Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newbornAuthorsRonald J Wong, BAVinod K Bhutani, MD, FAAPSection EditorsSteven A Abrams, MDElizabeth B Rand, MDDeputy EditorMelanie S Kim, MDDisclosures: Ronald J Wong, BA Nothing to disclose. Vinod K Bhutani, MD, FAAP Nothing to disclose. Steven A Abrams, MD Grant/Research/Clinical Trial Support: Mead-Johnson (infant nutrition [specialized formulas for preterm infants]). Elizabeth B Rand, MD Nothing to disclose. Melanie S Kim, MD Employee of UpToDate, Inc.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Apr 2014. | This topic last updated: Mar 04, 2014.INTRODUCTION — Almost all newborn infants develop a total serum or plasma bilirubin (TB) level greater than 1 mg/dL (17 micromol/L), which is the upper limit of normal for adults. As the TB increases, it produces neonatal jaundice, the yellowish discoloration of the skin and/or conjunctiva caused by bilirubin deposition [1].

Hyperbilirubinemia in infants ≥35 weeks gestation is defined as a TB >95th percentile on the hour-specific Bhutani nomogram [2]. Hyperbilirubinemia with a TB >25 to 30mg/dL (428 to 513 micromol/L) is associated with an increased risk for bilirubin-induced neurologic dysfunction (BIND), which occurs when bilirubin crosses the blood-brain barrier and binds to brain tissue. The term "acute bilirubin encephalopathy" (ABE) is used to describe the acute manifestations of BIND. The term "kernicterus" is used to describe the chronic and permanent sequelae of BIND. Appropriate intervention is important to consider in every infant with severe hyperbilirubinemia. However, even if these infants are adequately treated, long-term neurologic sequelae (kernicterus) can sometimes develop.

The pathogenesis and etiology of neonatal unconjugated hyperbilirubinemia is reviewed here. The clinical features, evaluation, and treatment of this disorder are discussed separately. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants" and "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants" and "Treatment of unconjugated hyperbilirubinemia in term and late preterm infants".)

BILIRUBIN METABOLISM — Knowledge of the basic steps in bilirubin metabolism is essential to the understanding of the pathogenesis of neonatal hyperbilirubinemia. Bilirubin metabolism is briefly reviewed here and is discussed in detail separately. (See "Bilirubin metabolism".)

Bilirubin production — Bilirubin is a product of heme catabolism. Approximately 80 to 90 percent of bilirubin is produced during the breakdown of hemoglobin from red blood cells or from ineffective erythropoiesis. The remaining 10 to 20 percent is derived from the breakdown of other heme-containing proteins, such as cytochromes and catalase.

Bilirubin is formed in two steps. The enzyme heme oxygenase (HO), located in the spleen and liver as well as all nucleated cells, catalyzes the breakdown of heme, resulting in the formation of equimolar quantities of carbon monoxide (CO) and biliverdin. Biliverdin then is converted to bilirubin by the enzyme biliverdin reductase. Measurements of CO production, such as end-tidal CO (ETCO) or carboxyhemoglobin (COHb), both corrected for ambient CO (ETCOc and COHbc, respectively), can be used as indices of in vivo bilirubin production. (See "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'End-tidal carbon monoxide concentration'.)

Bilirubin clearance and excretion — Clearance and excretion of bilirubin occurs in the following steps (figure 1):

●Hepatic uptake – Circulating bilirubin, which is bound to albumin, is transported to the liver. Bilirubin dissociates from albumin and is taken up by hepatocytes, where it is processed for excretion.●Conjugation – In hepatocytes, uridine diphosphogluconurate glucuronosyltransferase (UGT1A1) catalyzes the conjugation of bilirubin with glucuronic acid, producing bilirubin diglucuronides and, to a lesser degree, bilirubin monoglucuronides. Conjugated bilirubin, which is more water-soluble than unconjugated bilirubin, is excreted in bile.●Biliary excretion – Conjugated bilirubin is secreted into the bile in an active process that depends upon canalicular transporters, and then excreted into the digestive tract (figure 1). Conjugated bilirubin cannot be reabsorbed by the intestinal epithelial cells. It is broken down in the intestine by bacterial enzymes and, in the adult it is reduced to urobilin by bacterial enzymes. But at birth the infant's gut is sterile and, subsequently, infants have far fewer bacteria in the gut, so very little, if any, conjugated bilirubin is reduced to urobilin. Infants have beta-glucuronidase in the intestinal mucosa, which deconjugates the conjugated bilirubin. The unconjugated bilirubin can now be reabsorbed through the intestinal wall and recycled into the circulation, a process known as the "enterohepatic circulation of bilirubin".

NEONATAL JAUNDICE — Nonpathologic jaundice is caused by normal neonatal changes in bilirubin metabolism resulting in increased bilirubin production, decreased bilirubin clearance, and increased enterohepatic circulation.

●In term newborn infants, bilirubin production is two to three times higher than in adults. This occurs because newborns have more red blood cells (hematocrit between 50 to 60 percent) and fetal red blood cells have a shorter life span (approximately 85 days) than those in adults. The increased turnover of more red blood cells produces more bilirubin.●Bilirubin clearance is decreased in newborns, mainly due to the deficiency of the enzyme uridine diphosphogluconurate glucuronosyltransferase (UGT1A1). UGT activity in term infants at seven days of age is approximately 1 percent of that of the adult liver and does not reach adult levels until 14 weeks of age [3,4].●There is an increase in the enterohepatic circulation of bilirubin, further increasing the bilirubin load in the infant. (See 'Bilirubin clearance and excretion' above.)

These normal physiologic alterations generally result in the mild unconjugated (indirect-reacting) bilirubinemia that occurs in nearly all newborns [1].

●In Caucasian and African-American infants, the mean peak total serum or plasma bilirubin (TB) occurs at 48 to 96 hours of age and is 7 to 9 mg/dL (120 to 154micromol/L). The 95th percentile ranges from 13 to 18 mg/dL (222 to 308 micromol/L) [5].

●In some Asian infants, mean TB levels can reach 10 to 14 mg/dL (171 to 239 micromol/L) and can occur later, between 72 and 120 hours of age.

Primary neonatal jaundice resolves within the first one to two weeks after birth.

Peak TB is also later in infants born at 35 to 37 weeks gestational age. Physiologic jaundice resolves within the first one to two weeks after birth, usually by the fifth day in Caucasian and African-American infants, and by the 10th day in Asian infants.

Ethnic variation in conjugation ability — Differences in TB levels among races may result from specific genetic variations in conjugating ability [1]. As an example, polymorphisms in the UGT1A1 gene, due to differences in the number of thymine-adenine (TA) repeats in the promoter region of the gene, vary among individuals of Asian, African, and Caucasian ancestry [6]. These polymorphisms correlate with decreases in UGT1A1 enzyme activity resulting in increased TB levels.

Another cause of racial variation in the development of neonatal jaundice results from a common mutation in the UGT1A1 gene at Gly71Arg that occurs in Eastern Asians. This mutation leads to an increased incidence of severe neonatal hyperbilirubinemia (approximately 20 percent) in Asians [7,8]. The increased frequency of this polymorphism increases the risk of hyperbilirubinemia in infants born to mothers who are Eastern Asian. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Risk factors'.)

HYPERBILIRUBINEMIA — Hyperbilirubinemia (defined as a total serum or plasma bilirubin [TB] >95th percentile on the hour-specific Bhutani nomogram [2]) can be caused by certain pathologic conditions or by exaggeration of the mechanisms responsible for neonatal jaundice. Identification of the cause of neonatal hyperbilirubinemia is useful in determining whether therapeutic interventions can prevent severe hyperbilirubinemia. (See "Treatment of unconjugated hyperbilirubinemia in term and late preterm infants".)

