COMMON PROBLEMS IN THE TERM NEWBORN INFANT
Saturday, August 16, 2008
NEONATAL JAUNDICE
General Considerations
Jaundice is a common neonatal problem. Sixty-five percent of newborns develop clinical jaundice with a bilirubin level above 5 mg/dL during the first week of life. From an evolutionary standpoint, hyperbilirubinemia ought to confer some biologic advantage if it occurs so often. Bilirubin is a potent antioxidant and peroxyl scavenger that may help the newborn, who is deficient in most antioxidant substances such as vitamin E, catalase, and superoxide dismutase, to avoid oxygen toxicity in the days after birth. Hyperbilirubinemia can also be toxic, with high levels resulting in an encephalopathy known as kernicterus.
Metabolism of Bilirubin
Heme (iron protoporphyrin) is broken down by heme oxygenase to iron, which is conserved; carbon monoxide, which is exhaled; and biliverdin, which is then further metabolized to bilirubin by the enzyme bilirubin reductase. Each 1 g of hemoglobin breakdown results in the production of 34 mg of bilirubin (1 mg/dL = 17.2 µmol/L of bilirubin). Bilirubin is carried bound to albumin to the liver, where, in the presence of the enzyme uridyldiphosphoglucuronyl transferase (UDPGT; glucuronyl transferase), it is taken up by the hepatocyte and conjugated with two glucuronide molecules. The conjugated bilirubin is then excreted through the bile to the intestine. In the presence of normal gut flora, the conjugated bilirubin is metabolized further to stercobilins and excreted in the stool. In the absence of gut flora—and with slow intestinal motility, as in the first few days of life—the conjugated bilirubin remains in the intestinal lumen, where a mucosal enzyme (b-glucuronidase) can cleave off the glucuronide molecules, leaving unconjugated bilirubin to be reabsorbed (the enterohepatic circulation of bilirubin).
Bilirubin Toxicity
The exact mechanism by which bilirubin is toxic to cells is not known. It is assumed that if the amount of lipid-soluble unconjugated bilirubin exceeds the available binding sites on albumin, there will then be “free” bilirubin that can enter neurons and damage them. The blood-brain barrier probably plays an important role in protecting an individual from brain damage, but its integrity is impossible to measure clinically. It is not known whether there is a level of bilirubin above which brain damage would always occur even in a healthy individual.
The syndrome of bilirubin encephalopathy was well described in the era before exchange transfusion as treatment for Rh isoimmunization (see below). The pathologic correlate is known as kernicterus, named for the yellow staining of the subthalamic nuclei (kerns) seen at autopsy. The early symptoms of bilirubin encephalopathy consist of lethargy, hypotonia, and poor sucking, progressing to hypertonia, opisthotonos, and a high-pitched cry. Long-term sequelae include athetoid cerebral palsy, sensorineural deafness, limitation of upward gaze, and dental dysplasia. Whether or not bilirubin causes more subtle neurologic abnormalities remains debatable.
Bilirubin encephalopathy is very rare with current neonatal management. The only infant in which a specific bilirubin level (20 mg/dL [344 µmol/L] and above) has been associated with an increased risk of kernicterus is the Rh-isoimmunized infant. This observation—and the management strategy of keeping bilirubin under 20 mg/dL with exchange transfusion if needed—has been extended to other neonates with hemolytic disease despite an absence of data on the risk. The risk of bilirubin encephalopathy is probably very small for term infants without hemolysis even at bilirubin levels of 25 mg/dL (430 µmol/L). Premature infants are probably at some increased risk because of associated illnesses that may affect the integrity of the blood-brain barrier and reduced albumin levels. For this reason, a lower level of bilirubin is generally assumed to represent the “exchange level” in these infants and is usually determined arbitrarily based on the infant’s birth weight and gestational age. One common approach is to use 1% of the birth weight in grams as the exchange level in mg/dL (eg, 12 mg/dL for a 1200-g infant)—down to a low of 10 mg/dL. Many other approaches exist as well.
