Care of the high-risk neonate usually refers to care of the low-birth-weight infant or the sick term newborn. Although hyperbilirubinemia is certainly a matter of concern in these infants, the decisions that must be made regarding jaundice in the high-risk neonate are, in general, less complex than those that must be made in the healthy full-term infant. For the term and late preterm infant, shorter hospital stays, the need for outpatient surveillance and management, and the occasional disturbing case of extreme hyperbilirubinemia and even kernicterus raise new issues in the management of neonatal jaundice. Bilirubin has both salutary and toxic effects. At physiologic levels it exerts important antioxidant effects. Although its toxic effects are well documented, there are also some concerns that aggressive use of phototherapy in very low-birth-weight infants may not be entirely innocuous.
Most neonatal jaundice is the result of a combination of events—an increase in the rate of bilirubin production, reabsorption of bilirubin into the plasma from the gut (the enterohepatic circulation), and inability of the liver to clear sufficient bilirubin from the plasma.
Formation, Structure, and Properties of Bilirubin
Bilirubin is the end product of the catabolism of iron protoporphyrin, or heme, which comes predominantly from circulating hemoglobin ( Fig. 13-1 ). Bilirubin is a tetrapyrrole compound with specific substitutions in the side chains of the four pyrrole rings. The outer pyrrole rings are linked to the inner ones by methene bridges (containing one double bond each), but the two central rings are joined by a methane bridge (no double bond). Normally, the methene bridge oxidized in heme is in the α-position, and the resultant isomer is bilirubin IX-α (see Fig. 13-3 ), the predominant isomer of bilirubin in the body. Although its structure is conventionally represented in linear fashion as shown in Figure 13-2 , the actual structure of bilirubin revealed by x-ray crystallography is similar to that shown in Figure 13-3 , in which the bilirubin molecule is stabilized by the presence of intramolecular hydrogen bonds (indicated by the dashed lines). In this conformation, the hydrophilic, polar COOH and NH groups are not available for the attachment of water, whereas the hydrophobic hydrocarbon groups are on the perimeter, which makes the molecule insoluble in water but soluble in nonpolar solvents such as chloroform. The addition of methanol or ethanol interferes with hydrogen bonding and results in an immediate diazo reaction—the basis for measurement of indirect bilirubin by the van den Bergh reaction.
In the jaundiced newborn in whom the primary problem is excessive bilirubin formation or limited hepatic uptake and conjugation, unconjugated (i.e., indirect) bilirubin appears in the blood. When bilirubin glucuronide excretion is impaired (i.e., in cholestasis), conjugated bilirubin monoglucuronide and diglucuronide (direct reacting bilirubin) accumulate in the plasma and, because of their solubility, also appear in the urine. A fourth bilirubin fraction, known as delta bilirubin, is formed nonenzymatically from conjugated bilirubin, is covalently bound to albumin, and reacts directly with the diazo agent.
Neonatal Bilirubin Metabolism
Heme degradation leads to bilirubin production from two major sources ( Fig. 13-4 ). Approximately 75% of the daily bilirubin production in the newborn comes from senescent erythrocytes (the catabolism of 1 g of hemoglobin yields 35 mg of bilirubin), but 25% is contributed by nonhemoglobin heme contained in the liver (in enzymes such as cytochromes and catalyses and in free heme) and in muscle myoglobin, or comes from ineffective erythropoiesis in the bone marrow. Once it leaves the reticuloendothelial system, bilirubin is transported in the plasma, bound tightly to albumin, so that at physiologic pH the solubility of bilirubin is very low (about 4 nm/L [0.24 mg/dL]). When the bilirubin-albumin complex comes into contact with the hepatocyte, a proportion of the bilirubin, but not albumin, is transported into the cell, where it is bound to ligandin and then transported to the smooth endoplasmic reticulum for conjugation.
Conversion of unconjugated bilirubin to its water-soluble conjugate must occur before it can be excreted; this is achieved when bilirubin is combined enzymatically with a sugar, glucuronic acid, which produces bilirubin monoglucuronide and diglucuronide pigments that are more water soluble and sufficiently polar to be excreted into the bile or filtered through the kidney. The enzyme catalyzing this reaction is uridine diphosphate glucuronosyltransferase, a single form of which (UGT1A1) accounts for almost all of the bilirubin glucuronide in the human liver. The enzyme arises from the UGT1A1 gene complex situated on chromosome 2 at 2q37. Mutations and amino acid substitutions at different loci on this gene are responsible for the inherited unconjugated hyperbilirubinemias: Crigler-Najjar syndrome types I and II, and Gilbert syndrome. Data suggest a role for another bilirubin transporter, the hepatic solute carrier organic anion transporter 1B1 (SLCO1B1). Gene polymorphisms of SLC1B1 may lead to hyperbilirubinemia by limiting hepatic bilirubin uptake. Once conjugated, bilirubin is excreted via the bile canaliculi into the small intestine. A detailed review of the chemistry and metabolism of bilirubin can be found elsewhere.
Normal Serum Bilirubin Levels and the Natural History of Neonatal Jaundice
Unconjugated bilirubin is transported efficiently via the placenta from fetal blood into the maternal circulation by passive diffusion. The mean total serum bilirubin (TSB) levels in cord blood range from 1.4 to 1.9 mg/dL (24 to 32 µmol/L), whereas maternal TSB levels are less than 1 mg/dL (17.1 µmol). For years it has been taught that the TSB concentration in normal term infants increases from birth, reaches its apex on about the third or fourth day of life, and then declines, reaching normal levels by 7 to 10 days. When bilirubin levels are studied in large populations using transcutaneous bilirubin (TcB) measurements, however, it is clear that in those at or above the 50th percentile, the peak does not occur until about 96 hours and remains at that level through 120 hours ( Fig. 13-5 ). On the other hand, there are significant differences in the natural history in term and late preterm infants for each week of gestation. In those with a gestational age of 40 weeks or longer, the peak TcB occurs at about 60 hours, whereas in those with a gestational age of 35 to 396/7 weeks it does not occur until 96 hours or later ( Fig. 13-6 ). Because of intervention with phototherapy, no recent data are available on the natural history of bilirubinemia in infants of 34 weeks’ gestation or less.