The following features suggest severe hyperbilirubinemia [9]:

●Jaundice in the first 24 hours (usually caused by increased bilirubin production due to hemolysis).●TB greater than the hour-specific 95th percentile (figure 2). The risk for severe hyperbilirubinemia and the threshold for intervention based upon the hour-specific bilirubin value may be determined using the newborn hyperbilirubinemia assessment calculator (calculator 1). (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants".)●Rate of TB rise greater than 0.2 mg/dL (3.4 micromol/L) per hour.●Jaundice in a term newborn after two weeks of age.●Direct (conjugated) bilirubin concentration >1 mg/dL (17 micromol/L) if the total bilirubin is <5 mg/dL (86 micromol/L), or more than 20 percent of the total bilirubin if the total bilirubin is >5 mg/dL (86 micromol/L) [10]. An increase in direct (conjugated) bilirubin is suggestive of cholestasis. (See "Approach to neonatal cholestasis".)

CAUSES OF HYPERBILIRUBINEMIA

Increased production — The most common cause of pathologic indirect hyperbilirubinemia is increased bilirubin production due to hemolytic disease processes that include the following [5-7,11-15]:

●Isoimmune-mediated hemolysis (eg, ABO or Rh(D) incompatibility). (See "Hemolytic disease of the newborn: RBC alloantibodies in pregnancy and associated serologic issues" and "Red cell transfusion in infants and children: Selection of blood products", section on 'Hemolytic disease of the fetus and newborn'.)●Inherited red blood cell membrane defects (eg, hereditary spherocytosis and elliptocytosis). (See "Hereditary spherocytosis: Clinical features, diagnosis, and treatment" and "Hereditary elliptocytosis: Clinical features and diagnosis".)●Erythrocyte enzymatic defects (eg, glucose-6-phosphate dehydrogenase [G6PD] deficiency [16], pyruvate kinase deficiency, and congenital erythropoietic porphyria). (See "Clinical manifestations of glucose-6-phosphate dehydrogenase deficiency" and "Pyruvate kinase deficiency" and "Congenital erythropoietic porphyria".)●Sepsis is a known cause of hemolysis. The mechanism is not known; however, one theory suggests that increased oxidative stress due to sepsis damages neonatal red blood cells that are susceptible to cell injury [5].

Other causes of increased bilirubin production due to increased red blood cell breakdown include polycythemia or sequestration of blood within a closed space, which occurs in cephalohematoma. Macrosomic infants of diabetic mothers (IDM) also have increased bilirubin production due to either polycythemia or ineffective erythropoiesis. (See "Neonatal polycythemia" and "Infant of a diabetic mother".)

Decreased clearance — Inherited defects in the gene that encodes UGT1A1, which catalyzes the conjugation of bilirubin with glucuronic acid, decrease bilirubin conjugation. This reduces hepatic bilirubin clearance and increases total serum or plasma bilirubin (TB) levels [17]. These disorders include Crigler-Najjar syndrome types I and II and Gilbert syndrome, which are briefly summarized below and discussed in detail separately. (See "Crigler-Najjar syndrome" and "Gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction".)

Crigler-Najjar syndrome — There are two variants of Crigler-Najjar syndrome. (See "Crigler-Najjar syndrome".)

●Crigler-Najjar syndrome type I (CN-I) – Crigler-Najjar syndrome type I (CN-I) is the most severe form of inherited UGT1A1 disorders. UGT activity is essentially absent, and severe hyperbilirubinemia develops in the first two to three days after birth. Lifelong phototherapy is required to avoid bilirubin-induced neurologic dysfunction (BIND) unless liver transplantation is performed. The mode of inheritance is autosomal recessive.●Crigler-Najjar syndrome type II – Crigler-Najjar syndrome type II (CN-II) is less severe than is CN-I. UGT activity in this disorder is low, but detectable. Although some affected children develop severe jaundice, the hyperbilirubinemia often responds to phenobarbital treatment. CN-II usually is inherited in an autosomal recessive manner, although autosomal dominant transmission occurs in some cases.

Gilbert syndrome — Gilbert syndrome is the most common inherited disorder of bilirubin glucuronidation. It results from a mutation in the promoter region of the UGT1A1 gene [18]. The mutation causes a reduced production of UGT, leading to unconjugated hyperbilirubinemia. Breast milk jaundice during the second week after birth may be due to the concurrent neonatal manifestation of Gilbert syndrome.

In the United States, 9 percent of the population is homozygous and 42 percent heterozygous for the Gilbert mutation [19]. Newborns who are homozygous for the gene mutation have a higher

incidence of jaundice during the first two days after birth than normal infants or those who are heterozygous [20]. Similar findings have been noted in other parts of the world, especially in Asian countries [8,21].

The Gilbert genotype is particularly clinically apparent when affected newborns have increased bilirubin production or enhanced enterohepatic circulation. As an example, in one study, infants with the normal Gilbert genotype did not produce an increase in the incidence of hyperbilirubinemia; 9.7 percent of the deficient infants and 9.9 percent of the G6PD-sufficient normal infants had a TB ≥15 mg/dL (257 micromol/L) [22]. However, hyperbilirubinemia was more frequent in G6PD-deficient infants who were homozygous or heterozygous for the Gilbert mutation (50 and 32 percent, respectively). In another study of male infants with G6PD deficiency, mean TB was highest in patients who were homozygotes (11.1 mg/dL [190 micromol/L]), followed by heterozygotes for the Gilbert mutation (9.1 mg/dL [156 micromol/L]), and those without the mutation (8.8 mg/dL [150 micromol/L]) [23].

The combination of a usually benign polymorphism of Gilbert genotype coupled with another factor that increases TB may be the underlying cause of some of the rare cases of infants with extremely high TB levels (>25 mg/dL [428 micromol/L]) [24]. (See "Gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction".)

OATP-2 polymorphism — In addition to the polymorphisms of the UGT gene discussed above, a study of Taiwanese newborns reported that those with a polymorphic variant of the organic anion transporter protein OATP-2 (also known as OATP-C or solute carrier organic anion transporter 1B1 [SLCO1B1]) were more likely to develop severe hyperbilirubinemia [25]. Furthermore, the combination of the OATP-2 polymorphism with a UGT1A1 gene mutation increased this risk.

Other causes — Other causes of decreased bilirubin clearance include maternal diabetes [26], congenital hypothyroidism, and galactosemia, although in the latter case, infants typically present with elevated conjugated hyperbilirubinemia. These conditions usually are identified by metabolic screening programs; however, infants may develop severe and prolonged jaundice before screening results become available. (See "Clinical features and detection of congenital hypothyroidism" and "Galactosemia: Clinical features and diagnosis".)

Increased enterohepatic circulation — The major causes of increased enterohepatic circulation of bilirubin are breastfeeding failure jaundice, breast milk jaundice, or impaired intestinal motility caused by functional or anatomic obstruction.

Breast milk jaundice — Breast milk jaundice is defined as the persistence of physiologic jaundice beyond the first week of age. It typically begins after the first three to five days of life, peaks within two weeks after birth, and progressively declines to normal levels over 3 to 12 weeks [27]. Breast milk jaundice, a benign condition, needs to be distinguished from breastfeeding failure jaundice that occurs within the first seven days of life, which is caused by decreased intake resulting in excessive weight and fluid loss. (See 'Breastfeeding failure jaundice' below.)

