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Unconjugated hyperbilirubinemia in the newborn: Pathogenesis and etiology

Unconjugated hyperbilirubinemia in the newborn: Pathogenesis and etiology
Authors:
Ronald J Wong, BA
Vinod K Bhutani, MD, FAAP
Section Editors:
Steven A Abrams, MD
Elizabeth B Rand, MD
Deputy Editor:
Laurie Wilkie, MD, MS
Literature review current through: Feb 2022. | This topic last updated: Dec 02, 2021.

INTRODUCTION — Almost all newborn infants develop a total serum or plasma bilirubin (TB) level >1 mg/dL (17 micromol/L), which is the upper limit of normal for adults. As TB levels increase, neonatal hyperbilirubinemia can develop, noticeable as jaundice, a visible yellowish discoloration of the skin and/or conjunctiva, caused by bilirubin deposition (TB levels of 4 to 5 mg/dL [68 to 86 micromol/L]). 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, subsequently binds to brain tissue, and induces neurotoxicity.

The pathogenesis and etiology of progressive neonatal unconjugated hyperbilirubinemia is reviewed here. The clinical features, evaluation, prevention, and treatment 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 term and late preterm infants: Management" and "Unconjugated hyperbilirubinemia in the preterm infant (less than 35 weeks gestational age)".)

Causes of cholestasis in the newborn, which presents as direct or conjugated hyperbilirubinemia, are also discussed elsewhere. (See "Causes of cholestasis in neonates and young infants".)

DEFINITIONS — Although there is limited 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 >95th percentile on the hour-specific Bhutani nomogram (figure 1) [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) that can be prevented with phototherapy.

Extreme neonatal 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 (BIND) is due to selective 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. 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). BIND is a major complication of an elevated total serum/plasma bilirubin (TB) level (generally less than 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 a constellation of 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) is the chronic and permanent clinical manifestation of a pathologic condition previously referred to as kernicterus caused by bilirubin neurotoxicity. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Epidemiology and clinical manifestations", section on 'Chronic bilirubin encephalopathy (kernicterus)'.)

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 (figure 2). (See "Bilirubin metabolism".)

Bilirubin production — Bilirubin is a product of heme catabolism. In newborns, 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. Measurements of carbon monoxide (CO) production, such as end-tidal CO (ETCO) or carboxyhemoglobin (COHb) levels, both corrected for ambient CO (ETCOc and COHbc, respectively), can be used as indices of in vivo bilirubin production

Bilirubin is produced in two steps (figure 2).

The enzyme heme oxygenase (HO), located in all nucleated cells, catalyzes the breakdown of heme, resulting in the formation of equimolar quantities of iron, CO, and biliverdin.

Biliverdin then is rapidly converted to bilirubin by the enzyme biliverdin reductase. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Screening", section on 'Additional evaluation'.)

Bilirubin clearance and excretion — Clearance and excretion of bilirubin occur in the following subsequent steps (figure 2):

Hepatic uptake – Circulating bilirubin bound to albumin is transported to the liver. Bilirubin then dissociates from albumin and is taken up by hepatocytes, where it is processed for excretion.

Conjugation – In hepatocytes, the enzyme uridine diphosphogluconurate glucuronosyltransferase (UGT1A1) catalyzes the conjugation of bilirubin with glucuronic acid, producing bilirubin diglucuronides and, to a lesser degree, bilirubin monoglucuronides.

Biliary excretion – Conjugated bilirubin, which is more water-soluble than unconjugated bilirubin, is secreted into the bile in an active process that depends upon canalicular transporters, and then excreted into the digestive tract (figure 3).

Enterohepatic circulation – The secreted conjugated bilirubin cannot be reabsorbed by the intestinal epithelial cells. In the adult, it is reduced to urobilin by intestinal bacterial enzymes. However, at birth an 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. In the infant, beta-glucuronidase in intestinal mucosa deconjugates the conjugated bilirubin. The unconjugated bilirubin can then be reabsorbed through the intestinal wall and recycled into the circulation, a process known as the enterohepatic circulation of bilirubin.

