Henry C. Lee and Ashima Madan
RED BLOOD CELL DISORDERS
Hematologic problems arise frequently in the newborn period.1 This section is focused on disorders specific to the newborn period. For further discussion of the developmental changes that occur in hematopoiesis, see Chapter 429. Hematologic disorders, including congenital disorders, are discussed in detail in Section 23: Disorders of the Blood.
NUCLEATED RED BLOOD CELLS
Nucleated red blood cells (nRBCs) are not common in older children but can be found frequently in the peripheral blood smear of newborns.8 They represent circulating erythrocyte precursors, or normoblasts, which are normally found in the bone marrow. Healthy term newborns may have some nRBCs in the peripheral blood. However, elevated nRBCs may represent the result of pathologic processes such as relative in utero hypoxia resulting in increased erythropoietin, which stimulates increased production of red blood cells. Although many laboratories report nRBCs in relation to the number of white blood cells (nRBCs/100 WBC), it is probably more informative to express this as an absolute number per unit volume (ie, nRBCs/mm3). A value of 1000 nRBCs/mm3 may be considered the higher limit of normal for a normal term newborn. Preterm newborns typically have higher nRBCs at birth.
An increase in the number of circulating nRBCs can represent conditions of increased erythropoiesis or stress-mediated release of normoblasts from the bone marrow. Increased erythropoiesis may occur in times of chronic hypoxia as in preeclampsia and placental insufficiency. Infants born to smoking mothers have been found to have increased nRBCs.9 Increased erythropoiesis may result from blood loss from any cause, including hemolysis, which occurs in the context of red blood cell isoimmunization. Elevation of nRBCs also occurs in infants of diabetic mothers and in congenital infections.
Hypoxia does not have to be chronic to observe nRBC elevation at birth. Acute stress and subacute stress are also associated with increased circulating nRBCs. Elevated nRBCs in this context may serve as a marker for fetal asphyxia.10,11 Increased numbers of nRBCs correlates with lower umbilical cord pH and therefore may reflect degree and duration of asphyxia.12,13 Chronic asphyxia is typically associated with higher nRBCs than with acute asphyxia events.14
ANEMIA
The mean hemoglobin concentration in the term newborn ranges from 14 to 20 g/100 mL.15 In the first hours after birth, the hemoglobin concentration can rise due to a relative reduction in plasma volume. However, the hemoglobin level soon begins to decline, reaching a “physiologic nadir” at around 2 to 3 months of age. Preterm newborns have lower hemoglobin concentrations at birth and a larger decrease after birth, reaching a nadir at an earlier age, as early as 6 weeks for very-low-birth-weight infants.16 The causes of anemia in the newborn period include increased blood loss or decreased production of red blood cells.
Blood loss may occur before, during, or after birth. Fetal-to-maternal hemorrhage can be detected by the observation of fetal red blood cells in maternal blood by the Betke-Kleihauer test.17 Twin-to-twin transfusion can occur in monozygous twins with monochorionic placentas. This should be suspected when the hemoglobin concentration differs by more than 5 g/100 mL. Placental abruption can be chronic or acute in nature and, when severe, can result in morbidity or death in the absence of rapid resuscitation. Other placental disorders that can lead to significant hemorrhage include placenta previa, in which the placenta implants directly over the cervix and vasa previa, when fetal blood vessels overlie the cervical opening unprotected by the placenta or umbilical cord. Both conditions carry high risk of hemorrhage with vaginal delivery, and optimal outcomes depend on prenatal diagnosis and cesarean delivery.18
Closed hemorrhage into body spaces, which can serve as significant reservoirs of blood, may be associated with birth trauma in the newborn. This is more common in preterm infants. Cephalohematomas are generally self-limited and resolve over several days; larger hematomas may lead to anemia and jaundice. Subgaleal hemorrhage, which can be associated with vacuum extraction, may lead to more extensive anemia because bleeding is not limited by the periosteum. Caution and close monitoring are warranted because shock and coagulopathy may ensue.19 Other areas of “hidden” bleeding include the liver, spleen, adrenal glands, and retroperitoneum. Unexplained symptoms of hypovolemic shock may warrant exploration with abdominal ultrasound.