In breast milk jaundice, infants commonly have TB levels >5 mg/dL (86 micromol/L) for several weeks after delivery. Although the hyperbilirubinemia is generally mild and does not require intervention, it should be monitored to ensure that it remains unconjugated and does not increase. If TB levels begin to increase or there is a significant component of conjugated bilirubin, evaluation for other causes of hyperbilirubinemia should be performed including neonatal cholestasis. If after evaluation, the clinical diagnosis of breast milk jaundice is made, breast feeding can continue with the expectation of resolution by 12 weeks of age [28]. (See "Evaluation of unconjugated

hyperbilirubinemia in term and late preterm infants" and "Causes of neonatal cholestasis" and "Approach to neonatal cholestasis".)

Breast milk jaundice appears to be caused by a factor, which has not yet been identified, in human milk that promotes an increase in intestinal absorption of bilirubin. Beta-glucuronidase is one proposed substance as it deconjugates intestinal bilirubin, increasing its ability to be absorbed (ie, increasing enterohepatic circulation) [29]. Approximately 20 to 40 percent of women have high levels of beta-glucuronidase in their breast milk. Blocking the deconjugation of bilirubin through beta-glucuronidase inhibition may provide a mechanism to reduce intestinal absorption of bilirubin in breastfed infants [30]. Although some studies have found elevated fecal levels of beta-glucuronidase in breastfed infants with hyperbilirubinemia, this has not been a consistent finding.

Beta-glucuronidase inhibitors such as enzymatically-hydrolyzed casein or L-aspartic acid have been used prophylactically in breastfed newborns [30]. However, further studies are needed to determine whether these agents are effective and safe in promoting increased fecal bilirubin excretion, thereby resulting in lower TB. We do not currently recommend these agents for breast milk jaundice.

Intestinal obstruction — Ileus or anatomic causes of intestinal obstruction increase the enterohepatic circulation of bilirubin and result in jaundice. TB levels are frequently higher with small bowel than with large bowel obstruction. As an example, jaundice occurs in 10 to 25 percent of infants with pyloric stenosis when vomiting begins.

Breastfeeding failure jaundice — Breastfeeding compared with formula feeding is associated with an increased risk of jaundice and kernicterus.

●In a review of cases from the Pilot Kernicterus Registry, 59 of 61 infants with kernicterus were breastfed. Of the two infants who were formula-fed, both were found to have G6PD deficiency [31].●In one report, infants who were breastfed compared with bottle-fed infants at day three of life were more likely to have TB concentrations >13 mg/dL (222 micromol/L),(8.9 versus 2.2 percent) [32].●In another report, infants fed human milk compared with those fed formula had higher TB on day three of life and lower volumes of stool and urine output during the first week of life [33].

The primary mechanism for the increased likelihood of kernicterus and jaundice with breast versus formula feeding is the failure to successfully initiate breastfeeding rather than a direct effect of breast milk itself, as is seen in breast milk jaundice. A population-based study demonstrated that TB was only marginally higher in successfully breastfed compared with formula-fed infants [2].

Breastfeeding failure jaundice typically occurs within the first week of life, as lactation failure leads to inadequate intake with significant weight and fluid loss resulting in hypovolemia. This causes hyperbilirubinemia (jaundice) and in some cases, hypernatremia defined as a serum sodium >150 mEq/L. Decreased intake also causes slower bilirubin elimination and increased enterohepatic circulation that contribute to elevated TB. (See "Initiation of breastfeeding", section on 'Weight loss'.)

A root cause analysis identified the following as predictors of lactation failure in infants with kernicterus [34]. (See "Initiation of breastfeeding".)

●Inadequate education from clinicians and lactation consultants●Inadequate documentation of infant latching

●Inadequate measurement of milk transfer●Inadequate recording of urine output and stool pattern changes

In addition, maternal breastfeeding complications, such as engorgement, cracked nipples, and fatigue, and neonatal factors, such as ineffective suck, may not be properly addressed prior to hospital discharge and result in ineffective breastfeeding. (See "Common problems of breastfeeding and weaning".)

Although late preterm infants (defined as gestational age between 34 weeks, and 36 weeks and 6 days) are usually able to breastfeed, they are more likely to experience difficulty in establishing successful breastfeeding than term infants. Late preterm infants may not fully empty the breast because of increased sleepiness, fatigue, and/ordifficulty maintaining a latch because their oro-buccal coordination and swallowing mechanisms are not fully matured. (See "Breastfeeding the preterm infant", section on 'Late preterm infants'.)

Prevention — Initiation of successful breastfeeding, one of the mainstays of preventing hyperbilirubinemia, has become an increasing problem due to shortened postpartum length of stay for newborn infants and their mothers. Postnatal education, support, and care should be provided to the infant-mother dyad during the birth hospitalization and after discharge. The overall approach is briefly summarized here and is discussed in greater detail separately. (See "Breastfeeding: Parental education and support" and "Initiation of breastfeeding".)

●During the first postpartum week while breastfeeding is being established, mothers should nurse whenever the infant shows signs of hunger or when four hours have elapsed since the last feeding. This will usually result in 8 to 12 feedings in 24 hours, which is usually sufficient to prevent significant hyperbilirubinemia that requires intervention [35].●During the birth hospitalization, monitoring and assessment of breastfeeding are crucial. Problems identified in the hospital should be addressed at that time, and a documented plan for management after discharge should be communicated to both the parents and primary care provider.●At discharge, a primary care appointment should be scheduled so that the infant-mother dyad is evaluated 24 to 48 hours after discharge, and post-discharge lactation resources provided.●At the follow-up appointment, supplementation with banked human milk or commercial infant formula is recommended when the infant has lost more than 7 percent ofhis/her birth weight or exhibits signs of dehydration (eg, decreased urine output), stool output is less than three small stools a day, and mother's milk supply remains limited. Glucose water or sterile water feedings should not be used, as they do not provide adequate nutrition.

Severe hyperbilirubinemia — Although genetic factors may contribute to an increase in TB, clinical factors are the major contributors to the pathogenesis of severe hyperbilirubinemia defined as a TB >95th percentile. This was illustrated in a case-control study of term infants that compared genetic and clinical factors between infants with TB levels >95th percentile and those with TB levels <40th percentile [15]. There were no differences in the frequency of G6PD, UGT1A1, and SCLO1B1 (liver transport protein) genetic variants between the two groups. Among the group with severe hyperbilirubinemia, the most common cause of an elevated TB was hemolysis due to ABO incompatibility (31 percent) followed by breastfeeding failure (22 percent), although no cause was identified in 39 percent of the cases.

