Which factor contributed to the development of physiological jaundice in a newborn?

G6PD Deficiency and Hemolysis.

Most G6PD-deficient individuals lead perfectly normal lives and will, for the most part, be unaware of their inherited condition. However, G6PD deficiency may be associated with severe hemolytic episodes with resultant jaundice and anemia, following exposure to a hemolytic trigger. Classically, these episodes often occur after ingestion of or contact with the fava bean (favism). Medications and chemical substances may be suspected, but sometimes no offending trigger is identified. Infection may play a role in the pathogenesis of acute hemolysis.

In neonates, extreme hemolytic hyperbilirubinemia may develop suddenly and without previous warning. Some identifiable substances associated with neonatal hemolysis include naphthalene (used to store clothes), herbal medicines, henna applications, or menthol-containing umbilical potions. Frequently, the trigger cannot be recognized and the hemoglobin concentration may not drop, leading to the erroneous diagnosis that hemolysis is not occurring. There can, however, be no other viable explanation for the exponential increase in TB to dangerous levels. G6PD deficiency may, therefore, be the one reason that kernicterus may not be completely preventable. Exchange transfusion may be the only recourse. Early hospital discharge with delayed follow-up may place these patients at risk for severe sequelae.

In a Nigerian neonatal cohort, G6PD-deficient and -intermediate (presumable heterozygotes) had higher TB, lower hematocrit values, and a greater need for phototherapy during the first postnatal week than G6PD-normal counterparts, suggestive of increased hemolysis.20 Frequently, hematologic indices typical of hemolysis in older children and adults, including falling hemoglobin and hematocrit values and increasing reticulocyte counts, may be absent despite a clinical picture of hemolysis. However, studies of endogenous CO formation, reflective of the rate of heme catabolism, have demonstrated an important role of increased hemolysis in association with this condition. Significantly higher levels of COHb have been reported in Nigerian G6PD-deficient neonates who developed kernicterus compared with neonates who were hyperbilirubinemic but did not develop signs of kernicterus.

More frequently and less life threatening, G6PD-deficient neonates may have a moderate form of jaundice, which occurs at a rate several-fold that of controls. The jaundice usually responds to phototherapy, although exchange transfusion may also be necessary. These infants have a low-grade hemolysis that cannot be implicated as the primary icterogenic factor.135 Diminished bilirubin conjugation has been shown to be of major importance in the pathogenesis of the hyperbilirubinemia. An intriguing interaction has been noted between G6PD deficiency and a noncoding area (TA)7 promoter polymorphism in the gene encoding UGT1A1.138 This polymorphism, also known as UGT1A1*28, is associated with Gilbert syndrome. The incidence of a TB of at least 15 mg/dL (257 µmol/L) increased in a stepwise, dose-dependent fashion in G6PD-deficient neonates who were heterozygous or homozygous, respectively, for the polymorphism. This effect was not seen in the G6PD-normal control group. Furthermore, G6PD deficiency alone, in the absence of the promoter polymorphism, did not increase the incidence of hyperbilirubinemia over and above that of G6PD-normal counterparts. In Asians, in whom the (TA)7 promoter polymorphism is rare, a similar interaction was noticed between G6PD deficiency and coding area mutations of theUGT1A1 gene.115 In a recent study of African-American neonates, although 20.6% had variations in bothUGT1A1 andSLCO1B1 genes, these genetic variants did not have an effect on the incidence of hyperbilirubinemia.238 This may be because very few neonates in that cohort were G6PD-deficient, confirming the concept of a gene interaction necessary to influence the incidence of hyperbilirubinemia.

Classification

Hyperbilirubinemia is another term for jaundice. Neonatal jaundice is classified as either physiologic or nonphysiologic. Jaundice in full-term, healthy newborns is considered physiologic because hyperbilirubinemia occurs in all neonates. Nonphysiologic, or pathologic, jaundice is when the hyperbilirubinemia occurs less than 24 hours after birth, if bilirubin levels rise at a rate greater than 0.5 mg/dl per hour or 5 mg/dl per day, if total bilirubin levels exceed 15 mg/dl in a full-term infant, or 10 mg/dl in a premature infant, if evidence of acute hemolysis exists, or if hyperbilirubinemia persists beyond 10 days in a full-term infant or 21 days in a premature newborn Melton and Akinbi (1999).