Anemia can result from blood loss through hemolysis, which produces hyperbilirubinemia and jaundice. Hemolysis may be immune mediated when maternal antibodies are directed against antigens such as those in the Rh or ABO blood groups. Although the Rh(D) antigen has been implicated as causing the most severe cases, hemolytic disease can occur with other “minor” antigens such as the Kell, Duffy, Kidd, and other Rh(c) and Rh(E) antigens. Other causes of hemolysis include membrane defects such as hereditary spherocytosis or elliptocytosis, hemoglobin-opathies such as the thalassemia syndromes, and enzyme abnormalities such as pyruvate kinase deficiency and glucose-6-phosphate dehydrogenase deficiency.20
ERYTHROBLASTOSIS FETALIS
Erythroblastosis fetalis was first described in 1932 as a distinct condition comprising anemia, universal edema of the fetus (hydrops fetalis), and neonatal jaundice.21 The most important of the Rh membrane proteins is the D antigen. Mothers who lack the D antigen are designated as Rh-negative. When blood cells from an Rhpositive fetus leak into the maternal circulation, maternal sensitization to the antigen occurs with subsequent passage of anti-D antibodies into the fetal circulation with resulting hemolysis. Disease is rare during the first pregnancy, but with each subsequent pregnancy, there is increased risk of significant disease.
The incidence of severe erythroblastosis fetalis has decreased substantially with the use of anti-D immune globulin given to Rh-negative mothers who have not yet been sensitized.22,23 Administration of immune globulin should occur at 28 weeks, and an additional dose should be given after birth of an Rh-positive infant.
Mothers who have developed a significant antibody response need close fetal monitoring for possible intervention. Spectrophoto-metric estimation of bile pigment in the amniotic fluid can provide an estimate of the severity of disease.24 Ultrasound has more recently allowed for earlier detection of hydrops and also direct measurement of the fetal hemoglobin level by percutaneous umbilical blood sampling (PUBS).25 This technique also allows for intrauterine blood transfusion in cases of severe fetal anemia.
There is a spectrum of clinical manifestation in Rh hemolytic disease. For mild cases, there may be mild to moderate hyperbilirubinemia after birth. However, even those infants should have hemoglobin monitored after discharge because they are at risk of progressive anemia. In moderate to severe disease, exchange transfusion may be required if phototherapy is not sufficient. In severe cases, affected infants may be significantly hydropic and stillborn.
POLYCYTHEMIA
Neonatal polycythemia is usually defined as a central venous hematocrit greater than 65%, although blood flow may be impaired at a hematocrit as low as 60%. However, most infants with a high hematocrit are asymptomatic. Infants with increased blood viscosity from polycythemia and resulting organ dysfunction from impaired blood flow have hyper-viscosity syndrome.
The incidence of neonatal polycythemia is reported as between 1% to 5% of newborns and depends on the altitude of the study population.15 Polycythemia is less frequent in pre-term births due to lower red blood cell mass.
Neonatal polycythemia is usually caused by either increased intrauterine erythropoiesis or increased transfusion to the fetus or newborn just prior to ligation of the umbilical cord. Conditions associated with intrauterine hypoxia, such as placental insufficiency and maternal smoking, increase the risk of polycythemia. Newborns of mothers with hypertension are also at risk for polycythemia, even outside the context of intrauterine growth restriction.26 In cases of twin-to-twin transfusion syndrome in monochorionic twin pregnancies, the recipient twin is at higher risk of polycythemia.
The hematocrit generally peaks 2 hours after delivery and declines to cord levels at around 12 to 18 hours of age.27 Although capillary hematocrit may suffice as a screening tool, a venous hematocrit should be obtained to confirm the diagnosis and support treatment decisions.27,28
Hyperbilirubinemia is likely to occur from breakdown of the increased red blood cell mass, and therefore, the development of jaundice should be monitored closely. Hypoglycemia may accompany polycythemia and may be aggravated by conditions such as diabetes mellitus and placental insufficiency. Additional organ dysfunction associated with polycythemia and hyperviscosity include neurological symptoms such as hypotonia, irritability, and lethargy, tachypnea and respiratory distress, feeding difficulty, and thrombocytopenia.