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SUMMARY

●Total serum or plasma bilirubin (TB) levels >1 mg/dL (17 micromol/L) occur in almost all term and near-term newborn infants. Infants with severe hyperbilirubinemia (TB >25 to 30 mg/dL [428 to 513 micromol/L]) are at risk for bilirubin-induced neurologic dysfunction (BIND), presenting acutely as acute bilirubin encephalopathy (ABE) and, if inadequately treated, long-term neurologic sequelae or kernicterus.●Neonatal jaundice is primarily caused by normal neonatal alterations in bilirubin metabolism including increased bilirubin production, decreased bilirubin clearance, and increased enterohepatic circulation. These alterations generally result in mild unconjugated (indirect-reacting) hyperbilirubinemia with peak TB of 7 to 9 mg/dL (120 to 154 micromol/L) in Caucasian and African-American infants and higher values in Asian infants, 10 to 14 mg/L (171 to 239 micromol/L). (See 'Neonatal jaundice' above.)●Hyperbilirubinemia is caused by exaggeration of mechanisms that cause neonatal jaundice or by pathologic conditions that increase bilirubin production, decrease bilirubin clearance, or increase the enterohepatic circulation. Identification of the cause of neonatal hyperbilirubinemia is useful in determining whether therapeutic interventions can prevent severe hyperbilirubinemia. (See 'Hyperbilirubinemia' above and "Treatment of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Prevention of hyperbilirubinemia'.)●The following clinical findings are predictors for hyperbilirubinemia:

•Jaundice in the first 24 hours of life.•TB greater than the hour-specific 95th percentile (figure 2).•Conjugated bilirubin concentration >1 mg/dL (17 micromol/L) if the total bilirubin is <5 mg/dL (86 micromol/L), or more than 20 percent of the total bilirubin if the total bilirubin is >5 mg/dL (86 micromol/L). Conjugated bilirubinemia suggests neonatal cholestasis. (See "Approach to neonatal cholestasis".)•Rate of TB rise greater than 0.2 mg/dL (3.4 micromol/L) per hour.•Jaundice in a term newborn after two weeks of age.

●Causes of hyperbilirubinemia can be classified by pathogenesis as follows:•Increased production – Hemolytic disease, polycythemia, and sequestration of blood within a closed space increase bilirubin production because of increased red cell breakdown. (See 'Increased production' above.)

•Decreased clearance – Inherited defects in uridine diphosphogluconurate glucuronosyltransferase (UGT1A1), such as Crigler-Najjar syndrome types I and II and Gilbert's syndrome. In addition, metabolic disorders, such as congenital hypothyroidism, galactosemia, and infants of diabetic mothers, can decrease bilirubin clearance. (See 'Decreased clearance' above.)•Increased enterohepatic circulation of bilirubin.•Breast milk jaundice, and impaired intestinal motility caused by functional or anatomic obstruction increase enterohepatic circulation of bilirubin. (See 'Increased enterohepatic circulation' above and 'Breastfeeding failure jaundice' above.)

Treatment of unconjugated hyperbilirubinemia in term and late preterm infantsAuthorsRonald J Wong, BAVinod K Bhutani, MD, FAAPSection EditorSteven A Abrams, MDDeputy EditorMelanie S Kim, MDDisclosures: Ronald J Wong, BA Nothing to disclose. Vinod K Bhutani, MD, FAAP Nothing to disclose. Steven A Abrams, MD Grant/Research/Clinical Trial Support: Mead-Johnson (infant nutrition [specialized formulas for preterm infants]). Melanie S Kim, MD Employee of UpToDate, Inc.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Apr 2014. | This topic last updated: Sep 04, 2013.INTRODUCTION — Almost all newborn infants develop a total serum or plasma bilirubin (TB) value greater than 1 mg/dL (17.1 micromol/L), which is the upper limit of normal for adults. As TB increases, it causes neonatal jaundice, the yellowish discoloration of the skin and/or sclerae caused by bilirubin deposition in half of all newborn infants [1].

Hyperbilirubinemia in infants ≥35 weeks gestational age (GA) is defined as TB >95th percentile on the hour-specific Bhutani nomogram [2]. Hyperbilirubinemia with a TB >25 to 32 mg/dL (428 to 547 micromol/L) is associated with an increased risk for bilirubin-induced neurologic dysfunction (BIND), which occurs when bilirubin crosses the blood-brain barrier and binds to brain tissue. The term "acute bilirubin encephalopathy" (ABE) is used to describe the acute manifestations of BIND. The term "kernicterus" is used to describe the chronic and permanent sequelae of BIND. Appropriate intervention is important to consider in every infant with severe hyperbilirubinemia. However, even if these infants are adequately treated, long-term neurologic sequelae (kernicterus) can sometimes develop.

The treatment of neonatal unconjugated hyperbilirubinemia is reviewed here. The clinical manifestations, evaluation, pathogenesis, and etiology of this disorder are discussed separately. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants" and "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants" and "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn".)

OVERVIEW — Two advances in medical care had a significant impact on the need for treatment and the way in which hyperbilirubinemia is managed. The administration of Rh (D) immunoglobulin to Rh-negative mothers in the late 1960s decreased dramatically the incidence of neonatal Rh isoimmune hemolytic disease. At about the same time, the introduction of phototherapy in the United States reduced significantly the need for exchange transfusions and the risk of severe hyperbilirubinemia. Thus, the risk of kernicterus was significantly reduced from its peak incidence in the 1950s to the 1970s. Nevertheless, isolated cases of kernicterus, a preventable condition, continue to be reported. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Overview'.)

Limited data based upon case reports suggest that kernicterus occurs in term or late preterm infants with hyperbilirubinemia, defined as total serum or plasma bilirubin (TB) >95th percentile on the hour-specific Bhutani nomogram [2]. In order to prevent future cases of kernicterus, the management of unconjugated hyperbilirubinemia focuses on two key elements:

Prevention of hyperbilirubinemia by identifying at-risk infants and initiation of preventive therapeutic interventions (eg, phototherapy) as needed

Reduction of TB in infants with severe hyperbilirubinemia

Prevention of hyperbilirubinemia — Universal screening of all term and late preterm infants identifies at-risk infants for hyperbilirubinemia. In these patients, phototherapy is initiated to prevent hyperbilirubinemia when TB exceeds a threshold level based upon a nomogram of TB levels adjusted by the infant's age-in-hours [3] and the presence or absence of additional risk factors [2,3]. (See "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants" and 'Phototherapy indications' below.)

Treatment of severe hyperbilirubinemia — Therapeutic interventions for infants with hyperbilirubinemia include:

Phototherapy Exchange transfusion Improving the frequency and efficacy of breastfeeding or supplementing inadequate

breastfeeding with formula

PHOTOTHERAPY — Phototherapy is the most commonly used intervention to treat and prevent severe hyperbilirubinemia. In term and large preterm infants, phototherapy is safe based upon its extensive use in millions of infants over 30 years and only rare reports of significant toxicity [2]. (See 'Adverse effects' below.)

Phototherapy reduces the risk that total bilirubin (TB) concentration will reach the level at which exchange transfusion is recommended [4,5]. It decreases or blunts the rise of TB in almost all cases of hyperbilirubinemia regardless of the patient's ethnicity or the etiology of hyperbilirubinemia. It is estimated that 5 to 10 infants with TB between 15 and 20 mg/dL (257 to 342 micromol/L) must receive phototherapy to prevent one patient from developing a TB >20 mg/dL (342 micromol/L) [2]. (See 'Efficacy' below and'Exchange transfusion' below.)

Mechanisms — Phototherapy exposes the infant's skin to light of a specific wavelength, which reduces TB by the following three mechanisms:

Structural isomerization to lumirubin – Phototherapy converts bilirubin into lumirubin via structural isomerization that is not reversible [6]. Lumirubin, a more soluble substance than bilirubin, is excreted without conjugation into bile and urine. This is the principal mechanism by which phototherapy reduces TB concentration.

Photoisomerization to a less toxic bilirubin isomer – Phototherapy converts the stable 4Z,15Z bilirubin isomer to the 4Z,15E isomer, which is more polar and less toxic than the 4Z,15Z form. Like lumirubin, 4Z,15E isomer is excreted into bile without conjugation. Unlike structural isomerization to lumirubin, photoisomerization is reversible; however, clearance of the 4Z,15E isomer is very slow and the photoisomerization is reversible. Thus, some of the 4Z,15E isomer in bile is converted back to the stable 4Z,15Z isomer. As a result, this pathway may have little effect on TB values. In addition, standard laboratory measurements do not distinguish among the isomers, so these measurements do not reflect these changes. Nevertheless, photoisomerization does reduce the amount of potentially toxic bilirubin by rapidly converting 15 percent of it to a non-toxic form.