Neonatal Jaundice

The most common problem encountered in a term nursery population is jaundice.Jaundice is the visible manifestation of elevated serum concentrations of bilirubin. Neonatal hyperbilirubinemia occurs when the normal pathways of bilirubin metabolism and excretion are altered.Fig. 23.10 demonstrates the metabolism of bilirubin. The normal destruction of circulating red cells accounts for about 75% of the newborn's daily bilirubin production. The remaining sources include ineffective erythropoiesis and tissue heme proteins. Heme is converted to bilirubin in the reticuloendothelial system with carbon monoxide (CO) produced as a byproduct. Unconjugated bilirubin is lipid soluble and is transported in the plasma reversibly bound to albumin. Bilirubin enters the liver cells by dissociation from albumin in the hepatic sinusoids. Once in the hepatocyte, bilirubin is conjugated with glucuronic acid in a reaction catalyzed by uridine diphosphoglu­curonosyl transferase (UDPGT). The water-soluble conjugated bilirubin is excreted rapidly into the bile canaliculi and into the small intestine. The enzyme β-glucuronidase is present in the small bowel and hydrolyzes some of the conjugated bilirubin, converting it back to unconjugated bilirubin. This unconjugated bilirubin can be reabsorbed into the circulation, adding to the total unconjugated bilirubin load (enterohepatic circulation).

Elevations of either conjugated or unconjugated bilirubin can cause jaundice in the neonatal period. However,pathologic jaundice during the early neonatal period is indirect hyperbilirubinemia, usually caused by overproduction of bilirubin. Major predisposing factors of neonatal jaundice are (1) increased bilirubin load because of increased red cell volume with decreased cell survival, increased ineffective erythropoiesis, and the enterohepatic circulation; and (2) decreased hepatic uptake, conjugation, and excretion of bilirubin. These factors result in the presence of clinically apparent jaundice in approximately two thirds of newborns during the first week of life, and in most it is considered physiologic. Infants whose bilirubin levels are above the 95th percentile for age in hours and infants in high-risk groups to develop hyperbilirubinemia require close follow-up (Fig. 23.11 andBox 23.3).52

In the neonatal period, it is critically important to determine whether hemolysis is contributing to hyperbilirubinemia. Hyperbilirubinemia secondary to hemolysis must be diagnosed early to ensure effective treatment and prevent neurologic injury. Fetomaternal blood group incompatibilities—ABO, Rh, and other minor antibodies—are the most common cause of hemolysis in the neonatal period (seeChapter 40). Other causes of hemolysis include genetic disorders: specifically, hereditary spherocytosis and nonspherocytic hemolytic anemias, such as glucose-6-phosphate dehydrogenase (G6PD) deficiency. Performing a direct Coombs test on cord blood, early assessment of the reticulocyte count, and serial hemoglobin/hematocrits can help diagnose hemolysis.

Bronze-baby syndrome

Bronze-baby syndrome refers to the intense, gray-brown, or “bronze-like” hyperpigmentation that occurs in a subset of patients receiving visible light phototherapy for management of neonatal jaundice. Although it is classically associated with the use of phototherapy in children with conjugated hyperbilirubinemia, it also occurs in a subset of patients with unconjugated hyperbilirubinemia in association with hepatic dysfunction, particularly cholestasis. The cause of the bronze pigment is unclear, although there is evidence to suggest that biliverdin and bilifuscin-like photoproducts are involved. Phototherapy should therefore be avoided for infants with conjugated hyperbilirubinemia, and the occurrence of bronze-baby syndrome in an infant with unconjugated hyperbilirubinemia suggests the presence of coexisting hepatic dysfunction.

Physiologic Jaundice (Icterus Neonatorum)

Under normal circumstances, the level of indirect bilirubin in umbilical cord serum is 1-3 mg/dL and rises at a rate of <5 mg/dL/24 hr; thus, jaundice becomes visible on the 2nd or 3rd day, usually peaking between the 2nd and 4th days at 5-6 mg/dL and decreasing to <2 mg/dL between the 5th and 7th days after birth. Jaundice associated with these changes is designatedphysiologic and is believed to be the result of increased bilirubin production from the breakdown of fetal RBCs combined with transient limitation in the conjugation of bilirubin by the immature neonatal liver.