Causes of Unconjugated Hyperbilirubinemia
The causes of unconjugated hyperbilirubinemia can be grouped into two main categories: overproduction of bilirubin and decreased conjugation of bilirubin (Table 1–9).
A. Increased Bilirubin Production: Increased production of bilirubin results from an increased rate of red blood cell destruction (hemolysis) due to the presence of maternal antibodies against fetal cells (Coombs test–positive), abnormal red cell membrane shape (ie, spherocytosis), or abnormal red cell enzymes (ie, glucose-6-phosphate dehydrogenase [G6PD] deficiency). Antibodies can be directed against the major blood group antigens (the type A or type B infant of a type O mother) or the minor antigens (the Rh system: D, E, C, d, e, c, Kell, Duffy, and so on).
1. Antibody-mediated hemolysis (Coombs test–positive)—ABO blood group incompatibility is common, usually not severe, and can accompany any pregnancy in a type O mother. The severity is not predictable because of variability in the amount of naturally occurring anti-A or anti-B IgG antibodies in the mother. Although 20% of pregnancies are the appropriate “set-ups” for ABO incompatibility (mother O, baby A or B), only about 33% of such infants are Coombs test–positive and only about 20% of these develop excessive jaundice. In addition to hyperbilirubinemia in the first days of life, these infants may develop a significant anemia over the first several weeks and on occasion may need to be transfused at a few weeks of age.
Rh isoimmunization is much less common and increases in severity with each immunized pregnancy because of an increased maternal IgG antibody production each time. Most Rh disease can be prevented by administering high-titer Rho(D) immune globulin to an Rh-negative woman after any invasive procedure during pregnancy as well as after any miscarriage, abortion, or delivery of an Rh-positive infant. In severe cases, erythroblastosis fetalis (hydrops or generalized edema with heart failure related to severe anemia in the fetus) occurs, often resulting in fetal or neonatal death without appropriate antenatal intervention. In less severe cases, hemolysis is the main problem, with resultant hyperbilirubinemia and anemia. The cornerstone of antenatal management once isoimmunization has been diagnosed is transfusion of the fetus with Rh-negative cells, either directly into the umbilical vein via percutaneous cordocentesis or into the fetal abdominal cavity. Following delivery, phototherapy is usually started immediately, with exchange transfusion (see below) as needed. A 500 mg/kg dose of intravenous immune globulin (IVIG) given to the infant as soon after delivery as the diagnosis is made has been shown to decrease the need for exchange transfusion. Ongoing hemolysis will still occur until all maternal antibody is gone; therefore, these infants need to be followed carefully over the first 2 months for development of anemia severe enough to require transfusion. The role of erythropoietin therapy in treating late anemia is under investigation.
2. Nonimmune hemolysis (Coombs test– negative)—Hereditary spherocytosis is the most common red cell membrane defect, resulting in hemolysis because of decreased red cell deformability. These infants may have hyperbilirubinemia severe enough to require exchange transfusion. Mild to moderate splenomegaly may be present. Diagnosis is suspected by peripheral blood smear and confirmed by red cell osmotic fragility study. A family history of anemia, jaundice, and gallstones may be elicited.
G6PD deficiency is the most common red cell enzyme defect resulting in hemolysis and should be suspected in a male (it is X-linked) of African, Mediterranean, or Asian descent, particularly when the onset of jaundice is later than usual.
3. Nonhemolytic increased bilirubin production—Enclosed hemorrhage, such as cephalohematoma, intracranial hemorrhage, or extensive bruising in the skin, can lead to jaundice as the red blood cells are broken down and removed. Polycythemia leads to jaundice by increased red cell mass, with increased numbers of cells reaching senescence daily. Ileus, either paralytic or mechanical, related to a bowel obstruction, leads to hyperbilirubinemia secondary to increased enterohepatic circulation.