BENIGN NEONATAL HYPERBILIRUBINEMIA

Mechanism — Benign neonatal hyperbilirubinemia (also previously referred to as "physiologic jaundice") results in unconjugated (indirect-reacting) bilirubinemia that occurs in nearly all newborns [2]. It is a normal transitional phenomenon caused by the turnover of fetal red blood cells, the immaturity of the newborn's liver to efficiently metabolize (conjugate) bilirubin, and increased enterohepatic circulation.

Normal adult total serum or plasma bilirubin (TB) levels are <1 mg/dL, while term newborns typically have TB levels that peak at a median of approximately 8 to 9 mg/dL 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. After birth there is an increased turnover of fetal red blood cells, resulting in the production of more bilirubin.

Bilirubin clearance (conjugation and excretion) is decreased in newborns, mainly due to the deficiency of the hepatic enzyme uridine diphosphogluconurate glucuronosyltransferase (UGT1A1). UGT1A1 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 as the amount of unconjugated bilirubin increases due to the limited bacterial conversion of conjugated bilirubin to urobilin, allowing for increased deconjugation by beta-glucuronidase in the intestinal mucosa (figure 2). This further increasing the bilirubin load in the infant. (See 'Bilirubin clearance and excretion' above.)

Peak TB levels and time to resolution — Peak total serum or plasma bilirubin (TB) and time to resolution vary by an infant's diet, ethnicity, and gestational age (GA), likely because of differences in hepatic uptake, clearance, and excretion [5-7].

Peak TB – Both the height and the timing of peak TB typically vary based on ethnicity:

In White and Black term infants, mean TB levels peak at 48 to 96 hours of age and range from 7 to 9 mg/dL (120 to 154 micromol/L). The 95th percentile ranges from 13 to 18 mg/dL (222 to 308 micromol/L) [8].

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

Time to resolution – Visible jaundice resolves within the first one to two weeks after birth. Clinical jaundice typically resolves by one week in formula-fed White and Black infants, and by the 10th day in Eastern Asian infants. Jaundice resolves by three weeks in approximately 65 percent of exclusively breastfed newborns, although approximately one in five are still jaundiced at four weeks of age [9]. Persistence of hyperbilirubinemia beyond two weeks of age has been labelled as prolonged hyperbilirubinemia/jaundice and these infants require an assessment of their direct or conjugated bilirubin levels to rule out cholestatic jaundice [10]. (See "Approach to evaluation of cholestasis in neonates and young infants".)

These differences in peak TB levels and time needed for resolution among ethnic groups may result from specific genetic variations in hepatic conjugating ability of bilirubin [2]. As an example, polymorphisms in the UGT1A1 gene, due to differences in the number of thymine-adenine (TA) repeats or "TATA box" in the promoter region of the gene, vary among individuals of Eastern Asian, African, and European ancestries [11]. These polymorphisms correlate with decreases in UGT1A1 enzyme activity resulting in increased TB levels and longer duration for resolution.

Another cause of racial variation results from a common mutation in the UGT1A1 gene at Gly71Arg (known as UGT1A1*6 mutation) that occurs in Eastern Asian infants. This mutation leads to an increased incidence of severe neonatal hyperbilirubinemia (approximately 20 percent) [12,13]. The increased frequency of this polymorphism increases the risk of developing hyperbilirubinemia in infants born to mothers who are Eastern Asian. Other UGT1A1 polymorphisms have also been identified (UGT1A1*9, UGT1A1*16, UGT1A1*27, and UGT1A1*28), but further work is needed to fully elucidate the impact of these mutations on an infant's risk for developing severe hyperbilirubinemia. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Epidemiology and clinical manifestations", section on 'Risk factors'.)

CAUSES OF SIGNIFICANT UNCONJUGATED NEONATAL HYPERBILIRUBINEMIA

Overview — Hyperbilirubinemia can be caused by specific underlying pathologic conditions or by exaggerations of the mechanisms responsible for normal neonatal "physiologic jaundice" jaundice (figure 2). Identification of an underlying pathologic cause of neonatal hyperbilirubinemia is useful in determining whether therapeutic interventions are needed and timing of intervention to prevent severe hyperbilirubinemia. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Management".)

Any increase in bilirubin load resulting in significant hyperbilirubinemia is due to either or both an increase in bilirubin production or a decrease in bilirubin clearance (figure 4).