Polycythemic infants have an increase in red cell volume but normal plasma volume. Therefore, the recommended treatment is isovolemic partial exchange transfusion.29 The few randomized controlled trials evaluating partial exchange transfusion have been small in size and have not demonstrated a significant impact on long-term outcomes.30 Nevertheless, symptomatic infants with a venous hematocrit above 65% to 70% may benefit from prevention of ongoing injury with partial exchange transfusion. The exchange can best be accomplished by insertion of an umbilical venous catheter. The volume to be exchanged can be calculated using this formula:
volume (mL) = circulating blood volume × [(Hct current − Hct desired)/Hct current]
where the circulating blood volume can be estimated as 90 mL/kg times weight for term infants and 100 mL/kg times weight for preterm infants.31 No significant benefit has been seen for any particular dilution fluid whether it be albumin, plasma, or crystalloid.31 Therefore, normal saline should be used as the dilution fluid because it is low risk and low cost compared to blood-derived products. Glucose and calcium should be monitored during and after the exchange transfusion.
WHITE BLOOD CELL DISORDERS
NEUTROPENIA
Neutropenia is often seen in the newborn period and may be due to decreased production or increased destruction of white cells. It is commonly seen in infants born to mothers with pregnancy-induced hypertension. This neutropenia can be severe with an absolute neutrophil count less than 500/μL but is generally transient and resolves without any specific treatment in the first 3 to 5 days after birth.32,33There is usually an absence of a left shift in the white blood cell count.34
The neutropenia seen in neonatal sepsis syndromes is a result of accelerated neutrophil use and depleted bone marrow neutrophil storage pools. There is usually a left shift and other morphologic characteristics, such as toxic granulation, vacuolization, and Döhle bodies.32 This neutropenia is also transient, and clinical improvement is generally accompanied by resolution.
When neutropenia lasts more than several days, rarer causes should be investigated. Infants with congenital neutropenia (Kostmann syndrome) have profound neutropenia, often with an absolute neutrophil count of less than 200/μL. There is arrest at the promyelocyte stage in the bone marrow. Kostmann syndrome was initially described in a family with autosomal recessive inheritance, but the majority of other reported cases are sporadic mutations with an autosomal dominant inheritance.32,35 Congenital neutropenia can also be related to immune-mediated destruction with antibodies from either the mother or infant.36 Alloimmune neonatal neutropenia is caused by maternal sensitization to fetal neutrophil antigens. Maternal antibodies are directed against the infant’s neutrophils. This is analogous to alloimmune thrombocytopenia or Rh disease. Neutropenia can last for weeks, and infants are at risk for infection. Possible therapies include intravenous immune globulin, infusion of granulocytes that lack the specific antigen, and granulocyte colony-stimulating factor. For further discussion of granulocyte disorders see Chapter 441.
LEUKEMIAS
Although leukemia is an uncommon disorder in the neonatal period, it is the leading cause of death due to neoplastic disease in the neonate. The characteristics of leukemia in the newborn period also differ from leukemia in later childhood, with unique chromosomal rearrangements and differing prognoses.37 Trisomy 21 and 11q23 translocations are the most common chromosomal alterations seen in association with neonatal leukemias. In general, neonatal leukemia carries a grave prognosis, although recent use of multiagent chemotherapy has been promising.37,38 Acute myelocytic leukemia is more common than acute lymphocytic leukemia.38,39
Leukemia can present as early as in utero with hydrops and polyhydramnios, leading in some instances to stillbirth. Some neonates may present at birth, while others may appear normal and develop hematologic symptoms over the first weeks after delivery. Nodular cutaneous infiltrates or “blueberry muffin spots” may be evident, particularly in acute myelocytic leukemia.37 Other signs and symptoms include hepatosplenomegaly, anemia, and bleeding secondary to thrombocytopenia.
Children with trisomy 21 are at risk for development of leukemia, including a unique form that is seen in the newborn period and can resolve spontaneously without chemotherapy. This condition is called transient leukemia or transient myeloproliferative disorder and affects approximately 10% of newborns with trisomy 21.40 Although it shares many of the features of other leukemias, including varying degrees of hepatosplenomegaly, megakaryoblastic cells in the blood and marrow, thrombocytopenia, and anemia, there is a spontaneous regression over several months. However, some patients are at risk of severe disease and even death in the neonatal period from sepsis, hepatic fibrosis, and cardiopulmonary failure.41 Furthermore, even after spontaneous resolution, a significant proportion will eventually develop another hematologic disorder, most commonly acute megakaryoblastic leukemia.