B. Decreased Rate of Conjugation:
1. UDPGT deficiency–Crigler-Najjar syndrome type I (complete deficiency, autosomal recessive) and type II (partial deficiency, autosomal dominant) present as excessive and prolonged neonatal jaundice, but both forms are very rare.
2. Gilbert syndrome is a mild autosomal dominant disorder affecting 3–6% of the population and characterized by decreased hepatic UDPGT levels. Mild unconjugated hyperbilirubinemia without other liver function abnormalities occurs after puberty. The possible relationship of this disorder to exaggerated neonatal jaundice is under investigation.
C. Hyperbilirubinemia Caused by Unknown or Multiple Factors:
1. Physiologic jaundice—The contributing factors to physiologic jaundice include UDPGT inactivity at birth, a relatively high red cell mass even in the nonpolycythemic neonate, and an absence of intestinal flora, with initially slow intestinal motility leading to an active enterohepatic circulation of bilirubin. For jaundice to be physiologic rather than pathologic, the following criteria should be satisfied: (1) clinical jaundice appears after 24 hours of age; (2) total bilirubin rises by less than 5 mg/dL (86 µmol/L) per day; (3) peak bilirubin occurs at 3–5 days of age, with a total bilirubin of no more than 15 mg/dL (258 µmol/L); and (4) clinical jaundice is resolved by 1 week in the term infant and by 2 weeks in the preterm infant. Hyperbilirubinemia outside of these parameters—or jaundice that requires treatment—is not physiologic and must be evaluated further (see below).
2. High altitude—Infants at 3100 m (10,000 ft) have twice the incidence of bilirubin over 12 mg/dL (206 µmol/L) as infants at 1600 m (5200 ft) and four times that of infants at sea level: 39% versus 16% versus 8%, respectively. Possible mechanisms include increased bilirubin production secondary to increased hematocrit and decreased clearance caused by hypoxemia.
3. Racial differences—Asians are more likely than whites or blacks to have a bilirubin greater than 12 mg/dL (206 µmol/L): 23% versus 10–13% versus 4%, respectively.
4. Prematurity—Premature infants frequently have poor enteral intake, delayed stooling, and increased enterohepatic circulation. Even at 37 weeks’ gestation, they are four times more likely than at 40 weeks to have a bilirubin greater than 13 mg/dL (224 µmol/L).
5. Breast feeding and jaundice—There are two syndromes of jaundice associated with breast feeding: breast milk jaundice and breast feeding–associated jaundice (“lack-of-breast-milk jaundice”).
Evaluation of Hyperbilirubinemia
Clinical jaundice appears at a bilirubin level of 5 mg/dL (86 µmol/L) and appears first on the head, progressing down the chest and abdomen as the level increases. By the time jaundice is noted on the distal extremities, the level is likely to be at least 15 mg/dL (258 µmol/L). When checking serum bilirubin levels, the level should be assessed based on the age in hours at which the sample was obtained. Infants with a total serum bilirubin greater than the 95th percentile for age in hours have a 40% risk of developing subsequent significant hyperbilirubinemia (Figure 1–2). Infants who develop clinical jaundice on the first day of life—or who develop excessive jaundice—require evaluation. The minimal evaluation consists of a feeding and elimination history, weight (and comparison with birth weight), examination for any source of excessive heme breakdown, and laboratory evaluation for blood type, Coombs testing, complete blood count with smear, and total bilirubin level. A G6PD test should be considered if the infant is a male of African, Asian, or Mediterranean racial background, particularly if the jaundice presents later than usual. A fractionated bilirubin level should be obtained if the infant appears acutely ill, if jaundice is prolonged, or if the infant has dark urine with light stools.
Because of large interlaboratory variability, serial bilirubin levels should be obtained from a single laboratory whenever possible to make interpretation more accurate.