Increased production — The most common cause of significant unconjugated hyperbilirubinemia (>95th percentile on the Bhutani nomogram) is increased bilirubin production due to hemolytic disease processes, such as [8,11,12,14-18]:

Isoimmune-mediated hemolysis (eg, ABO or Rh[D] incompatibility) [19]. (See "Management of non-RhD red blood cell alloantibodies during pregnancy" and "Postnatal diagnosis and management of hemolytic disease of the fetus and newborn".)

Inherited red blood cell membrane defects (eg, hereditary spherocytosis and elliptocytosis). (See "Hereditary spherocytosis" and "Hereditary elliptocytosis and related disorders".)

Erythrocyte enzymatic defects (eg, glucose-6-phosphate dehydrogenase [G6PD] deficiency [20], pyruvate kinase deficiency, and congenital erythropoietic porphyria). (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency" and "Pyruvate kinase deficiency" and "Congenital erythropoietic porphyria".)

Sepsis – The mechanism is not known; however, one theory suggests that increased oxidative stress due to sepsis damages neonatal red blood cells [8].

Other causes of increased bilirubin production due to increased red blood cell breakdown include polycythemia or sequestration of blood within a closed space, such as in cephalohematomas. (See "Neonatal polycythemia".)

Macrosomic infants of diabetic mothers (IDM) have increased bilirubin production due to either polycythemia or ineffective erythropoiesis. (See "Infants of women with diabetes".)

Decreased clearance — Inherited defects in the gene that encodes the enzyme 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 [21]. These disorders include Crigler-Najjar syndrome types I and II and Gilbert syndrome. These syndromes 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) – This is the most severe form of inherited UGT1A1 disorders. UGT1A1 activity is essentially absent, and severe hyperbilirubinemia develops in the first two to three days after birth. Lifelong phototherapy is required to avoid the development of bilirubin-induced neurologic dysfunction (BIND) unless liver transplantation is performed. The mode of inheritance is autosomal recessive.

Crigler-Najjar syndrome type II (CN-II) – CN-II is less severe than is CN-I. UGT1A1 activity 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 due to mutations in the UGT1A1 gene. In White and Black patients, it results from a mutation in the promoter region of the UGT1A1 gene [22]. The mutation causes a reduced production of UGT1A1, leading to unconjugated hyperbilirubinemia. In the Eastern Asian population, Gilbert syndrome results from a missense mutation in the coding area of the UGT1A1 gene [12,23]. Breast milk jaundice during the second week after birth may be due to the concurrent neonatal manifestation of Gilbert syndrome. (See 'Breast milk jaundice' below.)

In the United States, 9 percent of the population is homozygous and 42 percent heterozygous for the Gilbert mutation [24]. Newborns who are homozygous for the gene mutation have a higher incidence of developing hyperbilirubinemia during the first two days after birth than infants without the mutation or those who are heterozygous [25]. Similar findings have been noted in other parts of the world, especially in Eastern Asian countries [13,26]. There is also evidence that increased hemolysis contributes to neonatal hyperbilirubinemia in addition to the reduction in bilirubin conjugation [27].

However, data from case series have reported that the Gilbert genotype alone is not sufficient to increase the incidence of hyperbilirubinemia [28,29]. Rather, the Gilbert genotype appears to only become clinically relevant when affected newborns have increased bilirubin production or enhanced enterohepatic circulation of bilirubin [30,31]. In particular, the combination of a Gilbert genotype with an underlying condition that increases TB production, such as G6PD deficiency, is associated with severe or significant hyperbilirubinemia [18,30,32]. (See "Gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction".)

OATP-2 polymorphism — In addition to the polymorphisms of the UGT1A1 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 [33]. Furthermore, the combination of the OATP-2 polymorphism with a UGT1A1 gene mutation increased this risk.

Other causes of decreased clearance — Other causes of decreased bilirubin clearance include maternal diabetes [34], congenital hypothyroidism, galactosemia, and panhypopituitarism, although in the latter two conditions, infants typically present with elevated conjugated hyperbilirubinemia. These disorders 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 of bilirubin — Causes of hyperbilirubinemia due to increased enterohepatic circulation of bilirubin include impaired intestinal motility caused by functional or anatomic obstruction and possibly breast milk jaundice, but the underlying mechanisms of the latter has not been confirmed.