PLATELET AND COAGULATION DISORDERS
THROMBOCYTOPENIA
Thrombocytopenia in the newborn can be classified as mild (100−150 × 109 platelets/L), moderate (50−100 × 109 platelets/L), and severe (< 50 × 109 platelets/L). Although some petechiae and bruising may be present over the presenting part secondary to pressure during the normal birth process, the platelet count should be checked when more than a few petechiae are present or in any sick infant. Thrombocytopenia occurs frequently in infants admitted to the neonatal intensive care unit: more than 20% of infants compared to less than 1% of healthy newborns.42-44 The low platelet counts seen in sick newborns reflects the severity of illness and resolves as the underlying condition, often sepsis, improves. Thrombocytopenia in a premature infant can be an early sign of sepsis or necrotizing enterocolitis. For patients in the intensive care unit, thrombocytopenia may also be caused as a side effect of medications such as heparin and ranitidine, although it is sometimes difficult to distinguish whether thrombocytopenia is due to medications used to treat sick infants or to the underlying condition.45 Indomethacin, used to treat patent ductus arteriosus, inhibits platelet function, and platelet count should be monitored during its use.
Immune destruction of platelets can occur from maternal antibodies. Mothers with autoimmune thrombocytopenia or (idiopathic thrombocytopenic purpura) can pass antiplatelet IgG through the placenta. Severe thrombocytopenia in infants is rare in these cases but, when present, can be treated with intravenous immune globulin and corticosteroids. However, alloimmune thrombocytopenia, which occurs when maternal antibodies form against fetal platelet antigens, can be associated with severe presentations, including intracranial hemorrhage and even in utero death.46 Potential prenatal therapies include intravenous immune globulin and corticosteroids administered to the mother, as well as in utero platelet transfusions. In Caucasians, human platelet antigen (HPA)-1a is the most common antigen, whereas in Asians, HPA-4 is more common.46 Diagnosis can be made by platelet typing of both parents and the infant. Testing for antiplatelet antibodies should be performed in the baby and the mother because it may be falsely negative in the baby. Cranial ultrasound should be obtained to check for hemorrhage. When platelet transfusion is necessary, washed maternal platelets or HPA-compatible platelets from the blood bank can be used. Intravenous immune globulin may also be used as adjunctive therapy.
Thrombocytopenia can be seen as a result of megakaryocyte disruption in fetal acidosis or hypoxia and in mothers with preeclampsia. Other causes include infection, both bacterial and in congenital viral infections, such as cytomegalovirus, toxoplasmosis, and rubella.44 Various syndromes that can present in the newborn period and are associated with thrombocytopenia include trisomy 13, 18, and 21; Fanconi anemia; and Bernard-Soulier syndrome. Thrombocytopenia absent radii syndrome is a rare, autosomal recessive disorder, presenting with severe thrombocytopenia and bilateral agenesis of radii. Platelet sequestration occurs as a result of localized disseminated vascular malformations in Kasabach-Merritt syndrome.
COAGULATION DISORDERS
Coagulation disorders can present in the newborn period as petechiae, purpura, or internal hemorrhage. Laboratory evaluation can be challenging due to the immature development of the hemostatic factors in newborns, and reference values for older children and adults may not be applicable for tests such as prothrombin time and activated partial thromboplastin time.47,48 Furthermore, premature infants will have higher values than term infants, and different laboratory reagents and systems can have differing results.49 These laboratory “abnormalities” are generally not associated with increased bleeding in most instances.
Much of the hemorrhagic problems occurring in the nursery are secondary to underlying illness such as sepsis and/or disseminated intravascular coagulation. Bleeding from vitamin K deficiency, previously known as hemorrhagic disease of the newborn, is due to decreased vitamin K levels after birth, which results in impaired carboxylation of vitamin K–dependent clotting factors, making them functionally inactive.50 Vitamin K deficiency is suggested by prolonged prothrombin time and activated partial thromboplastin time, in association with normal platelet count and fibrinogen, and can be confirmed with measurement of the specific vitamin K–dependent factors (II, VII, IX, and X). Treatment is with intravenous vitamin K. Routine newborn prophylaxis to prevent vitamin K deficiency using intramuscular vitamin K is optimal. Oral dosing has shown mixed results.50
Inherited conditions can also present with significant bleeding and can be diagnosed during the newborn period.51,52 Contrary to presentations in later life, such as bleeding into a joint or muscle, neonates often have excessive bleeding in response to various iatrogenic conditions such as venipuncture, heel stick, Vitamin K administration, and circumcision.53 Hemophilia A is diagnosed with prolonged activated partial thromboplastin time and decreased factor VIII levels, which should be within normal adult range. However, the diagnosis of hemophilia B may be difficult in milder cases because factor IX and other vitamin K–dependent factors are decreased in newborns, particularly at earlier gestations. In borderline cases, molecular analysis or repeat testing may be necessary at 6 months of age.53 Von Willebrand disease generally does not present in the newborn period because there is a physiologic increase in von Willebrand factor at birth. For further discussion, see Chapter 436.