Developmental Jaundice
The normal increase of TSB levels in the newborn has been termed physiologic jaundice, but there is good reason to consider abandoning this term. Depending on ethnic characteristics, breast feeding, and other factors, there are significant differences in TSB levels in different populations, so that what is physiologic for one infant may well be nonphysiologic for another. Particularly for low-birth-weight infants being cared for in the neonatal intensive care unit (NICU), the term physiologic jaundice has little meaning and is potentially dangerous. If no treatment is given, low-birth-weight infants have prolonged and exaggerated hyperbilirubinemia—the lower the birth weight, the higher the peak bilirubin level. A TSB of 10 mg/dL (171 µmol/L) on day 4 in a 750-g neonate is a normal bilirubin level for that infant and requires no investigation to identify a cause for the jaundice. Nevertheless, most neonatologists would treat this bilirubin level with phototherapy. Thus, TSB levels well within the physiologic range are considered potentially hazardous and are commonly treated with phototherapy. The natural history of hyperbilirubinemia in this population is never observed, and defining these bilirubin levels as physiologic in such infants seems illogical and potentially dangerous. A better term for this phenomenon is developmental jaundice.
The jaundice seen in almost every newborn results from a combination of mechanisms:
- •
The normal neonate produces about 6 to 8 mg/kg/day of bilirubin, which is about 2.5 times the rate of bilirubin production in the adult.
- •
The newborn reabsorbs significant amounts of unconjugated bilirubin from the intestine (the enterohepatic circulation). Unlike the adult, newborns have few bacteria in the small and large bowel and they have greater activity of the deconjugating enzyme β-glucuronidase. As a result, conjugated bilirubin (which cannot be reabsorbed), is not converted to urobilinogen but is hydrolyzed to unconjugated bilirubin. This can be reabsorbed and increases the bilirubin load on the liver.
- •
There is a decrease in clearance of bilirubin from the plasma. This is the result of a deficiency in ligandin, the predominant bilirubin-binding protein in the hepatocyte, and a deficiency of UGT1A1, which, at term, has approximately 1% of the activity found in the adult.
An Approach to the Jaundiced Infant
The overwhelming majority of both preterm and term infants who are jaundiced are not jaundiced as a result of any pathologic process. Their jaundice is the result of the mechanisms described earlier, and the relevant clinical and laboratory risk factors for the development of severe hyperbilirubinemia in the term and late preterm infant are well documented. The pathologic causes of indirect hyperbilirubinemia are listed in Box 13-1 .
Increased bilirubin production or load on the liver
Hemolytic disease
Immune mediated
- •
Rh alloimmunization
- •
ABO and other blood group incompatibilities
Heritable
Red cell membrane defects
- •
Spherocytosis, ∗
∗ Decreased clearance is also part of the pathogenesis of indirect hyperbilirubinemia.
elliptocytosis, stomatocytosis, pyknocytosis
Red cell enzyme deficiencies
- •
Glucose-6-phosphate dehydrogenase deficiency, ∗ pyruvate kinase deficiency, and other erythrocyte enzyme deficiencies
Hemoglobinopathies
α-thalassemia, γβ-thalassemia
Unstable hemoglobins
Heinz body hemolytic anemia
Other causes of increased production
† Elevation of direct-reacting bilirubin also occurs.
Disseminated intravascular coagulation
Extravasation of blood; hematoma; pulmonary, cerebral, or other occult hemorrhage
Polycythemia
Macrosomic infants of diabetic mothers
Increased enterohepatic circulation of bilirubin
Breast milk jaundice
Pyloric stenosis
Small or large bowel obstruction or ileus
Decreased clearance
Prematurity
Glucose-6-phosphate dehydrogenase deficiency
Metabolic
Crigler-Najjar syndrome types I and II, Gilbert syndrome
Tyrosinemia †
Hypermethioninemia †
Hypothyroidism
Hypopituitarism †
Who Is Jaundiced?
Jaundice is a clinical sign, and for years clinicians have assessed the intensity of jaundice and used this assessment to decide whether to obtain a serum bilirubin measurement. But the ability of clinicians to diagnose “clinically significant” jaundice varies widely, and this can lead to important errors in management. In addition, whether the TSB level is “clinically significant” depends both on the actual TSB level and the infant’s age, in hours ( Figs. 13-5 to 13-7 ). Currently, experts recommend that before discharge, TSB or TcB should be measured in all newborns.
Noninvasive Bilirubin Measurements
TcB measurements are being used with increasing frequency in hospital nurseries, in outpatient settings, and in the preterm population. They reduce significantly the number of TSB measurements needed in both the term nursery and the NICU, and they are invaluable in the outpatient setting. TcB measurements provide instantaneous information while reducing the likelihood that a clinically significant TSB will be missed. There is good evidence that TcB measurements provide excellent estimates of the TSB level, although they are not a substitute for TSB values.
The TcB value is a measurement of the yellow color of the blanched skin and subcutaneous tissues, not the serum bilirubin level, and should be used as a screening tool to help determine whether the TSB level should be measured. Because TcB measurements are noninvasive, they can be repeated several times during the birth hospitalization and provide useful information about the rate of rise of the bilirubin level. When plotted on a nomogram (see Figs. 13-5 to 13-7 ), TcB levels that are crossing percentiles indicate the need for additional observation and evaluation.