Treatment of Hyperbilirubinemia
A. Protoporphyrins: Tin and zinc protoporphyrin or mesoporphyrin (Sn-PP, Zn-PP; Sn-MP, Zn-MP) are inhibitors of heme oxygenase, the enzyme that begins the catabolism of heme (iron protoporphyrin). Studies are under way involving a single injection of these substances shortly after birth to prevent the formation of bilirubin. Although early results are promising, these drugs are still experimental.
B. Phototherapy: Phototherapy is used most commonly, because it is relatively noninvasive and safe. Light at a wavelength absorbed by bilirubin (blue or white spectrum) is used. The unconjugated bilirubin in the skin is converted by such light to a stereoisomer compound that is water soluble and able to be excreted in the bile without conjugation. A minimum of 10–12 µW/cm2 irradiance is required, and efficacy is dose dependent. The dose can be raised by increasing the body surface area exposed to the light and by moving the lights closer to the baby. Fiberoptic blankets are effective. The infant’s eyes should be shielded from the light to prevent damage to retinal cells. A frequent side effect of phototherapy is diarrhea, which is managed by feeding a non-lactose-containing formula for the duration of the treatment.
Phototherapy is started when the bilirubin level is approximately 5 mg/dL (86 µmol/L) lower than the exchange level for that infant (eg, at levels of 15–18 mg/dL [258–310 µmol/L] for a term infant), depending also on the infant’s age. Guidelines for the use of phototherapy in the term infant with and without ABO incompatibility are shown in Table 1–11 and Table 1–12. Although phototherapy has been shown to decrease the likelihood of exchange transfusion, the long-term benefits of its use in infants with less severe jaundice are unknown.
C. Exchange Transfusion: Double-volume exchange transfusion (approximately 160–200 mL/kg body weight) remains necessary in the rare case of hemolysis resulting from Rh isoimmunization, ABO incompatibility, or hereditary spherocytosis. In addition to decreasing the bilirubin level by approximately 50% acutely, the exchange also removes nearly 80% of the sensitized or abnormal red blood cells and offending antibody so that ongoing hemolysis will be decreased. The procedure is invasive and not without risk. The risk of mortality is greatest in the smallest, most immature, and otherwise unstable infants, but sudden death during the procedure can occur in any infant. Because of the rarity of the procedure and its inherent risk, it should be performed very cautiously, preferably at a referral center.
For the typical exchange transfusion, the umbilical vein is catheterized, and reconstituted whole blood with a hematocrit of approximately 50% is used in aliquots of 8–10 mL per pass. Hypocalcemia occurs during the procedure because of binding to the citrate-phosphate-dextrose anticoagulant and needs to be corrected periodically. Hypoglycemia is common following the procedure and requires close monitoring. Thrombocytopenia occurs because of the removal of platelets. The entire procedure should take 1–2 hours and should be performed using aseptic technique.
General Considerations
Jaundice is a common neonatal problem. Sixty-five percent of newborns develop clinical jaundice with a bilirubin level above 5 mg/dL during the first week of life. From an evolutionary standpoint, hyperbilirubinemia ought to confer some biologic advantage if it occurs so often. Bilirubin is a potent antioxidant and peroxyl scavenger that may help the newborn, who is deficient in most antioxidant substances such as vitamin E, catalase, and superoxide dismutase, to avoid oxygen toxicity in the days after birth. Hyperbilirubinemia can also be toxic, with high levels resulting in an encephalopathy known as kernicterus.
