive phototherapy (Grade 1B). We suggest exchange transfusion for infants with TB that exceeds threshold TB values based upon the guideline developed by the American Academy of Pediatrics (AAP) (infants at high-risk for developing BIND) who have failed initial intensive phototherapy (figure 4) (Grade 2C). (See 'Symptomatic patients' above and 'Exchange transfusion' above and "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Exchange transfusion'.)

•We suggest not to use prophylactic phototherapy (subthreshold therapy) in the routine care of newborns with good follow-up care who have subthreshold levels of TB during the birth hospitalization (Grade 2B). Although subthreshold phototherapy reduces the risk of readmission, it unnecessarily exposes many infants to phototherapy (and its potential adverse effects) and prolongs birth hospitalization. (See 'Subthreshold (prophylactic) phototherapy' above.)

•We suggest administering intravenous immunoglobulin (IVIG) to newborn infants with Rhesus isoimmune hemolytic disease (Grade 2C). (See 'Rhesus isoimmune hemolytic disease refractory to phototherapy' above.)

●Unproven therapies –Unproven or unavailable therapies include phenobarbital and metalloporphyrins. Ursodeoxycholic acid (UDCA) may be useful in the management of neonates with cholestasis. (See 'Unproven pharmacologic agents' above and "Biliary atresia", section on 'Choleretics'.)

●Outcome –When infants with hyperbilirubinemia can be identified and treated appropriately, the outcome is excellent with minimal or no additional risk for adverse neurodevelopmental sequelae. (See 'Outcome' above.)