Laboratory Evaluation—Seeking a Cause for Jaundice
In the NICU, many neonates are jaundiced simply because they were born prematurely and have extremely limited UGT1A1 activity (0.1% of adult levels at 30 weeks’ gestation). Even among term and late preterm infants who are readmitted to the hospital in the first 2 weeks of life with TSB levels of 18 to 20 mg/dL (308 to 340 µmol/L), only about 5% have an identifiable pathologic cause for jaundice ( Table 13-1 ).
| Diagnosis | Number | Percentage |
|---|---|---|
| Hyperbilirubinemia of unknown cause or breast milk jaundice | 290 | 94.8 |
| Cephalhematoma or bruising | 3 | 1.0 |
| ABO hemolytic disease † | 11 | 3.6 |
| Anti-E hemolytic disease | 1 | 0.3 |
| Galactosemia | 1 | 0.3 |
| Sepsis | 0 |
∗ Infants were readmitted after discharge as newborns. Mean age at admission was 5 days (range: 2-17 days), and mean bilirubin level was 18.5 ± 2.8 mg/dL (range: 12.7-29.1 mg/dL).
† Mother was type O, infant was type A or B, direct Coombs test result was positive.
The guideline of the American Academy of Pediatrics (AAP) recommends laboratory evaluation for the cause of hyperbilirubinemia in infants of 35 weeks’ gestation or more whose TSB levels exceed the 95th percentile or in whom the rate of increase appears to be crossing percentiles. In preterm infants, laboratory evaluation is indicated in any infant who meets the criteria for phototherapy. Table 13-2 provides an approach to the clinical and laboratory evaluation of the jaundiced newborn, and Box 13-1 lists the causes of indirect hyperbilirubinemia in the newborn.
| Indications | Assessments |
|---|---|
| Jaundice in first 24 hr | Measure TcB and/or TSB |
| Infant meets criteria for phototherapy ∗ or TSB rising rapidly (i.e., crossing percentiles [see Fig. 13-5 ]) | Perform blood typing and Coombs test, if not done on cord blood. Perform complete blood count, reticulocyte count, and smear examination. Measure direct or conjugated bilirubin. Consider G6PD testing. Repeat TSB in 4-24 hr. depending on infant’s age and TSB level. |
| TSB concentration approaching exchange levels or not responding to phototherapy | Perform investigations as above and G6PD testing and albumin level. |
| Elevated direct (or conjugated) bilirubin level | Do urinalysis and urine culture; evaluate for sepsis if indicated by history and physical examination. |
| Jaundice present at or beyond age 2-3 wk, or sick infant | Measure total and direct (or conjugated) bilirubin level. If direct bilirubin elevated, evaluate for causes of cholestasis. Check results of newborn thyroid and galactosemia screen, and evaluate infant for signs or symptoms of hypothyroidism. |
∗ Because phototherapy is used at low TSB levels in low-birth-weight infants (see Table 13-9), these investigations are often unnecessary in low-birth-weight infants who meet the criteria for phototherapy.
The timing of the onset of jaundice is important; jaundice that appears within the first 24 hours or increases rapidly and crosses percentiles is due to excessive bilirubin production (hemolysis) until proven otherwise. Most newborns whose TSB levels exceed the 75th percentile on the Bhutani nomogram (see Fig. 13-7 ) have evidence of hemolysis.
Pathologic Jaundice
Hemolytic Disease
Immune-Mediated Hemolytic Disease
The combination of antepartum and postpartum prophylaxis with Rh(D) immunoglobulin has dramatically reduced the incidence of erythroblastosis fetalis resulting from the Rh9 (D) antigen, and the incidence of Rh hemolytic disease is currently estimated to be about 1 in 1000 live births. Approximately half of affected newborns require little or no treatment.
ABO hemolytic disease generally occurs in infants of blood group A or B born to group O mothers. Because approximately 45% of Americans of Western European descent have type O blood and a similar percentage are type A, A-O incompatibility is the most common form of ABO incompatibility encountered in the United States. Although about one of every three group A or B infants born to a group O mother has anti-A or anti-B antibodies attached to their red cells, only one in five of those with a positive result on a direct antibody test (DAT) develops a modest to significant degree of hyperbilirubinemia. In an Israeli population of 162 DAT-positive group A or B newborns born to group O mothers, 52% developed a TSB higher than the 95th percentile on the Bhutani nomogram. Forty-eight percent of O-B babies developed hyperbilirubinemia in the first 24 hours compared with 26% of O-A babies. Of 258 Canadian infants who developed TSB levels of more than 425 µmol/L (24.9 mg/dL), 48 (16.7%) had ABO hemolytic disease. There appears to be considerable variation in the frequency with which ABO hemolytic disease is responsible for severe hyperbilirubinemia (see Table 13-1 ).
The diagnosis of ABO hemolytic disease as opposed to ABO incompatibility should generally be reserved for infants who have a positive DAT finding and clinical jaundice within the first 12 to 24 hours of life (icterus praecox). Reticulocytosis and the presence of microspherocytes on the smear support the diagnosis ( Box 13-2 ). Underscoring the importance of a positive DAT result in support of the diagnosis of ABO hemolytic disease, Herschel et al concluded that in DAT-negative newborns of ABO-incompatible mother-infant pairs who have significant hyperbilirubinemia, a cause other than isoimmunization should be sought. On the other hand, Kaplan and associates found that 43% of DAT-negative, ABO-incompatible infants who were homozygous for the variant UGT promoter associated with Gilbert syndrome had a TSB level of 15 mg/dL (256 µmol/L) or higher compared with none of the ABO-incompatible DAT-negative infants who were homozygous normal (for the promoter element) ( Fig. 13-8 ). There was no difference between ABO-incompatible and ABO-compatible DAT-negative newborns, as long as the ABO-incompatible neonates did not have Gilbert syndrome. This observation confirms that if another icterogenic factor is present, then ABO-incompatible newborns are at risk for hyperbilirubinemia even if they are DAT negative. There are other possible explanations for the finding of ABO hemolytic disease in the absence of a positive DAT result. Some cases may reflect the insensitivity of the DAT or may occur in infants who have a paucity of A and B antigens on their red cells or unusually efficient absorption of serum antibody by A and B antigen epitopes present in body tissues and fluids.