Metabolism of Bilirubin
Heme (iron protoporphyrin) is broken down by heme oxygenase to iron, which is conserved; carbon monoxide, which is exhaled; and biliverdin, which is then further metabolized to bilirubin by the enzyme bilirubin reductase. Each 1 g of hemoglobin breakdown results in the production of 34 mg of bilirubin (1 mg/dL = 17.2 µmol/L of bilirubin). Bilirubin is carried bound to albumin to the liver, where, in the presence of the enzyme uridyldiphosphoglucuronyl transferase (UDPGT; glucuronyl transferase), it is taken up by the hepatocyte and conjugated with two glucuronide molecules. The conjugated bilirubin is then excreted through the bile to the intestine. In the presence of normal gut flora, the conjugated bilirubin is metabolized further to stercobilins and excreted in the stool. In the absence of gut flora—and with slow intestinal motility, as in the first few days of life—the conjugated bilirubin remains in the intestinal lumen, where a mucosal enzyme (b-glucuronidase) can cleave off the glucuronide molecules, leaving unconjugated bilirubin to be reabsorbed (the enterohepatic circulation of bilirubin).
Bilirubin Toxicity
The exact mechanism by which bilirubin is toxic to cells is not known. It is assumed that if the amount of lipid-soluble unconjugated bilirubin exceeds the available binding sites on albumin, there will then be “free” bilirubin that can enter neurons and damage them. The blood-brain barrier probably plays an important role in protecting an individual from brain damage, but its integrity is impossible to measure clinically. It is not known whether there is a level of bilirubin above which brain damage would always occur even in a healthy individual.
The syndrome of bilirubin encephalopathy was well described in the era before exchange transfusion as treatment for Rh isoimmunization (see below). The pathologic correlate is known as kernicterus, named for the yellow staining of the subthalamic nuclei (kerns) seen at autopsy. The early symptoms of bilirubin encephalopathy consist of lethargy, hypotonia, and poor sucking, progressing to hypertonia, opisthotonos, and a high-pitched cry. Long-term sequelae include athetoid cerebral palsy, sensorineural deafness, limitation of upward gaze, and dental dysplasia. Whether or not bilirubin causes more subtle neurologic abnormalities remains debatable.
Bilirubin encephalopathy is very rare with current neonatal management. The only infant in which a specific bilirubin level (20 mg/dL [344 µmol/L] and above) has been associated with an increased risk of kernicterus is the Rh-isoimmunized infant. This observation—and the management strategy of keeping bilirubin under 20 mg/dL with exchange transfusion if needed—has been extended to other neonates with hemolytic disease despite an absence of data on the risk. The risk of bilirubin encephalopathy is probably very small for term infants without hemolysis even at bilirubin levels of 25 mg/dL (430 µmol/L). Premature infants are probably at some increased risk because of associated illnesses that may affect the integrity of the blood-brain barrier and reduced albumin levels. For this reason, a lower level of bilirubin is generally assumed to represent the “exchange level” in these infants and is usually determined arbitrarily based on the infant’s birth weight and gestational age. One common approach is to use 1% of the birth weight in grams as the exchange level in mg/dL (eg, 12 mg/dL for a 1200-g infant)—down to a low of 10 mg/dL. Many other approaches exist as well.
Causes of Unconjugated Hyperbilirubinemia
The causes of unconjugated hyperbilirubinemia can be grouped into two main categories: overproduction of bilirubin and decreased conjugation of bilirubin (Table 1–9).
A. Increased Bilirubin Production: Increased production of bilirubin results from an increased rate of red blood cell destruction (hemolysis) due to the presence of maternal antibodies against fetal cells (Coombs test–positive), abnormal red cell membrane shape (ie, spherocytosis), or abnormal red cell enzymes (ie, glucose-6-phosphate dehydrogenase [G6PD] deficiency). Antibodies can be directed against the major blood group antigens (the type A or type B infant of a type O mother) or the minor antigens (the Rh system: D, E, C, d, e, c, Kell, Duffy, and so on).
1. Antibody-mediated hemolysis (Coombs test–positive)—ABO blood group incompatibility is common, usually not severe, and can accompany any pregnancy in a type O mother. The severity is not predictable because of variability in the amount of naturally occurring anti-A or anti-B IgG antibodies in the mother. Although 20% of pregnancies are the appropriate “set-ups” for ABO incompatibility (mother O, baby A or B), only about 33% of such infants are Coombs test–positive and only about 20% of these develop excessive jaundice. In addition to hyperbilirubinemia in the first days of life, these infants may develop a significant anemia over the first several weeks and on occasion may need to be transfused at a few weeks of age.