Photo-oxidation to polar molecules – Photo-oxidation reactions convert bilirubin to colorless, polar compounds that are excreted primarily in the urine. This is a slow process and accounts for a small proportion of bilirubin elimination.

Technique — The dose of phototherapy, known as irradiance (measured in microW/cm2/nm), determines its efficacy. Irradiance depends upon the type of the light used, distance between the light and infant (except with light emitting diodes), and the exposed surface area of the infant. Irradiance usually is expressed for a certain wavelength band (spectral irradiance) [7]. In conventional phototherapy, the irradiance dosing is typically 6 to 12 microW/cm2 of body surface area exposed per nm of wavelength (425 to 475 nm) and with intensive phototherapy it is ≥30 microW/cm2/nm.

For TB levels ≥20 mg/dL (342 micromol/L), phototherapy should be administered continuously, until the TB falls below 20 mg/dL (342 micromol/L). Once this occurs, phototherapy can be interrupted for feeding and parental visits.

During phototherapy, the area covered by the diaper should be minimized. The eyes should be shielded with an opaque blindfold and care should be taken to prevent the blindfold from covering the nose. With fluorescent lights, the infant should be placed in an open crib, bassinet, or on a warmer, rather than in an incubator (the top of the incubator prevents the light from being brought sufficiently close to the infant). Lining the sides of the bassinet or warmer with aluminum foil or white material increases the exposed surface area of the infant and the efficiency of phototherapy [8,9]. The use of reflective white curtains around the phototherapy light source has also been shown to increase phototherapy efficiency [10].

Light sources and devices — Bilirubin absorbs light most strongly in the blue region of the spectrum near 460 nm. Several light sources, utilizing different wavelengths of light and varying degrees of irradiance, and devices are available for phototherapy.

Fluorescent blue light – Fluorescent special blue light, F20 T12/BB and TL52 tubes (Philips, The Netherlands), should be used. They are the most effective light source in lowering TB because they deliver light in the blue-green spectrum, which penetrates the skin well and is absorbed maximally. Fluorescent special blue light should not be confused with regular blue light or blue light-emitting diodes (LEDs).

Halogen white light – Halogen white lamps are hot and can cause thermal injury. They should be placed at the distance from the patient recommended by the manufacturer.

Fiberoptic blankets or pads – Fiberoptic blankets or pads generate little heat and can be placed close to the infant, providing higher irradiance than do fluorescent lights [11]. However, blankets are small and rarely cover sufficient surface area to be effective when used alone in term infants. They can be used as an adjunct to overhead fluorescent or halogen lights. Fiberoptic blankets also can be used during feedings when overhead fluorescent or halogen lights are discontinued. This is particularly helpful for infants with severe hyperbilirubinemia.

Blue LEDs – LEDs use high-intensity blue gallium nitride and are commercially available as both overhead and underneath devices [7,12,13]. These devices, which deliver high intensity narrow band light in the absorption spectrum of bilirubin, are as effective as conventional fluorescent blue light [14,15]. The mattress LED device is preferable to the fiberoptic pad because it is large enough to cover the entire surface (in contact with the mattress) of a term infant.

For effective (intensive) phototherapy, high levels of irradiance (usually ≥30 microW/cm2/nm) are delivered to as much of an infant's surface area as possible [2]. The necessary irradiance can be achieved using a phototherapy light placed at a distance of 10 to 30 cm from the infant's body depending on the manufacturer’s recommendation in combination with a fiberoptic pad, LED mattress, or special blue lights below the infant [16]. LEDs at the distance dictated by the device also provide an irradiance of 30 microW/cm2/nm.

Although there are no trials comparing the efficacy of phototherapy devices in term and late preterm infants, a trial in extremely low birth weight preterm infants (birth weight ≤1000 g) found that the absolute and relative decrease of TB during the first 24 hours of life was greatest for LEDs, followed by spotlights, bank of lights, and blankets [17]. (See "Hyperbilirubinemia in the premature infant (less than 35 weeks gestation)", section on 'Light source and devices'.)

Home phototherapy — As an alternative to readmission to the hospital, phototherapy can be administered to term infants at home. Home phototherapy is less disruptive to the family and can be considered for otherwise healthy term infants (>38 weeks gestational age [GA]) without hemolysis or other risk factors who have TB levels 2 to 3 mg/dL (34 to 51 micromol/L) below the recommended threshold level for initiation of hospital phototherapy, are feeding well, and can be closely followed [2]. (See'Phototherapy indications' below.)

Sunlight exposure — Although exposure to sunlight provides sufficient irradiance in the 425 to 475 nm band and is known to lower the TB [18], exposure to sunlight is not recommended to prevent severe hyperbilirubinemia [2]. The difficulties of avoiding sunburn while exposing a naked infant to sunlight preclude the use of sunlight exposure as a reliable therapeutic option.

Selection of light source — Although there is a wide selection of commercially available phototherapy devices, there are no standardized methods of reporting and measuring phototherapy devices. (See 'Light sources and devices' above.)

In order to help guide clinicians and hospitals to provide the most “effective phototherapy,” a technical report from the American Academy of Pediatrics (AAP) summarized the key features to consider in the selection of a device to treat neonatal hyperbilirubinemia [16]. After review of the available literature, the report concluded that the most effective devices displayed the following characteristics:

Emission of light in the blue-to-green range (460 to 490 nm). Lights with broader emission also will work, but not as effectively.

Irradiance of at least 30 microW/cm2/nm (confirmed by an appropriate irradiance meter calibrated over the appropriate wavelength range).

Ability to illuminate maximal body surface. Blocking the light source or reducing the exposed body surface area should be avoided.

Demonstration of a decrease in TB during the first four to six hours of exposure.

Phototherapy indications — The following discussion on the indications for phototherapy for term and late preterm infants (≥35 weeks GA) is based upon the practice guideline developed by the AAP [2]. Similar guidelines for term infants based on TB and postnatal age have been developed by the United Kingdom’s National Institute for Health and Clinical Excellence (NICE guideline for Neonatal Jaundice). National guidelines have also been developed in Norway, which are based on TB values, birth weight (BW), and postnatal age [19].

Initiation of phototherapy is based upon hour-specific TB values [3], GA, and the presence or absence of risk factors that include isoimmune hemolytic disease, glucose-6-phosphate dehydrogenase (G6PD) deficiency, asphyxia, lethargy, temperature instability, sepsis, acidosis, or albumin <3 g/dL (if measured) (figure 1). These are conditions that increase the risk of brain damage because of their negative effects on albumin binding of bilirubin, the blood-brain barrier, and the susceptibility of the brain cells to damage by bilirubin. (See "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Risk assessment' and "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Bilirubin/albumin ratio'.)

The risk for severe hyperbilirubinemia and the threshold for intervention based upon the hour-specific bilirubin value may be determined using the newborn hyperbilirubinemia assessment calculator (calculator 1). In general, the guidelines for phototherapy are as follows:

For infants at low risk (≥38 weeks GA and without risk factors), phototherapy is started at the following TB values.

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)

Infants in this category who have TB levels 2 to 3 mg/dL (34 to 51 micromol/L) below the recommended levels may be treated with fiberoptic or conventional phototherapy at home.