Mother group O, infant group A or B
and
Positive result on DAT
Jaundice appearing within 12-24 hr
Microspherocytes on blood smear
Negative DAT result but homozygous for Gilbert syndrome mutation
DAT, Direct antibody test.
Heritable Causes of Hemolysis
Defects in the red cell membrane include hereditary spherocytosis, elliptocytosis, stomatocytosis, and infantile pyknocytosis. Although these conditions can occur in the newborn period, newborns frequently exhibit substantial variations in red cell size and shape, and it is not always easy to establish one of these diagnoses. Spherocytes are not usually seen on red cell smears and, when present, suggest the diagnosis of hereditary spherocytosis or ABO hemolytic disease. A recent observation suggests that a mean corpuscular hemoglobin concentration of 36 g/dL or more is a useful marker to identify neonates who might have spherocytosis. Because hereditary spherocytosis has an autosomal dominant inheritance pattern, a family history can often be elicited. In addition, the presence of severe jaundice in neonates with hereditary spherocytosis is closely related to an interaction with the Gilbert syndrome allele, a phenomenon also observed (as noted earlier) in infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Red Cell Enzyme Deficiencies
G6PD deficiency is a problem that affects hundreds of millions of people around the world. Nevertheless, most neonatologists in the United States do not (but should) think about this enzyme deficiency as a likely cause of significant hyperbilirubinemia. Although G6PD deficiency occurs in approximately 12% of African American males and 4% of African American females, severe hyperbilirubinemia does not develop in most G6PD-deficient newborns. Nevertheless, extreme hyperbilirubinemia and kernicterus have been described in G6PD-deficient infants of African American descent. In the kernicterus registry, G6PD deficiency was the cause of the hyperbilirubinemia in 21% of cases. G6PD deficiency is an X-linked disorder, and hemolysis can occur following exposure to an oxidative challenge. Agents potentially involved include naphthalene (a component of mothballs), dyes, and infection, but more often than not, no offending agent is identified. Interestingly, in some, but not all, G6PD-deficient infants in whom severe hyperbilirubinemia develops, there are no signs of overt hemolysis (anemia and reticulocytosis), and significant hyperbilirubinemia associated with G6PD deficiency is primarily the result of abnormal bilirubin clearance rather than hemolysis. Other researchers disagree with this view and suggest that overt signs of hemolysis are not found because the hemolysis is self-limited and extravascular, and involves an older fraction of the red cell population.
The identification of a molecular marker for Gilbert syndrome in the promoter region of the UGT1A1 gene has demonstrated a remarkable association between hyperbilirubinemia, G6PD deficiency, and Gilbert syndrome. The most common genetic polymorphism encountered in whites with Gilbert syndrome is an additional TA insertion in the TA TAA box of the UGT1A1 gene promoter. Affected individuals are homozygous for the variant promoter and have 7 repeats—(TA) 7 TAA (7/7) instead of the more usual 6 repeats—(TA) 6 TAA (6/6). Heterozygotes have 1 allele each of the wild-type and variant promoter (6/7). In Israel, G6PD-deficient infants with TSB levels of 15 mg/dL (257 µmol/L) more, only 10% were homozygous for the normal UGT1A1 promoter (6/6), whereas 50% were homozygous for the variant Gilbert UGT1A1 promoter (7/7). TSB levels ≥15 mg/mL did not develop in either the neonates with G6PD deficiency alone or in those with only the variant UGT1A1 promoter (7/7).
Pyruvate kinase deficiency is an autosomal recessive disorder that is less common than G6PD deficiency but may present with significant jaundice, anemia, and reticulocytosis. In particular, pyruvate kinase deficiency should be considered in neonates of Amish descent with marked neonatal hyperbilirubinemia.
Unstable Hemoglobins
The term unstable hemoglobins is applied to hemoglobins exhibiting reduced solubility or higher susceptibility to oxidation of amino acid residues within the individual globin chains. More than 100 structurally different unstable hemoglobin mutants have been documented, and the clinical syndrome associated with unstable hemoglobin disorders is often called congenital Heinz body hemolytic anemia. Some of these infants can manifest severe hemolytic anemia and hyperbilirubinemia.
Other Causes of Increased Bilirubin Production or Load on the Liver
The hemoglobinopathies rarely manifest themselves as jaundice in the neonatal period, although such cases have been described occasionally. Cephalhematomas, intracranial or pulmonary hemorrhage, or any occult bleeding may lead to an elevated TSB level from breakdown of the extravascular erythrocytes. In some studies, the presence of periventricular-intraventricular hemorrhage has been associated with an increase in TSB levels in very low-birth-weight infants, but others have not found this association. Polycythemia is usually listed as a cause of hyperbilirubinemia, because the catabolism of 1 g of hemoglobin produces 35 mg of bilirubin. Nevertheless, mean bilirubin levels and the incidence of hyperbilirubinemia are similar in polycythemic infants receiving partial exchange transfusion and in those receiving symptomatic treatment.
Any small or large bowel obstruction, ileus, or delayed passage of meconium exaggerates the enterohepatic circulation of bilirubin (this is also thought to be the mechanism for hyperbilirubinemia associated with pyloric stenosis). In any of these conditions, correction of the obstruction produces a prompt decline in bilirubin levels. Macrosomic infants of mothers with insulin-dependent diabetes are at an increased risk of hyperbilirubinemia, probably as a result of increased bilirubin production.