Rh isoimmunization is much less common and increases in severity with each immunized pregnancy because of an increased maternal IgG antibody production each time. Most Rh disease can be prevented by administering high-titer Rho(D) immune globulin to an Rh-negative woman after any invasive procedure during pregnancy as well as after any miscarriage, abortion, or delivery of an Rh-positive infant. In severe cases, erythroblastosis fetalis (hydrops or generalized edema with heart failure related to severe anemia in the fetus) occurs, often resulting in fetal or neonatal death without appropriate antenatal intervention. In less severe cases, hemolysis is the main problem, with resultant hyperbilirubinemia and anemia. The cornerstone of antenatal management once isoimmunization has been diagnosed is transfusion of the fetus with Rh-negative cells, either directly into the umbilical vein via percutaneous cordocentesis or into the fetal abdominal cavity. Following delivery, phototherapy is usually started immediately, with exchange transfusion (see below) as needed. A 500 mg/kg dose of intravenous immune globulin (IVIG) given to the infant as soon after delivery as the diagnosis is made has been shown to decrease the need for exchange transfusion. Ongoing hemolysis will still occur until all maternal antibody is gone; therefore, these infants need to be followed carefully over the first 2 months for development of anemia severe enough to require transfusion. The role of erythropoietin therapy in treating late anemia is under investigation.
2. Nonimmune hemolysis (Coombs test– negative)—Hereditary spherocytosis is the most common red cell membrane defect, resulting in hemolysis because of decreased red cell deformability. These infants may have hyperbilirubinemia severe enough to require exchange transfusion. Mild to moderate splenomegaly may be present. Diagnosis is suspected by peripheral blood smear and confirmed by red cell osmotic fragility study. A family history of anemia, jaundice, and gallstones may be elicited.
G6PD deficiency is the most common red cell enzyme defect resulting in hemolysis and should be suspected in a male (it is X-linked) of African, Mediterranean, or Asian descent, particularly when the onset of jaundice is later than usual.
3. Nonhemolytic increased bilirubin production—Enclosed hemorrhage, such as cephalohematoma, intracranial hemorrhage, or extensive bruising in the skin, can lead to jaundice as the red blood cells are broken down and removed. Polycythemia leads to jaundice by increased red cell mass, with increased numbers of cells reaching senescence daily. Ileus, either paralytic or mechanical, related to a bowel obstruction, leads to hyperbilirubinemia secondary to increased enterohepatic circulation.
B. Decreased Rate of Conjugation:
1. UDPGT deficiency–Crigler-Najjar syndrome type I (complete deficiency, autosomal recessive) and type II (partial deficiency, autosomal dominant) present as excessive and prolonged neonatal jaundice, but both forms are very rare.
2. Gilbert syndrome is a mild autosomal dominant disorder affecting 3–6% of the population and characterized by decreased hepatic UDPGT levels. Mild unconjugated hyperbilirubinemia without other liver function abnormalities occurs after puberty. The possible relationship of this disorder to exaggerated neonatal jaundice is under investigation.
C. Hyperbilirubinemia Caused by Unknown or Multiple Factors:
1. Physiologic jaundice—The contributing factors to physiologic jaundice include UDPGT inactivity at birth, a relatively high red cell mass even in the nonpolycythemic neonate, and an absence of intestinal flora, with initially slow intestinal motility leading to an active enterohepatic circulation of bilirubin. For jaundice to be physiologic rather than pathologic, the following criteria should be satisfied: (1) clinical jaundice appears after 24 hours of age; (2) total bilirubin rises by less than 5 mg/dL (86 µmol/L) per day; (3) peak bilirubin occurs at 3–5 days of age, with a total bilirubin of no more than 15 mg/dL (258 µmol/L); and (4) clinical jaundice is resolved by 1 week in the term infant and by 2 weeks in the preterm infant. Hyperbilirubinemia outside of these parameters—or jaundice that requires treatment—is not physiologic and must be evaluated further (see below).