For infants at medium risk (≥38 weeks GA with risk factors or 35 to 37 6/7 weeks gestation without risk factors), phototherapy is started at the following TB values.

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.

For infants at high risk (35 to 37 6/7 weeks GA with risk factors), phototherapy is initiated at the following TB values.

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)

Special circumstances — Infants with clinical jaundice within the first 24 hours frequently have hemolysis. They require immediate evaluation and close surveillance to assess the need for phototherapy.

In infants with other causes of increased bilirubin production, such as cephalohematoma or extensive bruising, or in infants suspected of having genetic disorder of bilirubin conjugation (eg, Crigler-Najjar or Gilbert's syndromes), we start phototherapy when the hour-specific TB concentration is in the high intermediate risk zone (>75th percentile) (figure 2). The risk for severe hyperbilirubinemia and the threshold for intervention based upon the hour-specific TB value may be determined using the newborn hyperbilirubinemia assessment calculator (calculator 1). (See "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn".)

Efficacy of phototherapy — Although there are no data showing that phototherapy improves neurodevelopmental outcome, phototherapy does reduce the likelihood that TB reaches a level associated with an increased risk of kernicterus or at which exchange transfusion is recommended [20,21]. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Overview'.)

Intensive phototherapy results in a decline of TB of at least 2 to 3 mg/dL (34 to 51 micromol/L) within four to six hours. A decrease in TB can be measured as soon as two hours after initiation of treatment. In infants ≥35 weeks GA, 24 hours of intensive phototherapy can result in a 30 to 40 percent decrease in the initial TB [22]. With conventional phototherapy, a decline of 6 to 20 percent can be expected in the first 18 to 24 hours [11,23,24].

The efficacy of phototherapy in preventing a rise in TB to the exchange transfusion threshold was demonstrated in a large retrospective cohort study of 281,898 infants born ≥35 weeks GA [25]. Overall, 23 percent of patients received phototherapy within eight hours after reaching a TB within 3 mg/dL (51 micromol/L) of the AAP phototherapy threshold (figure 1). Only 1.6 percent (354 infants) ever exceeded the AAP exchange threshold (figure 3) and only three received exchange transfusions. Multivariate analysis demonstrated that lower GA and birth weight, younger age at the time TB level reached the phototherapy threshold, and a positive direct antiglobulin test (DAT) were associated with an increased risk in reaching the AAP exchange transfusion threshold. Based upon these results, phototherapy was found to be highly effective in preventing TB from rising to the AAP exchange transfusion threshold, especially in full-term infants who are appropriate size for GA, older than 48 hours at the time TB level reached the phototherapy threshold, and are not DAT positive.

The rate of decline of TB during phototherapy is affected by a number of factors [2].

Increased irradiance increases the rate of TB decline Greater surface area exposure to phototherapy increases the rate of TB reduction The higher the initial TB, the more rapid is the rate of decline (as much as

10 mg/dL [171 micromol/L] within a few hours) Phototherapy is less effective in infants whose hyperbilirubinemia is due to cholestasis or

hemolysis with a DAT than in infants with other causes

Monitoring — During phototherapy, the dose of phototherapy (irradiance) and the infant's temperature, hydration status, time of exposure, and TB are monitored. Phototherapy may increase both the body and environmental temperature resulting in increased insensible fluid loss. LED-based devices emit low levels of heat, and thus fluid loss is less of a concern with these devices [8]. (See 'Hydration' below.)

The frequency of TB measurements depends upon the initial TB value. When infants are discharged and readmitted with TB values exceeding the 95th percentile for hour-specific TB levels [3] (figure 2), the TB measurement should be repeated two to three hours after initiation of phototherapy to assess the response. When phototherapy is started for a rising TB, TB should be measured after 4 to 6 hours and then within 8 to 12 hours, if TB continues to fall.

If, despite intensive phototherapy, the TB is at or approaches the threshold for exchange transfusion, blood should be sent for immediate type and cross-match. In addition, if exchange transfusion is being considered, the serum albumin level should be measured so that the serum bilirubin/albumin (B/A) ratio can be used in conjunction with the TB level and other factors to determine the need for exchange transfusion. (See 'Exchange transfusion' below.)

Hydration — It is important to maintain adequate hydration and urine output during phototherapy since urinary excretion of lumirubin is the principal mechanism by which phototherapy reduces TB. Thus, during phototherapy, infants should continue oral feedings by breast or bottle. For TB levels that approach the exchange transfusion level, phototherapy should be continuous until the TB has declined to about 20 mg/dL (342 micromol/L). Thereafter phototherapy can be interrupted for feeding. (See 'Technique'above.)

Intravenous hydration may be necessary to correct hypovolemia in infants with significant volume depletion whose oral intake is inadequate; otherwise, intravenous fluid is not recommended [2].

Breastfeeding — Breastfed infants whose intake is inadequate, with excessive weight loss (>12 percent of BW), or who have evidence of hypovolemia, should receive supplementation with expressed breast milk or formula [2]. The temporary interruption of breastfeeding with the substitution of formula may enhance the efficacy of phototherapy by decreasing the enterohepatic circulation of bilirubin [4,26,27]. (See "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn", section on 'Breastfeeding failure jaundice' and "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Breastfed infants'.)

If breastfeeding is interrupted, it should be resumed as soon as possible. (See "Infant benefits of breastfeeding".)

Discontinuation — For infants who have been readmitted for phototherapy, we discontinue the phototherapy when the TB has reached 12 to 14 mg/dL (205 to 239micromol/L). For those who required phototherapy during the birth hospitalization, phototherapy is started at a significantly lower level and, therefore, is stopped at a lower level. For these infants, we generally discontinue phototherapy when the TB has fallen to, or below, the level at which phototherapy was initiated because, by this time, the infant is significantly older and the level for initiation of phototherapy has, consequently, increased.

TB is measured 18 to 24 hours after phototherapy is terminated. This is important in infants who need phototherapy during their birth hospitalization, but might not be necessary in those who have been readmitted where the risk of rebound is much lower. The readmitted infant should not be kept in the hospital pending measurement of rebound. If necessary, this can be done as an outpatient.

Although the value following discontinuation is known as the rebound bilirubin, typically it is lower than the TB value before the initiation of phototherapy.

In one study of 161 infants with BW >1800 g, TB was significantly lower 17 hours after termination of phototherapy compared with TB at the time of termination (11.5 versus 12.2 mg/dL [197 versus 209 micromol/L]) [28].

However, in another study of 226 infants, which included 110 neonates with a positive DAT (Coombs’ test), 13 percent had rebound TB levels >15 mg/dL (257 micromol/L)[29]. Risk factors for significant rebound (TB levels >15 mg/dL [257 micromol/L]) were initial phototherapy beginning <72 hours of age (odds ratio [OR] 3.61, 95% CI 1.21-10.77), GA <37 weeks (OR 3.21, 95% CI 1.29-7.96), and a positive DAT test (OR 2.44, 95% CI 1.25-4.74).

Adverse effects — Phototherapy is considered safe. Side effects include transient erythematous rashes, loose stools, and hyperthermia. Increased insensible water loss may lead to dehydration. Phototherapy is not associated with an increase in nevus count [30]. (See 'Hydration' above.)

The "bronze baby syndrome" is an uncommon complication of phototherapy that occurs in some infants with cholestatic jaundice. It is manifested by a dark, grayish-brown discoloration of the skin, serum, and urine [31]. Although the etiology of the bronze appearance remains unknown, it is proposed that the color is a result of impaired biliary excretion of bile pigment photoproducts due to cholestasis [31,32]. The condition gradually resolves without sequelae within several weeks after discontinuation of phototherapy [33]. It remains controversial whether the bronze pigments have potential neurotoxic consequences.