Breast milk jaundice — Breast milk jaundice is defined as the persistence of benign neonatal hyperbilirubinemia beyond the first two to three weeks of age. It typically presents 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 [9,35]. Breast milk jaundice needs to be distinguished from breastfeeding (lactation) failure jaundice, the latter is due to suboptimal fluid and caloric intake during the first seven days of life. (See 'Lactation failure jaundice' below.)

In infants with jaundice who exclusively receive human milk, TB levels >5 mg/dL (86 micromol/L) often persist for several weeks after delivery [9]. Although the hyperbilirubinemia is generally mild and typically does not require intervention, it should be monitored to ensure that it remains in the unconjugated form 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. In the case of elevated conjugated bilirubin, causes of cholestasis need to be considered. If after evaluation human milk intake is the only remaining viable factor, human milk feeding can continue if the TB remains in a safe zone with the expectation of resolution by 12 weeks of age [36]. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Screening" and "Causes of cholestasis in neonates and young infants" and "Approach to evaluation of cholestasis in neonates and young infants".)

The underlying mechanism of "breast milk jaundice" is not fully known. Human milk contains high concentrations of beta-glucuronidase, which catalyzes the hydrolysis of beta-D-glucuronic acid [37]. In contrast, there is negligible amounts of beta-glucuronidase in infant formula, and formula-fed infants have lower levels of bilirubin than those who receive human milk [38,39]. For breast milk-fed infants, the loss of beta-D-glucuronic acid due to increased degradation is thought to promote an increase in intestinal absorption of unconjugated bilirubin [37] (figure 2). Beta-glucuronidase inhibitors, such as enzymatically-hydrolyzed casein or L-aspartic acid, which is contained in casein hydrolysate formula, have been used prophylactically in breastfed newborns [40]. However, the prolonged unconjugated hyperbilirubinemia associated with human milk is benign, and there appears to be no benefit for the use of these agents [41]. As a result, we do not recommend these agents for treating breast milk jaundice.

Another potential underlying mechanism is polymorphic mutation of the UGT1A1 gene. In a Japanese study of 170 neonates with breast milk jaundice, half of infants were homozygous for the UGT1A1*6 genotype [42]. These infants had higher TB levels than infants with other polymorphisms. The UGT1A1*6 genotype was not detected in control infants. However, further studies in other areas of the world are needed to determine whether there is a causal relationship between genetic variation of the UGT1A1 gene and breast milk jaundice. Thus, currently genetic testing should not be used in the evaluation of breast milk-related jaundice.

Ileus or intestinal obstruction — Ileus or anatomic causes of intestinal obstruction increase the enterohepatic circulation of bilirubin and result in hyperbilirubinemia. TB levels are frequently higher with small bowel than with large bowel obstructions. As an example, hyperbilirubinemia occurs in 10 to 25 percent of infants with pyloric stenosis when vomiting begins. (See "Infantile hypertrophic pyloric stenosis", section on 'Clinical associations'.)

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

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

Late preterm infants (defined as gestational age [GA] between 34 and 36 weeks and 6 days) 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/or difficulty maintaining a latch because their oro-buccal coordination and swallowing mechanisms are not fully matured. As a result, additional support and close monitoring are warranted for this group of infants and their mothers. (See "Breastfeeding the preterm infant", section on 'Late preterm infants'.)

Establishment of successful breastfeeding, one of the mainstays of preventing hyperbilirubinemia, is challenging 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 and is discussed in greater detail separately. (See "Breastfeeding: Parental education and support" and "Initiation of breastfeeding".)

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 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.)

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

SUMMARY

Introduction and definitions – 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 mg/dL [428 micromol/L]) are at risk for developing bilirubin-induced neurologic dysfunction (BIND), presenting acutely as acute bilirubin encephalopathy (ABE) and, if not treated appropriately or in a timely manner, leading to long-term neurologic sequelae of chronic bilirubin encephalopathy (CBE, previously referred to as kernicterus). (See 'Introduction' above and 'Definitions' above.)