THROMBOTIC DISORDERS
Thromboembolic events in the perinatal period are rare. Even so, there has been increasing recognition of the potential morbidities associated with hereditary prothrombotic states. Thromboembolic events occur in the newborn period most often as a complication of indwelling vascular catheters. A prothrombotic state may also present as perinatal stroke. Although stroke is a rare event in this population, evidence suggests that some of these events may be related to prothrombotic states such as factor V Leiden and mutations in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene54 (see Chapters 52and 552). Other maternal conditions that may increase the risk of thrombosis include diabetes mellitus, systemic lupus erythematosus, and antiphospholipid syndrome. Renal vein thrombosis can occur spontaneously and occurs more frequently in preterm infants.55 Presenting signs are hematuria, flank mass, and thrombocytopenia.
Laboratory testing for evaluation of thrombophilia include assays for known factors associated with prothrombotic states. These include factor V Leiden, prothrombin gene mutation, antithrombin deficiency, proteins C and S deficiencies, and MTHFR mutation.56 Mild deficiency states may prove difficult to detect in the newborn period because many factors are normally below adult levels.57 Follow-up testing at 6 months of age may be useful.
There is no consensus regarding anticoagulant and thrombolytic therapy for newborns. All potential treatments carry the risk of major bleeding. Therefore, supportive care and close observation may be an optimal approach. When medications are used, the therapy will depend on thrombus location, degree of impairment, and cause of thrombosis if known. Unfractionated heparin is monitored by frequent measurement of activated partial thromboplastin time, which guides dosing of heparin boluses and altering of heparin infusion rates. Low molecular weight heparin is becoming a preferred treatment because it is an easier alternative, having more predictable pharmacokinetics and requiring less monitoring via anti-Xa levels.58 Higher doses than those used in adults are generally necessary to achieve therapeutic levels. Adverse effects such as major bleeding appear to occur less frequently than with unfractionated heparin.
Thrombolytic agents act by converting plasminogen to plasmin, and their use in neonates is limited by the relatively low concentrations of plasminogen in newborns. Tissue plasminogen activator is currently the thrombolytic therapy of choice for neonates due to its availability and increased fibrin specificity.59 Due to the potential risk of major bleeding and lack of controlled trials, its use is limited to organ-or life-threatening situations. Oral anticoagulation with warfarin is difficult in newborns because warfarin is a vitamin K antagonist and vitamin K–dependent factors are already low in newborns. The low concentrations of vitamin K in breast milk and the supplementation of vitamin K in formula also make the monitoring and use of warfarin inappropriate in most cases of neonatal thrombosis.59
JAUNDICE
Jaundice, one of the most common conditions encountered in the care of newborn infants, refers to the yellow discoloration of the skin and sclerae resulting from bilirubin deposition in tissues. The condition arises when the rate of bilirubin production exceeds the rate at which bilirubin is eliminated. Newborn infants have a rate of bilirubin formation that is 2 to 3 times higher than that of adults and is attributable mainly to the higher hematocrit and the shorter life span of the red blood cells in the newborn.60 The decrease in bilirubin elimination occurs from the limited ability of the newborn liver to conjugate bilirubin and increased enterohepatic circulation. Although jaundice can result from an increase in either unconjugated (indirect) or conjugated (direct) bilirubin, a rise in the indirect fraction is the most common cause of newborn jaundice and is the focus of this section. The approach to evaluation of a conjugated hyperbilirubinemia is discussed in Chapter 419.
BILIRUBIN METABOLISM
Bilirubin is derived from the catabolism of heme. Approximately 75% of bilirubin is derived from the breakdown of hemoglobin from senescent red blood cells. The remainder arises from ineffective erythropoiesis and from the breakdown of hemoproteins, such as cytochromes, myoglobin, nitric oxide synthase, glutathione peroxidase, and catalase (Fig. 53-1).