Decreased Bilirubin Clearance
Inherited Unconjugated Hyperbilirubinemia—Inborn Errors of Bilirubin UGT1A1 Activity
UGT1A1 accounts for almost all of the bilirubin glucuronidation activity in the human liver, and three degrees of inherited UGT1A1 deficiency are recognized. Crigler-Najjar syndrome type I is inherited in an autosomal recessive pattern with marked genetic heterogeneity, and more than 30 different genetic mutations have been identified. Infants with this condition have virtually complete absence of bilirubin UGT1A1 activity, severe jaundice develops in the first 2 to 3 days of life, and intensive phototherapy and, often, exchange transfusions are required. Unless these children receive a liver transplant, which is curative, they are committed to lifelong phototherapy, which becomes less and less effective as they get older.
Type II Crigler-Najjar disease, also known as Arias syndrome, has a pattern of inheritance that is usually autosomal recessive, but it may also be autosomal dominant. The disorder is characterized by low but detectable activity of bilirubin UGT1A1, and the hyperbilirubinemia usually shows some response to phenobarbital therapy. Although jaundice is generally less severe than in patients with Crigler-Najjar syndrome type I, marked hyperbilirubinemia develops in some children with Crigler-Najjar syndrome type II, and kernicterus can also occur.
At one time the diagnosis of Gilbert syndrome was never made until adolescence, when it manifests as a mild, benign, chronic unconjugated hyperbilirubinemia with no evidence of liver disease or overt hemolysis. Gilbert syndrome affects approximately 9% of the population, and both autosomal dominant as well as recessive inheritance patterns have been found. The identification of the genetic basis for this disorder (a variant promoter for the gene encoding UGT1A1) has permitted its identification in the newborn. Newborns who are homozygous for the A(TA)7TAA polymorphism have somewhat higher TSB levels in the first days of life than do heterozygous or normal infants, although the effect is modest. The Gilbert syndrome genotype is also an important contributor to the prolonged indirect hyperbilirubinemia found in some breast-feeding infants. Twenty-seven percent of breast-fed infants who had TSB levels of more than 5.8 mg/dL (100 µmol/L) at age 28 days had the Gilbert syndrome genotype, and 16 of 17 breast-fed Japanese infants with prolonged jaundice had at least 1 mutation of the UGT1A1 gene, primarily of the G7IR type. The association of the Gilbert genotype with significant jaundice in G6PD-deficient infants, ABO-incompatible DAT-negative infants (see Fig. 13-8 ), and infants with hereditary spherocytosis has been discussed earlier.
Other Inborn Errors of Metabolism
Jaundiced infants who have vomiting, excessive weight loss, hepatomegaly, and splenomegaly should be suspected of having galactosemia. In galactosemia, the hyperbilirubinemia during the first week of life is almost exclusively unconjugated, but the conjugated fraction tends to increase during the second week, which probably reflects liver damage. A test of the urine for reducing substances using alkaline copper sulfate reagent tablets (Clinitest, Bayer Corp., Elkhart, Ind.) helps to make the diagnosis. Infants with tyrosinemia and hypermethioninemia are jaundiced primarily as a result of the presence of neonatal liver disease, so that indirect hyperbilirubinemia is generally accompanied by some evidence of cholestasis. Prolonged indirect hyperbilirubinemia is one of the clinical features of congenital hypothyroidism, a condition that should be identified by routine metabolic screening programs currently used for newborns. Other causes of prolonged indirect hyperbilirubinemia are listed in Box 13-3 .
Breast milk jaundice
Hemolytic disease
Hypothyroidism
Extravascular blood
Pyloric stenosis
Crigler-Najjar syndrome
Gilbert syndrome genotype in breast-fed infants
Breast Feeding and Jaundice
A strong association between breast feeding and an increased incidence of neonatal hyperbilirubinemia has been found in most but not all studies. The primary contributors to jaundice associated with breast feeding are a decreased caloric intake in the first few days of life and an increased enterohepatic circulation. Breast-fed infants usually receive fewer calories in the first days after birth than do those fed formula, and caloric deprivation itself appears to enhance the enterohepatic circulation of bilirubin. Increasing the frequency of breast feeding significantly reduces the risk of hyperbilirubinemia, which provides further support for the important role of caloric deprivation and the enterohepatic circulation in the pathogenesis of breast-feeding jaundice. The stools of breast-fed infants weigh less, and the cumulative wet and dry stool output of breast-fed infants is lower than that of formula-fed infants.
Mixed Forms of Jaundice
Sepsis
Jaundice is one sign of bacterial sepsis, but septic infants almost always have other signs and symptoms. Unexplained indirect hyperbilirubinemia as the only sign of sepsis is rare (see Table 13-1 ), and lumbar punctures or blood and urine cultures in jaundiced infants who otherwise appear well are not recommended. On the other hand, those who appear sick or have direct hyperbilirubinemia or other findings in the physical examination or laboratory evaluation that are out of the ordinary should be evaluated for possible sepsis. Other causes of mixed forms of jaundice include congenital syphilis, the TORCH ( t oxoplasmosis, o ther infections r ubella, c ytomegalovirus infection, h erpes simplex) group of intrauterine infections, and Coxsackie B virus infection.
Cholestatic Jaundice
Cholestasis refers to a reduction in bile flow and is the term used to describe a group of disorders associated with conjugated (or direct reacting) hyperbilirubinemia. Such jaundice indicates inadequate bile secretion or biliary flow. Although it is frequently transient in sick low-birth-weight infants, particularly those receiving parenteral nutrition, a pathologic cause must always be ruled out. For a detailed discussion of the causes and management of cholestatic jaundice, refer to a review of this subject.