Overall, 6–7% of full-term infants have indirect bilirubin levels >13 mg/dL, and <3% have levels >15 mg/dL. Risk factors for elevated indirect bilirubin include maternal age, race (Chinese, Japanese, Korean, Native American), maternal diabetes, prematurity, drugs (vitamin K3, novobiocin), altitude, polycythemia, male sex, trisomy 21, cutaneous bruising, blood extravasation (cephalohematoma), oxytocin induction, breastfeeding, weight loss (dehydration or caloric deprivation), delayed bowel movement, and a family history of, or a sibling who had, physiologic jaundice (seeTable 123.2). In infants without these variables, indirect bilirubin levels rarely rise >12 mg/dL, whereas infants with several risk factors are more likely to have higher bilirubin levels. A combination of breastfeeding, variant-glucuronosyltransferase activity (1A1), and alterations of the organic anion transporter-2 gene increases the risk of hyperbilirubinemia. Predicting which neonates are at risk for exaggerated physiologic jaundice can be based onhour-specific bilirubin levels in the 1st 24-72 hr of life (Fig. 123.10). Transcutaneous measurements of bilirubin are linearly correlated with serum levels and can be used for screening. Indirect bilirubin levels in full-term infants decline to adult levels (1 mg/dL) by 10-14 days of life. Persistent indirect hyperbilirubinemia beyond 2 wk suggests hemolysis, hereditary glucuronyl transferase deficiency, breast milk jaundice, hypothyroidism, or intestinal obstruction. Jaundice associated with pyloric stenosis may be the result of caloric deprivation, relative deficiency of hepatic UDP–glucuronyltransferase, or an increase in the enterohepatic circulation of bilirubin from the ileus. In premature infants, the rise in serum bilirubin tends to be the same or somewhat slower but of longer duration than in term infants. Peak levels of 8-12 mg/dL are not usually reached until the 4th-7th day, and jaundice is infrequently observed after the 10th day, corresponding to the maturation of mechanisms for bilirubin metabolism and excretion.

The diagnosis of physiologic jaundice in term or preterm infants can be established only by excluding known causes of jaundice on the basis of the history, clinical findings, and laboratory data (seeTable 123.4). In general, a search to determine the cause of jaundice should be made if (1) it appears in the 1st 24-36 hr after birth, (2) serum bilirubin is rising at a rate faster than 5 mg/dL/24 hr, (3) serum bilirubin is >12 mg/dL in a full-term infant (especially in the absence of risk factors) or 10-14 mg/dL in a preterm infant, (4) jaundice persists after 10-14 days after birth, or (5) direct bilirubin fraction is >2 mg/dL at any time. Other factors suggesting a pathologic cause of jaundice are family history of hemolytic disease, pallor, hepatomegaly, splenomegaly, failure of phototherapy to lower the bilirubin level, vomiting, lethargy, poor feeding, excessive weight loss, apnea, bradycardia, abnormal vital signs (including hypothermia), light-colored stools, dark urine positive for bilirubin, bleeding disorder, and signs of kernicterus (seeChapter 123.4).

Bronze Baby Syndrome

Bronze baby syndrome is a term used to describe infants who develop a grayish-brown discoloration of the skin, serum, and urine while undergoing phototherapy for hyperbilirubinemia. Although the exact source of the pigment causing the discoloration is not clear, the syndrome usually begins 1 to 7 days after the initiation of phototherapy, resolves gradually over a period of several weeks after phototherapy is discontinued, and appears to be related to a combination of photoisomers of bilirubin or biliverdin or a photoproduct of copper-porphyrin metabolism.16–18 Infants who develop bronze baby syndrome usually have modified liver function, particularly cholestasis, of various origins.19 Although not all babies with cholestasis develop bronze baby syndrome during phototherapy, those that do should be investigated for underlying liver disease.20 The disorder should be differentiated from neonatal jaundice, cyanosis associated with neonatal pulmonary disorders or con­genital heart disease, an unusual progressive hyperpigmentation (universal-acquired melanosis, the “carbon baby” syndrome),21 and chloramphenicol intoxication (the “gray baby” syndrome), which is a disorder in infants with immature liver function who are unable to conjugate chloramphenicol and is characterized by elevated serum chloramphenicol levels, progressive cyanosis, abdominal distention, hypothermia, vomiting, irregular respiration, and vasomotor collapse.22 A distinctive purpuric eruption on exposed skin has also been described in newborns receiving phototherapy and is possibly related to a tran­sient increase in circulating porphyrins.23 This condition, however, is unlikely to be confused with bronze baby syndrome.