Heme is degraded in a 2-step process by the enzyme heme oxygenase resulting in formation of biliverdin and carbon monoxide in equimolar amounts. Carbon monoxide, which diffuses from the cell, binds to hemoglobin in circulating red blood cells to form carboxyhemoglobin (COHb) and is eventually excreted during exhalation (measurable as end-tidal carbon monoxide). Bilirubin is produced from biliverdin by the action of biliverdin reductase. Upon entering the circulation bilirubin binds to albumin and is transported to the liver. Inside the hepatocyte, bilirubin binds to ligandin and subsequently undergoes conjugation to glucuronic acid catalyzed by uridine diphosphate glucuronosyltransferase (UGT) into a water soluble form that is easily excretable. Distribution of bilirubin into tissues depends on its binding to albumin and the serum pH. The greater the binding to albumin and the more alkaline the pH, the more likely bilirubin will remain in circulation until it enters the liver. Conjugated bilirubin is excreted into the intestine via the bile, where it is either deconjugated by enzyme β-glucuronidase and reabsorbed into the circulation (enterohepatic circulation) or converted by bacteria to nonabsorbable breakdown products. Because the newborn infant has less intestinal bacteria, the enterohepatic circulation of bilirubin is active in the newborn and contributes to the increased propensity for jaundice.
FIGURE 53-1. Bile pigment metabolism in the newborn. RBC, erythrocytes. (Source: Adapted from MacDonald GB and Avery MG. Neonatology: Pathophysiology and Management of the Newborn. Lippincott, 2005, pp. 768-846.)
JAUNDICE
Although not all full-term infants become visibly jaundiced, nearly all have a high serum total bilirubin (STB) concentration (hyperbilirubinemia, > 1 mg/dL) compared to adults.61 The range of normal STB levels in a population depends on various factors, including racial composition, genetic factors, and incidence of breast-feeding. In studies of infants of Northern European origin, the mean peak STB averaged approximately 7.1 mg/dL between days 3 and 6 of life.62 The 95th percentile for STB was 12.9 mg/dL in the National Collaborative Perinatal Project conducted from 1955 to 1961 when fewer mothers breastfed their infants.63 In a more recent international study, peak STB levels were 8.9 mg/dL in breastfed infants and 7.6 mg/dL in formula-fed infants at 96 hours of age.64 Two separate studies from the United States and the international study reported the 95th percentile at 96 hours to be 17.4 mg/dL.64-66 In term, healthy infants, jaundice resolves by 2 weeks of age. In late preterm infants (including those from 35 to 37 weeks in gestation), who are often cared for in well-baby nurseries, as well as some East Asian infants, peak STB concentrations may not be reached until the end of the first week of life and may show an even more protracted decline.
PATHOLOGIC HYPERBILIRUBINEMIA
Severe hyperbilirubinemia requiring treatment can occur by either an exaggeration of the normal physiologic processes discussed or pathologic conditions. Jaundice in the first 24 hours of life or persisting beyond 2 weeks of age in a term infant, a rapid rate of rise of bilirubin greater than 0.2 mg/dL/hour, a serum bilirubin level greater than the 95th percentile for age in hours, or a direct bilirubin level greater than 1 mg/dL are all suggestive of pathologic jaundice.
All of the pathologic causes of newborn jaundice can be understood in terms of an imbalance between increased bilirubin production and decreased elimination. An increased production of the pigment is seen with hemolysis arising from blood group incompatibilities, erythrocyte enzyme deficiencies, or structural defects of the erythrocytes. Increased production is also seen in premature infants because of the shortened red cell life span; in infants of diabetic mothers because of polycythemia or ineffective erythropoiesis; in infants with closed-space bleeding, such as bruising, hematoma formation, and hemorrhage into internal organs due to the breakdown of extruded blood; in infants with polycythemia; and in infants with sepsis. Decreased elimination of bilirubin can result from either a genetic defect in hepatic uptake, as seen in newborn infants with a polymorphic variant of the organic anion transporter protein OATP-2 gene, or impaired conjugation of bilirubin from inherited defects in UGT as seen in Gilbert syndrome and Crigler-Najjar syndrome types I (severe deficiency) and II (less severe form). In Gilbert syndrome, the mildly decreased UGT activity is related to an increased number of the thymineadenine repeats in the promoter region of the UG1TA gene, the principal gene encoding for this enzyme.67 Similar polymorphisms may contribute to the variations in conjugating capacity observed in infants independent of their maturity. In Asian infants, a DNA sequence variant (Gly71Arg), resulting in an amino acid change in the UGT protein, has been associated with neonatal hyperbilirubinemia.68
Increased enterohepatic circulation of bilirubin is a more common cause of decreased elimination. As mentioned earlier, the enterohepatic circulation of bilirubin is a normal process that can contribute to the transitional neonatal hyperbilirubinemia observed after birth. An exaggeration of this process is seen in cases of failure to establish breast-feeding or conditions that result in decreased intestinal motility such as ileus, pyloric stenosis, or intestinal obstruction. In breast-feeding failure characterized by a decreased feeding frequency, weight loss, and dehydration, there is not only increased enterohepatic circulation but also caloric deprivation. True breast milk jaundice syndrome develops more gradually, presents typically in the second week of life, and requires the exclusion of other causes of unconjugated hyperbilirubinemia. In severe cases, cessation of breast-feeding may help confirm the diagnosis and avoid attaining elevated STB levels. Although the etiology of breast milk jaundice syndrome remains uncertain, it is most likely due to an exaggerated enterohepatic circulation and possibly to the presence of β-glucuronidase or some other substance in the breast milk.69 The condition generally resolves between 1 to 3 months of age.