2. High altitude—Infants at 3100 m (10,000 ft) have twice the incidence of bilirubin over 12 mg/dL (206 µmol/L) as infants at 1600 m (5200 ft) and four times that of infants at sea level: 39% versus 16% versus 8%, respectively. Possible mechanisms include increased bilirubin production secondary to increased hematocrit and decreased clearance caused by hypoxemia.
3. Racial differences—Asians are more likely than whites or blacks to have a bilirubin greater than 12 mg/dL (206 µmol/L): 23% versus 10–13% versus 4%, respectively.
4. Prematurity—Premature infants frequently have poor enteral intake, delayed stooling, and increased enterohepatic circulation. Even at 37 weeks’ gestation, they are four times more likely than at 40 weeks to have a bilirubin greater than 13 mg/dL (224 µmol/L).
5. Breast feeding and jaundice—There are two syndromes of jaundice associated with breast feeding: breast milk jaundice and breast feeding–associated jaundice (“lack-of-breast-milk jaundice”).
- Breast milk jaundice is an uncommon syndrome of prolonged unconjugated hyperbilirubinemia believed to be caused by a prolonged increased enterohepatic circulation of bilirubin in some breast-fed infants, perhaps related to increased free fatty acids in the milk. The presence of moderate unconjugated hyperbilirubinemia for 6–8 weeks in a thriving infant without evidence for hemolysis, hypothyroidism, or other disease strongly suggests this diagnosis. The hyperbilirubinemia peaks at 10–15 days of age, with a maximal level of 10–30 mg/dL (172–516 µmol/L), and declines slowly by 3–12 weeks of age. If nursing is interrupted for 24–48 hours, the bilirubin level falls quickly and will not rebound to the same level when nursing is resumed. This is indicated only if the hyperbilirubinemia is severe.
- Breast feeding–associated jaundice, also known as “lack-of-breast-milk jaundice,” is a common entity. Breast-fed infants have a higher incidence (9%) of bilirubin over 13 mg/dL (224 µmol/L) than formula-fed infants (2%) and are more likely to have bilirubin over 15 mg/dL (258 µmol/L) than formula-fed infants: 2% versus 0.3%. The pathogenesis appears to be decreased enteral intake and increased enterohepatic circulation. No increase in bilirubin production is seen, as measured by carbon monoxide exhalation. Although rarely associated with bilirubin encephalopathy, this type of jaundice should be considered a sign of failure to establish an adequate milk supply and should prompt specific inquiries into this possibility (Table 1–10). If inadequate intake is present, the infant should receive supplementation with formula if needed, and the mother should be instructed to nurse more frequently and to pump her breasts with an electric breast pump every 2 hours to enhance milk production. A consultation with a certified lactation specialist should be considered, because many physicians feel inadequately prepared to handle these situations. Because hospital discharge of normal newborns occurs before the milk supply is established, a follow-up visit 2–3 days after discharge is of obvious importance.
- These two entities may sometimes overlap in the same infant, because prolonged jaundice is common in breast-fed infants (20–30%), and many of those infants with high bilirubin levels in the first days also persist longest.
- Prolonged Hyperbilirubinemia: Causes of prolonged hyperbilirubinemia include hemolytic disease, breast milk jaundice, Crigler-Najjar syndrome, bowel obstruction, congenital hypothyroidism, and galactosemia. Galactosemia generally presents with hepatomegaly in an ill-appearing, often septic infant, and the hyperbilirubinemia is usually mixed.