Conditions most likely associated with conjugated hyperbilirubinemia in the neonatal period are listed in Box 13-4 . Cholestasis occurs in about 1 in 2500 infants and can be categorized as obstructive or hepatocellular. Most cases of conjugated hyperbilirubinemia in early infancy are the result of neonatal hepatitis or biliary atresia. Neonatal hepatitis is characterized by prolonged conjugated hyperbilirubinemia without any obvious evidence of bacterial or viral infection or the other causes listed in Box 13-4 . Extrahepatic biliary atresia occurs when there is obliteration of the lumen of part of the biliary tract or absence of some or all of the extrahepatic biliary system. Extrahepatic biliary atresia occurs in 1 in 10,000 to 19,000 newborn infants, and it is important to make the diagnosis expeditiously before irreversible sclerosis of the intrahepatic ducts occurs, particularly if the biliary atresia is a component of the biliary atresia splenic malformation syndrome or is the cystic form of biliary atresia (see later discussion). The identification of cholestatic jaundice and initiation of the necessary diagnostic investigations will occur in a timely fashion if every infant who is clinically jaundiced beyond the age of 2 to 3 weeks undergoes measurement of direct-reacting bilirubin ( Tables 13-2 and 13-3 , and Fig. 13-9 ). Earlier laboratory investigations are mandatory in any jaundiced infant who has pale stools or dark urine (the urine of most newborns is nearly colorless). This simple approach ensures timely evaluation and treatment of infants with extrahepatic biliary atresia.
Obstructive cholestasis
Biliary atresia
Choledochal cyst
Gallstones or biliary sludge
Alagille syndrome
Inspissated bile
Cystic fibrosis
Congenital hepatic fibrosis/Caroli disease
Hepatocellular cholestasis
Idiopathic neonatal hepatitis
Viral infection
- •
Cytomegalovirus
- •
HIV
- •
Bacterial infection
- •
Urinary tract infection
- •
Sepsis
- •
Syphilis
- •
Genetic/metabolic disorders
- •
α1-antitrypsin deficiency
- •
Tyrosinemia
- •
Galactosemia
- •
Hypothyroidism
- •
Progressive familial intrahepatic cholestasis (PFIC)
- •
Cystic fibrosis
- •
Panhypopituitarism
- •
Toxic/secondary disorders
- •
Parenteral nutrition-associated cholestasis
- •
| Recommendation | Level of Evidence |
|---|---|
| It is recommended that any infant noted to be jaundiced at 2 weeks of age be clinically evaluated for cholestasis with measurement of total and direct serum bilirubin. However, breast-fed infants who can be reliably monitored and who have an otherwise normal history (no dark urine or light stools) and physical examination may be asked to return at 3 weeks of age, and if jaundice persists, total and direct serum bilirubin are measured at that time. | C |
| Retest any infant with an acute condition or other explanation for jaundice whose jaundice does not resolve with appropriate management of the diagnosed condition. | D |
| Ultrasonography is recommended for infants with cholestasis of unknown cause. | A |
| Liver biopsy is recommended for most infants with cholestasis of unknown cause. | A |
| Measurements of γ-glutamyl transpeptidase and lipoprotein X are not routinely recommended in the evaluation of cholestasis in young infants. | C |
| Scintigraphy and analysis of duodenal aspirate are not routinely recommended but may be useful in situations in which other tests are not readily available. | A |
| Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography (ERCP) are not routinely recommended, although ERCP may be useful in experienced hands. | C |
The initial treatment of extrahepatic biliary atresia is a portoenterostomy or Kasai procedure in which a loop of small intestine is anastomosed to the porta hepatis following excision of the atretic ducts. About one third of patients who undergo the Kasai procedure survive for longer than 10 years without liver transplantation. About one third have adequate bile drainage, but complications of cirrhosis develop and liver transplantation is necessary before the age of 10 years. The remaining one third require earlier liver transplantation because bile flow is inadequate following portoenterostomy and progressive fibrosis and cirrhosis develop. Overall survival of these children, including those undergoing liver transplantation, is now about 90% at age 4 years. Portoenterostomy must be done before there is irreversible sclerosis of the intrahepatic bile ducts, but the effect of the timing of the Kasai procedure on outcome remains controversial. Although recent data from France suggest that the outcome following this procedure is best when the procedure is performed before age 31 days, data from the United Kingdom show no difference in outcome of isolated biliary atresia regardless of whether the Kasai procedure is performed before 40 days or between 41 and 60 days. On the other hand, there is a major deleterious effect of delaying surgery in those infants whose biliary atresia is a component of the biliary atresia splenic malformation syndrome (splenic malformation, situs inversus, preduodenal portal vein, absence of the vena cava) and in those with cystic biliary atresia.
By far the most common association with cholestasis in the NICU is prolonged use of intravenous alimentation. When total parenteral nutrition (TPN) is used for 2 weeks or longer, and particularly when such use is exclusive of enteral feedings, cholestatic jaundice may appear. Cholestasis develops in as many as 80% of infants who receive TPN for longer than 60 days, and 50% of those with birth weights of less than 1000 g are affected. The pathogenesis of TPN-associated cholestasis is not clear, but it is thought to be related to a combination of factors, including immaturity of bile secretion in preterm infants, a decrease in bile flow that occurs with no enteral feeding, the use of omega-6 poly unsaturated fatty acids, and potential toxicity of both trace elements and amino acids.
The term neonatal hepatitis, which implies an inflammatory or infectious process, is a misnomer. The term transient neonatal cholestasis is preferred because the clinical and biopsy findings are the result of a combination of factors, including (1) immaturity of bile secretion associated with prematurity; (2) chronic or acute ischemia-hypoxia of the liver following intrauterine growth restriction, acute perinatal distress, or lung disease; (3) liver damage caused by perinatal or postnatal sepsis; and (4) decrease in bile flow resulting from delays in enteral feeding.