Although the effect of phototherapy on the eyes of infants is not known, animal studies indicate that retinal degeneration may occur after 24 hours of continuous exposure [34]. As a result, it is essential that the eyes of all neonates treated with phototherapy are sufficiently covered to eliminate any potential eye exposure.

Limited data on long-term effects are conflicting, with some studies suggesting that blue light phototherapy (using broadband light emitting light in the UV region) increases the risk of melanocytic nevi in children and adolescents [35]. (See "Acquired melanocytic nevi (moles)".)

EXCHANGE TRANSFUSION — Exchange transfusion is used to remove bilirubin from the circulation when intensive phototherapy fails or in infants with signs of bilirubin-induced neurologic dysfunction (BIND). The term ABE, or "acute bilirubin encephalopathy," is used to describe the acute manifestations of overt BIND. The term "kernicterus" is used to describe the chronic and permanent sequelae of overt BIND and differentiate these from the subtle signs observed in the syndrome of BIND [36]. Exchange transfusion is especially useful for infants with increased bilirubin production resulting from isoimmune hemolysis because circulating antibodies and sensitized red blood cells also are removed.

Although exchange transfusion is both expensive and time consuming, it is the most effective method for removing bilirubin rapidly. Exchange transfusion is indicated when intensive phototherapy cannot prevent a continued rise in the total bilirubin (TB) or in infants who already display signs indicative of BIND. Exchange transfusions should be performed only by trained personnel in a neonatal or pediatric intensive care unit equipped with full monitoring and resuscitation capabilities [2]. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Neurologic manifestations'.)

The need for exchange transfusions has decreased with the prevention of Rh isoimmune hemolytic disease and the systemic application of the 2004 American Academy of Pediatrics (AAP) Guideline for identification and treatment of infants at risk for severe hyperbilirubinemia with phototherapy [37-39].

This was best illustrated in a study from a large Northern California health maintenance organization of over 18,000 neonates with a gestational age (GA) ≥35 weeks born between 2005 and 2007 following the initiation of universal screening. In this cohort, only 22 patients (0.1 percent) had a TB level that exceeded the AAP recommended threshold for exchange transfusion [39]. Fourteen of these infants were <38 weeks GA. Only one exchange transfusion was performed and there were no reported sequelae.

A similar incidence was reported from a single institution with an exchange transfusion rate of 0.015 percent (8 of 55,128 inborn infants) between 1988 and 1997 [37]. (See"Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Systematic approach' and 'Phototherapy indications' above.)

Morbidity and mortality — Because exchange transfusions are rarely performed, it is difficult to assess the current risks of morbidity and mortality associated with this procedure. Studies published in 1985 reported mortality rates of 0.3 percent associated with the procedure [40,41] and a significant complication rate of 1 percent [41]. Subsequent studies are limited by the number of patients due to the infrequency of the procedure.

In the previously mentioned retrospective 21-year review, 5 of the 141 patients died within seven days of the exchange transfusion; however, none of the deaths appeared to be related to the procedure [38]. In this study, the most common complications were thrombocytopenia (38 percent of patients) and hypocalcemia (38 percent).

In a retrospective study of 55 infants cared for at two neonatal intensive care units between 1992 and 2002, there was only one death, which was a critically ill preterm infant [42]. There was a high rate of complications including thrombocytopenia (44 percent), hypocalcemia (29 percent), and metabolic acidosis (24 percent).

In another retrospective study published in 1997, which reviewed 106 patients who underwent exchange transfusion over 15 years from two neonatal intensive care units (NICUs), two patients died because of complications attributed to exchange transfusions. These two deaths occurred in patients classified as "ill," having other existing comorbidities [43].

Procedure — The infant's circulating blood volume is approximately 80 to 90 mL/kg. A double-volume exchange transfusion (160 to 180 mL/kg) replaces approximately 85 percent of the infant's circulating red blood cells with appropriately cross-matched reconstituted (from packed red blood cells and fresh frozen plasma) blood.

Irradiated blood products should be used to reduce the risk of graft versus host disease. In infants born to cytomegalovirus (CMV) seronegative mothers, CMV-safe blood products should be used. (See "Red cell transfusion in infants and children: Selection of blood products".)

The procedure involves placement of at least a central catheter and removing and replacing blood in aliquots that are approximately 10 percent or less of the infant's blood volume. Exchange transfusion usually reduces TB by approximately 50 percent [44]. Infusion of albumin (1 g/kg) one to two hours before the procedure shifts more extravascular bilirubin into the circulation, allowing

removal of more bilirubin, although this has not been shown to decrease the need for repeat exchange transfusion.

Indications — The following discussion on the indications for exchange transfusions for term and late preterm infants (≥35 weeks GA) is based upon the clinical practice guideline developed by the AAP [2]. Similar guidelines for term infants based on TB and postnatal age have been developed by the United Kingdom’s National Institute for Health and Clinical Excellence (NICE guideline for Neonatal Jaundice). National guidelines have also been developed in Norway, which are based on TB values, birth weight (BW), and postnatal age [19].

Exchange transfusions are indicated in the following settings [2]:

Jaundiced infants with signs of ABE, such as significant lethargy, hypotonia, poor sucking, or high-pitched cry, irrespective of the TB level. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Acute bilirubin encephalopathy'.)

or

Infants with a TB greater than threshold values established by the AAP (figure 3). For infants who have not yet been discharged from the birth hospital, exchange transfusion

is recommended if the TB reaches the threshold level despite intensive phototherapy [2]. Infants who have been discharged from the nursery to home and have TB concentrations

that are approaching or exceed threshold values for exchange transfusion are initially treated with phototherapy. If TB remains above the threshold TB after about six hours of phototherapy, then exchange transfusion is indicated. This approach reduces the number of infants requiring an invasive therapy that has significant morbidity and mortality. (See 'Phototherapy' above.)

The risk for severe hyperbilirubinemia and the threshold for intervention based upon the hour-specific TB value may be determined using the newborn hyperbilirubinemia assessment calculator (calculator 1).

The following are general age-in-hours specific TB threshold values for exchange transfusion recommended by the AAP based upon gestational age and the presence or absence of risk factors (isoimmune hemolytic disease, glucose-6-phosphate dehydrogenase [G6PD] deficiency, asphyxia, significant lethargy, temperature instability, sepsis, acidosis, or albumin <3 g/dL [if measured]) [2]:

For infants at low risk (≥38 weeks GA and without risk factors), exchange transfusion is indicated for the following TB values.

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)

For infants at medium risk (≥38 weeks GA with risk factors or 35 to 37 6/7 weeks GA without risk factors), exchange transfusion is indicated for the following TB values.

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.

For infants at high risk (35 to 37 6/7 weeks GA with risk factors), exchange transfusion is indicated for the following TB values.

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)

Infants who are close or meet the criteria for exchange transfusion should be directly admitted or transferred to the neonatal or pediatric intensive care unit. Referral should not be through an emergency department, because this delays the initiation of treatment [45]. Upon admission, a type and cross-match of the infant’s blood and placement of umbilical catheter are performed promptly, so that exchange transfusion can be started as quickly as possible. (See 'Technique' above.)

Special circumstances — In infants with isoimmune hemolytic disease and rising TB despite intensive phototherapy, administration of intravenous immunoglobulin (IVIG) is recommended since it may avoid the need for exchange transfusion. (See 'Intravenous immunoglobulin' below.)