Benign hyperbilirubinemia – Benign ("nonpathologic") neonatal hyperbilirubinemia, previously referred to as "physiologic jaundice," is a normal transitional phenomenon caused by the turnover of fetal red blood cells, immaturity of the newborn's liver to efficiently metabolize bilirubin, and sterile newborn gut, resulting in decreased bilirubin clearance and increased enterohepatic circulation (figure 2). It typically presents as mild unconjugated (indirect-reacting) hyperbilirubinemia. Mean TB levels normally peak at 7 to 9 mg/dL (120 to 154 micromol/L) in White and Black infants and are higher in Eastern Asian infants, 10 to 14 mg/dL (171 to 239 micromol/L). (See 'Benign neonatal hyperbilirubinemia' above.)

Mechanism of neonatal hyperbilirubinemia – Hyperbilirubinemia is due to increased bilirubin load either due to an increase in bilirubin production or decrease in clearance, or both (figure 4). (See 'Mechanism' above and 'Increased production' above and 'Decreased clearance' above.)

Clinically significant hyperbilirubinemia – For infants with severe and extreme hyperbilirubinemia, identification of the cause of their hyperbilirubinemia is useful in determining whether therapeutic interventions are needed and their timing. (See 'Causes of significant unconjugated neonatal hyperbilirubinemia' above.)

Causes of significant unconjugated neonatal hyperbilirubinemia can be classified by pathogenesis as follows:

-Increased production of bilirubin – Hemolytic disease, polycythemia, and sequestration of blood within a closed space increase bilirubin production because of increased red cell breakdown. (See 'Increased production' 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 of bilirubin' above.)

-Inadequate intake of breast milk due to unsuccessful establishment of breastfeeding (lactation failure) resulting in hypovolemia and inadequate caloric intake. (See 'Lactation failure jaundice' above.)

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  31. Kaplan M, Renbaum P, Vreman HJ, et al. (TA)n UGT 1A1 promoter polymorphism: a crucial factor in the pathophysiology of jaundice in G-6-PD deficient neonates. Pediatr Res 2007; 61:727.
  32. Watchko JF. Vigintiphobia revisited. Pediatrics 2005; 115:1747.
  33. Huang MJ, Kua KE, Teng HC, et al. Risk factors for severe hyperbilirubinemia in neonates. Pediatr Res 2004; 56:682.
  34. Stevenson DK, Ostrander CR, Hopper AO, et al. Pulmonary excretion of carbon monoxide as an index of bilirubin production. IIa. Evidence for possible delayed clearance of bilirubin in infants of diabetic mothers. J Pediatr 1981; 98:822.
  35. Grunebaum E, Amir J, Merlob P, et al. Breast mild jaundice: natural history, familial incidence and late neurodevelopmental outcome of the infant. Eur J Pediatr 1991; 150:267.
  36. Preer GL, Philipp BL. Understanding and managing breast milk jaundice. Arch Dis Child Fetal Neonatal Ed 2011; 96:F461.
  37. Gourley GR, Arend RA. beta-Glucuronidase and hyperbilirubinaemia in breast-fed and formula-fed babies. Lancet 1986; 1:644.
  38. Gourley GR, Kreamer B, Arend R. The effect of diet on feces and jaundice during the first 3 weeks of life. Gastroenterology 1992; 103:660.
  39. Gourley GR, Kreamer B, Cohnen M, Kosorok MR. Neonatal jaundice and diet. Arch Pediatr Adolesc Med 1999; 153:184.
  40. Gourley GR, Li Z, Kreamer BL, Kosorok MR. A controlled, randomized, double-blind trial of prophylaxis against jaundice among breastfed newborns. Pediatrics 2005; 116:385.
  41. Bhutani VK. Abuse of casein hydrolysate formulas for treating infants with severe hyperbilirubinemia. Pediatrics 2006; 117:2317; author reply 2317.
  42. Maruo Y, Morioka Y, Fujito H, et al. Bilirubin uridine diphosphate-glucuronosyltransferase variation is a genetic basis of breast milk jaundice. J Pediatr 2014; 165:36.
Topic 5020 Version 41.0

References

1 : Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation.