An approach to the evaluation of infants with cholestatic jaundice is provided in Figure 13-9 . Imaging findings may permit some shortcuts and even avoid the necessity for liver biopsy in some cases. Magnetic resonance cholangiography provides visualization of the extrahepatic bile ducts. Failure to see the bile ducts is highly suggestive of biliary atresia. Other studies suggest that identification of the “triangular cord” (a triangular or tube-shaped echogenic density just cranial to the portal vein bifurcation on a transverse or longitudinal ultrasound scan) can distinguish infants with extrahepatic biliary atresia (in whom the triangular cord is present) from those who have other causes of cholestasis. The cord represents the fibrous remnant in the porta hepatis, and when it is seen, the authors recommend prompt laparotomy without further investigation. When it is absent, hepatic scintigraphy is done.
Treatment of Cholestasis
The treatment of neonatal cholestasis involves treating the cause, although some pharmacologic agents have been used in an attempt to stimulate bile flow. Phenobarbital increases the uptake of bilirubin by the liver, induces conjugation, enhances bile acid synthesis, and increases bile flow. The administration of phenobarbital before performance of hepatic scintigraphy has helped to improve the reliability of this diagnostic test, but the therapeutic use of phenobarbital to improve bile flow and lower serum bilirubin concentrations in conditions such as TPN-associated cholestasis has been disappointing.
The use of ursodeoxycholic acid (UDCA) appears to offer more promise. UDCA is a hydrophilic bile acid with a significant choleretic effect. It appears to be a relatively safe agent when used in children who do not have a fixed obstruction to bile flow. It has been used in the treatment of cholestatic jaundice in infants with cystic fibrosis, as well as in erythroblastosis fetalis. UDCA may also be of value in the treatment of extreme hyperbilirubinemia in older children with Crigler-Najjar syndrome. The mechanism of action of UDCA is not well understood, but it may affect the enterohepatic circulation of endogenous bile salts and increase hepatic bile flow.
Bilirubin Toxicity
The presence of bilirubin pigment at autopsy in the brains of infants who were severely jaundiced was observed more than 100 years ago, and the term kernicterus was applied to infants who died and demonstrated bilirubin staining of the “kern,” or nuclear region of the brain. The areas of the brain most commonly affected are the basal ganglia, particularly the subthalamic nucleus and the globus pallidus ( Fig. 13-10 ); the hippocampus; the geniculate body; various brain stem nuclei, including the inferior colliculus, oculomotor, vestibular, cochlear, and inferior olivary nuclei; and the cerebellum, especially the dentate nucleus and vermis. Neuronal necrosis is the dominant histopathologic feature after 7 to 10 days of postnatal life.
The areas of neuronal injury explain the clinical sequelae of bilirubin encephalopathy. In classic kernicterus, markedly jaundiced infants pass through three clinical phases. Initially, the infant becomes lethargic and hypotonic, and sucks poorly. Subsequently, hypertonia, fever, and a high-pitched cry develop. The hypertonia is characterized by backward arching of the neck (retrocollis) and trunk (opisthotonos). After about a week, the hypertonia subsides and is replaced by hypotonia. In those who survive, extrapyramidal disturbances (choreoathetosis), auditory abnormalities (sensorineural hearing loss most severe in the high frequencies), gaze palsies, and dental enamel hypoplasia develop. The presence of retrocollis and opisthotonos (the acute intermediate phase of bilirubin encephalopathy) was thought to represent irreversible damage, but with urgent intervention using phototherapy and exchange transfusion, a normal outcome is possible in some cases.
The diagnosis of kernicterus can be confirmed by magnetic resonance imaging (MRI). (see Fig. 13-10 ). The characteristic image is a bilateral, symmetric, high-intensity signal in the globus pallidus seen on both T 1 – and T 2 -weighted images. High signal intensity may also be found in the hippocampus and thalamus, with the subthalamic nucleus commonly involved. In addition, hyperechogenicity on cranial ultrasonography has been seen in the basal ganglia and globus pallidus in term and preterm infants who subsequently manifested signs of kernicterus.
Although there is no doubt about the relationship between extremely high bilirubin levels and acute bilirubin encephalopathy, it is possible that this outcome is only the most obvious and extreme manifestation of a spectrum of bilirubin toxicity. At the other end of the spectrum might lie more subtle forms of neurodevelopmental impairment (NDI) that occur at lower bilirubin levels and in the absence of any obvious clinical findings in the neonatal period. Nevertheless, prospective studies of large populations of hyperbilirubinemic infants have not found evidence of subtle NDI.
Kernicterus in the Term and Late Preterm Newborn
Kernicterus remains a significant problem in the developing world and still occurs in the United States, Canada, and Western Europe. Contrary to the experience in the 1940s and 1950s, however, these are not infants with Rh hemolytic disease; rather, most are term and late preterm newborns who are apparently healthy at the time of discharge but who subsequently develop extreme hyperbilirubinemia (usually a TSB level of >30 mg/dL). Such bilirubin levels occur in only about 1 in 10,000 infants, and the risk of kernicterus at these TSB levels is about 1 in 7, or 14%. Some of the factors that appear to have contributed to this situation are short hospital stays and inadequate follow-up for newborns; increased incidence of hyperbilirubinemia related to an increase in breast feeding; less concern by pediatricians about jaundice; and failure to interpret bilirubin levels according to the baby’s age in hours, not days.
Short Hospital Stays for Newborns
There is evidence that early discharge is associated with an increased risk of significant hyperbilirubinemia. The AAP recommends that infants discharged at less than 72 hours be seen within 2 days of discharge unless the risk of hyperbilirubinemia is very low. A recent commentary provides detailed guidelines for risk assessment and follow-up (see later discussion). Figures 13-5 to 13-7 make one thing clear: If newborns leave the hospital before they are 36 hours old, their peak bilirubin level will occur after they are discharged. Thus, jaundice is now primarily an outpatient problem, and monitoring and surveillance following discharge are essential if extreme hyperbilirubinemia is to be prevented.