An increase in bilirubin production combined with impaired elimination places the infant at greatest risk for severe hyperbilirubinemia.
BILIRUBIN TOXICITY AND KERNICTERUS
Bilirubin is toxic to the central nervous system. Prevention and treatment of indirect hyperbilirubinemia is undertaken for the purpose of preventing neurotoxicity. Bilirubin toxicity presenting with symptoms in the newborn period is called acute bilirubin encephalopathy, and the term kernicterus, the most severe form of bilirubin toxicity, is reserved for cases of permanent neurologic injury.70 Kernicterus is characterized pathologically by staining and necrosis of neurons in the basal ganglia, hippocampus, and subthalamic nuclei of the brain. Magnetic resonance imaging of kernicteric infants have shown abnormalities in these regions.71 Acute bilirubin encephalopathy in the infant presents with a poor suck, lethargy, hypotonia in the first 1 to 2 days followed by hypertonia of extensor muscles, opisthotonus, retrocollis, and fever in the middle of the first week and hypertonia after the first week. Surviving infants can have exaggerated deep tendon reflexes, obligatory tonic neck reflexes, delayed motor skills, and after the first year, movement disorder (choreoathetosis, ballismus, tremor), upward gaze, paralytic palsies, intellectual deficits, and sensorineural hearing loss.72 Besides this classic presentation, bilirubin encephalopathy can be more subtle and associated with changes in brainstem-evoked responses and infant cry. These changes are not always correlated with STB levels in term newborns.73 However, the changes have been linked to elevations in “free” or unbound bilirubin levels. Their relationship to long-term permanent injury, however, remains uncertain.74,75
In the very-low-birth-weight infant, sensorineural hearing loss, which is more common than in term infants, has been described at lower STB levels.76 Current studies do not suggest that a specific STB concentration, when less than 30 mg/dL in nonhemolytic hyperbilirubinemia in term infants, is unequivocally linked to neurotoxicity.77 Results from of a recent prospective study of infants weighing more than 2000 g and of more than 36 weeks’ gestation suggests that in nonhemolytic hyperbilirubinemia, when treated with phototherapy or exchange transfusion, an STB level of 25 to 30 mg/dL is not likely to result in adverse long-term neurodevelopment.78 Other studies suggest that STB levels greater than 20 mg/dL are associated with subtle neurologic abnormalities and higher risk of intelligence quotient below 85 on follow-up at school age.79
The neurologic sequelae of prolonged exposure to moderately high bilirubin levels is also unclear. Besides the STB concentration, the other major factor determining risk is the albumin binding of bilirubin.80Serum bilirubin is bound to albumin; 8.2 mg of bilirubin can be bound by 1 g of albumin. In an ideal situation, not seen in premature or sick newborns, an infant with a serum albumin concentration of 3 g/dL could theoretically bind approximately 25 mg/dL of bilirubin. Use of agents such as sulfisoxazole and benzyl alcohol can interfere with bilirubin-albumin binding and predispose an infant to bilirubin neurotoxicity. A decrease in blood pH may render unbound (free) bilirubin lipophilic, thereby enhancing tissue uptake. Thus, avoiding acidosis is clinically important. Under normal circumstances, albumin-bound bilirubin and conjugated bilirubin do not cross the blood-brain barrier. However, under some conditions, such as prematurity and sepsis, bilirubin may access vulnerable areas of the developing brain. Premature infants are particularly at risk because of low serum albumin concentrations and frequency of acidosis.