Exchange transfusion should be considered in infants receiving phototherapy who develop the "bronze baby" syndrome, if phototherapy has been ineffective in reducing TB below the threshold range for intensive phototherapy [2]. (See 'Adverse effects' above.)

Bilirubin/albumin ratio — The bilirubin/albumin (B/A) 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 [2,46]. (See "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Bilirubin/albumin ratio'.)

For infants ≥38 weeks GA, consider exchange transfusion when TB (mg/dL)/albumin (g/dL) ratio is >8 or TB (micromol/L)/albumin (micromol/L) is >0.94.

For infants 35 to 37 6/7 weeks GA and well, or ≥38 weeks with high risk (eg, isoimmune hemolytic disease or G6PD deficiency), consider exchange transfusion when TB (mg/dL)/albumin (g/dL) ratio is >7.2 or TB (micromol/L)/albumin (micromol/L) is >0.84.

For infants 35 to 37 6/7 weeks GA with high risk (eg, isoimmune hemolytic disease or G6PD deficiency), consider exchange transfusion when TB (mg/dL)/albumin(g/dL) ratio is >6.8 or TB (micromol/L)/albumin (micromol/L) is >0.8.

Efficacy — After a successful procedure, TB typically falls to approximately one-half of the pre-exchange value, then increases to approximately two-thirds of that of the pre-exchange concentration because there is re-equilibration between extravascular and vascular bilirubin.

Observational studies report that exchange transfusions decreased the risk for prominent neurologic abnormalities in term infants with TB >20 mg/dL (342 micromol/L) [47] and improved abnormal brainstem auditory-evoked response (BAER) in infants with severe hyperbilirubinemia [48-51]

Risks — The risks of exchange transfusion result from the use of blood products and from the procedure itself. Complications include:

Blood-borne infection Thrombocytopenia and coagulopathy Graft versus host disease Necrotizing enterocolitis (NEC) Portal vein thrombosis Electrolyte abnormalities (eg, hypocalcemia and hyperkalemia) Cardiac arrhythmias

(See "Administration and complications of red cell transfusion in infants and children".)

As previously mentioned, the current morbidity and mortality rates associated with exchange transfusions are not known because the procedure is rarely performed [37]. Studies published in 1985 reported mortality rates of 0.3 percent associated with exchange transfusions [40,41] and a significant complication rate of 1 percent [41]. In a retrospective review of 15 years experience from 1981 to 1995 at two academic medical centers, 1 of 81 healthy infants developed necrotizing enterocolitis after exchange transfusion and none died [52].

PHARMACOLOGIC AGENTS — Pharmacologic agents, including intravenous immunoglobulin (IVIG), phenobarbital, ursodeoxycholic acid, and metalloporphyrins can be used to inhibit hemolysis, increase conjugation and excretion of bilirubin, increase bile flow, or inhibit the formation of bilirubin, respectively. However, currently only IVIG is used to treat unconjugated hyperbilirubinemia.

Intravenous immunoglobulin — IVIG can reduce the need for exchange transfusion in infants with hemolytic disease caused by Rh or ABO incompatibility [53-55]. Several systematic reviews and meta-analyses have shown that infants who received IVIG compared with the control group had lower rates of exchange transfusions [53-57]. Avoiding exchange transfusion reduces the risk of any of its potential adverse effects; as a result, the administration of IVIG should be considered based on the relative benefits and risks of the two interventions.

IVIG (dose 0.5 to 1 g/kg over two hours) is recommended in infants with isoimmune hemolytic disease if the total bilirubin (TB) is rising despite intensive phototherapy or is within 2 or 3 mg/dL (34 to 51 micromol/L) of the threshold for exchange transfusion [2,56]. The dose may be repeated in 12 hours if necessary [2]. (See 'Exchange transfusion' above.)

The mechanism is uncertain, but IVIG is thought to inhibit hemolysis by blocking antibody receptors on red blood cells. (See "Overview of Rhesus (Rh) alloimmunization in pregnancy".)

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 [58,59]. As a result, phenobarbital is not routinely used to treat indirect neonatal hyperbilirubinemia.

Ursodeoxycholic acid — Ursodeoxycholic acid increases bile flow and helps to lower TB levels. It is also useful in the treatment of cholestatic jaundice.

Metalloporphyrins — Synthetic metalloporphyrins, such as tin mesoporphyrin (SnMP), reduce bilirubin production by competitive inhibition of heme oxygenase [60-67]. There are limited data upon the safety of SnMP [67], and SnMP is not available for general use.

In one report, term infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency given SnMP at approximately 27 hours of age had lower and earlier peak TB values than did control infants with and without G6PD deficiency [60]. No treated infant required phototherapy, compared with 31 and 15 percent in the controls with and without G6PD deficiency, respectively.

In a systematic review of three randomized trials including 170 infants, short-term benefits of metalloporphyrin therapy included lower maximum TB, lower frequency of severe hyperbilirubinemia, decreased need for phototherapy, and shorter duration of hospitalization [61,62,66]. None of the enrolled infants required exchange transfusion. None of the studies reported on kernicterus, death, or long-term neurodevelopmental outcome.

SnMP is not approved for use in the United States.

OUTCOME — When infants with hyperbilirubinemia are identified and treated appropriately, the outcome is excellent with minimal or no additional risk for adverse neurodevelopmental sequelae [68-70]. This was illustrated in a prospective cohort control study of 140 infants with total bilirubin (TB) levels ≥25 mg/dL (428 micromol/L)identified from a cohort of 106,627 term or late preterm infants [68]. The study group also included 10 infants with TB ≥30 mg/dL (513 micromol/L). Treatment of hyperbilirubinemia 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), Asian, and were exclusively breastfed during birth hospitalization. At two-year follow-up, results were as follows:

There were no reports of kernicterus in either the hyperbilirubinemic or control group. Formal cognitive testing was performed in 82 children with neonatal hyperbilirubinemia and

168 control children at two and six years of age. There was no difference between patients with hyperbilirubinemia and matched controls in cognitive testing, reported behavioral problems, and frequency of parental concerns.

On physical examination, patients with hyperbilirubinemia compared with control patients had a lower prevalence of abnormal neurologic findings (14 versus 29 percent). The degree and duration of hyperbilirubinemia had no effect on these outcomes.

In a subset analysis, nine patients with hyperbilirubinemia and a positive direct antiglobulin test (DAT, 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 ≥2000 g between 1959 and 1966 [69]. Results showed an adverse effect on cognitive testing was only seen in children who had a TB ≥25 mg/dL (428micromol/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 severe 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 gender, age, gestational age, and municipality of residency [71].

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 for hyperbilirubinemia in term and late preterm infants [70]. There were no differences in the overall neurologic composite outcome (cerebral palsy, developmental delay, hearing and vision abnormalities, attention-deficit disorder, and autism) in infants with severe (TB ≥19 mg/dL [325 mmol/L]) or moderate (TB ≥19 mg/dL [325mmol/L]) hyperbilirubinemia compared with those without hyperbilirubinemia. However, subset analysis for each neurologic outcome suggested that some neurologic impairment might be associated with hyperbilirubinemia. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Neurologic dysfunction'.)

These results support the American Academy of Pediatrics (AAP) treatment guidelines 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.

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 5th to 6th 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 10th to 12th 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 information: Jaundice in babies (The Basics)") Beyond the Basics topics (see "Patient information: Jaundice in newborn infants (Beyond the

Basics)")

A list of frequently asked questions and answers for parents is available through the American Academy of Pediatrics (AAP):http://www.healthychildren.org/English/news/Pages/Jaundice-in-Newborns.aspx

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