Conclusion

Neonatal jaundice continues to be a common problem. Kernicterus, although rare, is a very real concern in both full-term and preterm infants due to the devastating lifelong neurological damage resulting from severe hyperbilirubinemia. The diagnosis of kernicterus requires not only bilirubin staining in a characteristic pattern in the brain but also neuronal damage. With careful pathological evaluation, kernicterus should be distinguishable from brain damage associated with asphyxia and hypoxia. Early hospital discharge and breast-feeding are risk factors for the development of kernicterus. Prompt effective therapy for neonatal jaundice can prevent kernicterus. In the United States, there is currently no generally accepted method to predict hyperbilirubinemia or kernicterus. BAER and MRI can both be used effectively to monitor the effects of severe hyperbilirubinemia.

117 A newborn develops dark skin discoloration and dark urine after beginning phototherapy. What is the diagnosis?

Bronze baby syndrome. Infants who develop the syndrome typically have an elevated direct serum bilirubin concentration. The bronze baby syndrome results from the retention of photoproducts (e.g., lumirubin) that cannot be excreted in the bile. Most infants appear to recover without complications. Direct hyperbilirubinemia is not a contraindication to phototherapy.

Key Points:

Hematology and Hyperbilirubinemia

The switch from fetal to adult hemoglobin occurs in a preprogrammed manner.

Late preterm infants are at higher risk than term infants for bilirubin encephalopathy.

Although ABO incompatibility is common, sensitization and hemolysis are not.

Exchange transfusion for hyperbilirubinemia in healthy full-term infants without evidence of hemolysis is almost never required.

Every newborn infant should have a predischarge assessment of risk for the development of severe hyperbilirubinemia.

DISEASE DESCRIPTION

Neonatal jaundice is one of the most common problems encountered by pediatricians. Up to 60% of term infants may have clinical jaundice in the first days of life, but few have significant underlying disease. The challenge for the clinician is to determine when clinical jaundice needs further evaluation. Jaundice in the newborn period can be associated with serious illnesses such as hematologic disorders, metabolic diseases, endocrine diseases, infections, and diseases of the liver or the biliary tree. It is critical to know when to pursue an evaluation and to know what tests to order.

Almost all jaundice in the first days of life is due to indirect bilirubin and is a physiologic self-resolving problem. Physiologic hyperbilirubinemia develops as a combination of increased bilirubin production, decreased ability to eliminate bilirubin, and a significant enterohepatic circulation of bilirubin. On a per-kilogram basis, the average newborn produces almost 2.5 times as much bilirubin as an adult.

At times, the pediatrician is presented with a neonate who warrants further analysis, thus the need to approach the problem expeditiously.

Bronze Baby Syndrome

The bronze baby syndrome is a term used to describe infants who develop a grayish-brown discoloration of the skin, serum, and urine while undergoing phototherapy for hyperbilirubinemia. Although the exact source of the pigment causing the discoloration is not clear, the syndrome usually begins 1–7 days after the initiation of phototherapy, resolves gradually over a period of several weeks after phototherapy is discontinued, and appears to be related to a combination of photoisomers of bilirubin or biliverdin or a photoproduct of copper-porphyrin metabolism.14–16 Infants who develop bronze baby syndrome may have modified liver function, particularly cholestasis, of various origins.17 The disorder should be differentiated from neonatal jaundice, cyanosis associated with neonatal pulmonary disorders or congenital heart disease, an unusual progressive hyperpigmentation (universal-acquired melanosis, the ‘carbon baby’ syndrome),18 and chloramphenicol intoxication (the ‘gray baby’ syndrome), which is a disorder in infants with immature liver function, who are unable to conjugate chloramphenicol characterized by elevated serum chloramphenicol levels, progressive cyanosis, abdominal distention, hypothermia, vomiting, irregular respiration, and vasomotor collapse.19 A distinctive purpuric eruption on exposed skin has also been described in newborns receiving phototherapy, possibly related to a transient increase in circulating porphyrins.20 This condition, however, is unlikely to be confused with bronze baby syndrome.