Hemolytic Disease and Outcome
Initial observations in the late 1940s and early 1950s showed a strong relationship between increasing TSB levels (particularly levels of >20 mg/dL [>342 µmol/L]) and the risk of kernicterus in infants with Rh hemolytic disease. Hsia et al reported that the incidence of kernicterus in their erythroblastotic population was 8% for those with TSB levels of 19 to 24 mg/dL (325 to 410 µmol/L), 33% for those with TSB levels of 25 to 29 mg/dL (428 to 496 µmol/L), and 73% for those with levels higher than 30 mg/dL (513 µmol/L). Subsequent studies, however, found strikingly different outcomes. In a study of 129 infants born between 1957 and 1958, all of whom had indirect bilirubin levels of more than 20 mg/dL (342 µmol/L), neurodevelopmental damage was seen in only 2 of 92 (2%) who underwent detailed psychometric, neurologic, and audiologic evaluations at 5 to 6 years of age. The presence of hemolysis is considered to be a risk factor for bilirubin encephalopathy, although the reason for this is not clear. Recent studies have shown that infants with TSB levels of 25 mg/dL (428 µmol/L) or more and a positive DAT result are at greater risk for low IQ scores at ages 5 to 8 years.
Outcome in Infants without hemolytic disease
The relationship between hyperbilirubinemia and poor developmental outcome in full-term and late preterm infants who do not have hemolytic disease has been studied extensively. When analyzed as a whole, the data tend to demonstrate that, in otherwise healthy neonates without hemolytic disease, TSB levels that do not exceed approximately 25 mg/dL (428 µmol/L) do not place these infants at risk of NDI. In such infants, there has been no convincing demonstration of any adverse affect of these bilirubin levels on IQ, definite neurologic abnormalities, or sensorineural hearing loss.
A relationship has been described between neurologic and psychometric abnormalities and the duration of exposure to elevated TSB levels. In a Turkish study, exposure to TSB levels of more than 20 mg/dL (342 µmol/L) for fewer than 6 hours was associated with a 2.3% incidence of neurologic abnormality. The incidence increased to 18.7% if exposure lasted 6 to 11 hours and to 26% with 12 or more hours of exposure. In the large National Institute of Child Health and Human Development (NICHD) collaborative phototherapy trial, a 6-year follow-up of 224 control group infants who did not receive phototherapy and who had birth weights of less than 2000 g show no association between IQ and duration of exposure to elevated bilirubin levels.
Hyperbilirubinemia and the Preterm Infant
Compared with term infants, sick very low-birth-weight infants are at greater risk of developing kernicterus and autopsy-proven “low bilirubin kernicterus” at TSB levels of 5 to 7 mg/dL. Although pathologic kernicterus in premature newborns is now rare, it has not disappeared completely, and whether or not modest elevations of TSB cause brain damage in preterm infants is controversial. Two studies of large populations of extremely low-birth-weight infants suggest an association between NDI and small increases in TSB. Higher peak TSB levels were associated with an increased risk of death, hearing loss, and NDI in extremely low-birth-weight infants (<1000 g birth weight) born between 1994 and 1997. In a randomized controlled trial of aggressive versus conservative phototherapy for extremely low-birth-weight infants, there was no difference between treatment groups in the primary outcome of death or NDI at 18 to 22 months of corrected age. Among survivors, however, aggressive phototherapy produced a significant decrease in NDI, hearing loss, profound impairment, and athetosis compared with conservative phototherapy (see Table 13-4 for the details of how phototherapy was used in this study). Mean TSB levels in infants with hearing loss were 6.5 ± 1.7 mg/dL versus 5.5 ± 1.5 mg/dL in those with no hearing loss ( P < .001). Peak TSB levels in infants with NDI were 8.6 ± 2.3 versus 8.3 ± 2.3 in unimpaired survivors ( P = .02). Whether these small differences in TSB levels or the use of aggressive phototherapy was responsible for the outcomes is difficult to say.
| Phototherapy | Exchange Transfusion | |
|---|---|---|
| Gestational Age (wk) | Initiate Phototherapy Total Serum Bilirubin (mg/dL) | Total Serum Bilirubin (mg/dL) |
| <28 | 5-6 | 11-14 |
| 28 <SPAN role=presentation tabIndex=0 id=MathJax-Element-1-Frame class=MathJax style="POSITION: relative" data-mathml='07′>0707 0 7 -29 <SPAN role=presentation tabIndex=0 id=MathJax-Element-2-Frame class=MathJax style="POSITION: relative" data-mathml='67′>6767 6 7 | 6-8 | 12-14 |
| 30 <SPAN role=presentation tabIndex=0 id=MathJax-Element-3-Frame class=MathJax style="POSITION: relative" data-mathml='07′>0707 0 7 -31 <SPAN role=presentation tabIndex=0 id=MathJax-Element-4-Frame class=MathJax style="POSITION: relative" data-mathml='67′>6767 6 7 | 8-10 | 13-16 |
| 32 <SPAN role=presentation tabIndex=0 id=MathJax-Element-5-Frame class=MathJax style="POSITION: relative" data-mathml='07′>0707 0 7 -33 <SPAN role=presentation tabIndex=0 id=MathJax-Element-6-Frame class=MathJax style="POSITION: relative" data-mathml='67′>6767 6 7 | 10-12 | 15-18 |
| 34 <SPAN role=presentation tabIndex=0 id=MathJax-Element-7-Frame class=MathJax style="POSITION: relative" data-mathml='07′>0707 0 7 -34 <SPAN role=presentation tabIndex=0 id=MathJax-Element-8-Frame class=MathJax style="POSITION: relative" data-mathml='67′>6767 6 7 | 12-14 | 17-19 |
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