2 : Neonatal hyperbilirubinemia.

3 : Neonatal hyperbilirubinemia.

4 : The prenatal and postnatal development of UDP-glucuronyltransferase activity towards bilirubin and the effect of premature birth on this activity in the human liver.

5 : Impact of fatty acids on human UDP-glucuronosyltransferase 1A1 activity and its expression in neonatal hyperbilirubinemia.

6 : Reduced expression of UGT1A1 in intestines of humanized UGT1 mice via inactivation of NF-κB leads to hyperbilirubinemia.

7 : Role of extrahepatic UDP-glucuronosyltransferase 1A1: Advances in understanding breast milk-induced neonatal hyperbilirubinemia.

8 : Role of extrahepatic UDP-glucuronosyltransferase 1A1: Advances in understanding breast milk-induced neonatal hyperbilirubinemia.

9 : The natural history of jaundice in predominantly breastfed infants.

10 : Guideline for the Evaluation of Cholestatic Jaundice in Infants: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

11 : Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism?

12 : Neonatal hyperbilirubinemia and mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene: a common missense mutation among Japanese, Koreans and Chinese.

13 : Neonatal hyperbilirubinemia and Gly71Arg mutation of UGT1A1 gene: a Chinese case-control study followed by systematic review of existing evidence.

14 : Hidden risks: early discharge and bilirubin toxicity due to glucose 6-phosphate dehydrogenase deficiency.

15 : Glucose-6-phosphate dehydrogenase deficiency and carboxyhemoglobin concentrations associated with bilirubin-related morbidity and death in Nigerian infants.

16 : Exaggerated jaundice in Navajo neonates. The role of bilirubin production.

17 : Comparison of bilirubin production in Japanese and Caucasian infants.

18 : Complex multifactorial nature of significant hyperbilirubinemia in neonates.

19 : Direct antiglobulin titer strength and hyperbilirubinemia.

20 : Glucose-6-phosphate dehydrogenase deficiency and borderline deficiency: association with neonatal hyperbilirubinemia.

21 : UGT1A1 genetic analysis as a diagnostic aid for individuals with unconjugated hyperbilirubinemia.

22 : The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome.

23 : Association of neonatal hyperbilirubinemia with bilirubin UDP-glucuronosyltransferase polymorphism.

24 : Interaction of coding region mutations and the Gilbert-type promoter abnormality of the UGT1A1 gene causes moderate degrees of unconjugated hyperbilirubinaemia and may lead to neonatal kernicterus.

25 : Gilbert syndrome accelerates development of neonatal jaundice.

26 : Prolonged unconjugated hyperbiliriubinemia in breast-fed male infants with a mutation of uridine diphosphate-glucuronosyl transferase.

27 : Hemolysis and bilirubin conjugation in association with UDP-glucuronosyltransferase 1A1 promoter polymorphism.

28 : Severe neonatal hyperbilirubinemia and UGT1A1 promoter polymorphism.

29 : Extreme neonatal hyperbilirubinemia and a specific genotype: a population-based case-control study.

30 : Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia.

31 : (TA)n UGT 1A1 promoter polymorphism: a crucial factor in the pathophysiology of jaundice in G-6-PD deficient neonates.

32 : Vigintiphobia revisited.

33 : Risk factors for severe hyperbilirubinemia in neonates.

34 : Pulmonary excretion of carbon monoxide as an index of bilirubin production. IIa. Evidence for possible delayed clearance of bilirubin in infants of diabetic mothers.

35 : Breast mild jaundice: natural history, familial incidence and late neurodevelopmental outcome of the infant.

36 : Understanding and managing breast milk jaundice.

37 : beta-Glucuronidase and hyperbilirubinaemia in breast-fed and formula-fed babies.

38 : The effect of diet on feces and jaundice during the first 3 weeks of life.

39 : Neonatal jaundice and diet.

40 : A controlled, randomized, double-blind trial of prophylaxis against jaundice among breastfed newborns.

41 : Abuse of casein hydrolysate formulas for treating infants with severe hyperbilirubinemia.

42 : Bilirubin uridine diphosphate-glucuronosyltransferase variation is a genetic basis of breast milk jaundice.