Evaluation of Hyperbilirubinemia
Clinical jaundice appears at a bilirubin level of 5 mg/dL (86 µmol/L) and appears first on the head, progressing down the chest and abdomen as the level increases. By the time jaundice is noted on the distal extremities, the level is likely to be at least 15 mg/dL (258 µmol/L). When checking serum bilirubin levels, the level should be assessed based on the age in hours at which the sample was obtained. Infants with a total serum bilirubin greater than the 95th percentile for age in hours have a 40% risk of developing subsequent significant hyperbilirubinemia (Figure 1–2). Infants who develop clinical jaundice on the first day of life—or who develop excessive jaundice—require evaluation. The minimal evaluation consists of a feeding and elimination history, weight (and comparison with birth weight), examination for any source of excessive heme breakdown, and laboratory evaluation for blood type, Coombs testing, complete blood count with smear, and total bilirubin level. A G6PD test should be considered if the infant is a male of African, Asian, or Mediterranean racial background, particularly if the jaundice presents later than usual. A fractionated bilirubin level should be obtained if the infant appears acutely ill, if jaundice is prolonged, or if the infant has dark urine with light stools.
Because of large interlaboratory variability, serial bilirubin levels should be obtained from a single laboratory whenever possible to make interpretation more accurate.
Treatment of Hyperbilirubinemia
A. Protoporphyrins: Tin and zinc protoporphyrin or mesoporphyrin (Sn-PP, Zn-PP; Sn-MP, Zn-MP) are inhibitors of heme oxygenase, the enzyme that begins the catabolism of heme (iron protoporphyrin). Studies are under way involving a single injection of these substances shortly after birth to prevent the formation of bilirubin. Although early results are promising, these drugs are still experimental.
B. Phototherapy: Phototherapy is used most commonly, because it is relatively noninvasive and safe. Light at a wavelength absorbed by bilirubin (blue or white spectrum) is used. The unconjugated bilirubin in the skin is converted by such light to a stereoisomer compound that is water soluble and able to be excreted in the bile without conjugation. A minimum of 10–12 µW/cm2 irradiance is required, and efficacy is dose dependent. The dose can be raised by increasing the body surface area exposed to the light and by moving the lights closer to the baby. Fiberoptic blankets are effective. The infant’s eyes should be shielded from the light to prevent damage to retinal cells. A frequent side effect of phototherapy is diarrhea, which is managed by feeding a non-lactose-containing formula for the duration of the treatment.
Phototherapy is started when the bilirubin level is approximately 5 mg/dL (86 µmol/L) lower than the exchange level for that infant (eg, at levels of 15–18 mg/dL [258–310 µmol/L] for a term infant), depending also on the infant’s age. Guidelines for the use of phototherapy in the term infant with and without ABO incompatibility are shown in Table 1–11 and Table 1–12. Although phototherapy has been shown to decrease the likelihood of exchange transfusion, the long-term benefits of its use in infants with less severe jaundice are unknown.
C. Exchange Transfusion: Double-volume exchange transfusion (approximately 160–200 mL/kg body weight) remains necessary in the rare case of hemolysis resulting from Rh isoimmunization, ABO incompatibility, or hereditary spherocytosis. In addition to decreasing the bilirubin level by approximately 50% acutely, the exchange also removes nearly 80% of the sensitized or abnormal red blood cells and offending antibody so that ongoing hemolysis will be decreased. The procedure is invasive and not without risk. The risk of mortality is greatest in the smallest, most immature, and otherwise unstable infants, but sudden death during the procedure can occur in any infant. Because of the rarity of the procedure and its inherent risk, it should be performed very cautiously, preferably at a referral center.
For the typical exchange transfusion, the umbilical vein is catheterized, and reconstituted whole blood with a hematocrit of approximately 50% is used in aliquots of 8–10 mL per pass. Hypocalcemia occurs during the procedure because of binding to the citrate-phosphate-dextrose anticoagulant and needs to be corrected periodically. Hypoglycemia is common following the procedure and requires close monitoring. Thrombocytopenia occurs because of the removal of platelets. The entire procedure should take 1–2 hours and should be performed using aseptic technique.
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