PREDICTION OF HYPERBILIRUBINEMIA
Some cases of kernicterus may not be preventable because of sudden, unpredictable, and marked increases in STB concentrations (eg, in infants with glucose-6-phosphate dehydrogenase [G6PD] deficiency exposed to an environmental oxidant) or because of comorbidities, which increase the likelihood of bilirubin toxicity. However, kernicterus is usually a preventable condition. Case reports and a recent kernicterus registry demonstrate that, unfortunately, kernicterus still occurs in apparently healthy full-term infants.81,82 Most of the reported kernicteric infants born in the 1990s were male, breastfed, and discharged before 72 hours of age. The median STB value at readmission of 90 kernicteric infants reported to the Pilot Kernicterus Registry was 39 mg/dL.82
Because most infants are discharged from the hospital within the first 2 days of life and thus before STB levels have reached a maximum, hyper-bilirubinemia requiring phototherapy is the most common readmission diagnosis during the neonatal period. The rate of rise of STB concentrations is an important factor when considering the need for intervention. In an effort to avoid missing pathologic jaundice (> 18 mg/dL), a shift from thinking about STB concentrations in terms of days of life after birth to thinking about STB concentrations in terms of age in hours is recommended.65
Compliance with the Practice Guideline of the American Academy Pediatrics for Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks Gestation (AAP Practice Guideline; http://aappolicy.aappublications.org/cgi/content/full/pediatrics; 114/1/297), combined with its Appendix on Phototherapy, can serve as the basis for safe practice.70 The clinician must be aware of the different criteria for treatment for infants of less than 38 weeks’ gestation and those with hemolytic disease. The newest guidelines recommending the use of hour-specific STB concentrations are available for public use at http://www.bilitool.org. In the absence of jaundice, the need for obtaining an STB level can be disputed.83 However, estimation of the degree of hyperbilirubinemia in the presence of jaundice is unreliable when based solely on visual inspection, even considering the cephalocaudal progression of jaundice. At a minimum, an STB measurement should be performed on every infant who is jaundiced in the first 24 hours of life and seriously considered on any jaundiced infant discharged before the maximum STB level has been reached. Values plotted according to the infant’s age in hours provide a more accurate assessment of risk level for subsequent hyperbilirubinemia as shown in Figure 53-2. This practice reduces the risk of failing to (1) identify high-risk infants, such as those who present with jaundice in the first 24 hours (who are very likely to have hemolysis) or those of less than 38 weeks’ gestation; (2) ensure timely follow-up or measure STB levels in a jaundiced infant at follow-up; (3) recognize when intensive therapy is needed.
Since hyperbilirubinemia from hemolysis confers a greater risk for the development of bilirubin encephalopathy, the diagnosis of hemolysis becomes paramount for planning the approach to treatment. ABO hemolytic disease is the most common form of hemolysis diagnosed in the newborn. Only half of those infants with a positive direct antibody (Coombs) test are likely to have significant hemolysis. On the other hand, some infants with a negative direct Coombs test have increased rates of hemolysis. Reticulocytosis and the presence of microspherocytes on a peripheral blood smear may help confirm the diagnosis but are not pathognomonic. A noninvasive technique for the measurement of end-tidal carbon monoxide may also provide an index of hemolysis in the future.
Various epidemiologic or clinical conditions can help identify infants at risk for hyperbilirubinemia. These include a previous jaundiced sibling, East Asian race, infant of a diabetic mother, male sex, bruising, cephalhematoma, gestational age less than 37 weeks, breast-feeding, excessive postnatal weight loss, visible jaundice before discharge, serum or transcutaneous bilirubin level above the 75th percentile for age in hours, G6PD deficiency, and short hospital stay.84,85
Most newborns are discharged from the hospital before they have reached their maximum STB concentration. Universal screening of STB and the use of an hour-specific STB concentration nomogram is suggested as a means of predicting the risk of developing hyperbilirubinemia, with infants in the higher percentiles being more at risk.82 Conversely, infants with hour-specific STB concentrations below the 40th percentile are probably at very low risk for subsequent hyperbilirubinemia (> 95th percentile). A multicenter prospective study showed that measurements of ETCOc (end-tidal carbon monoxide concentration, an index of bilirubin production) alone or in combination with STB concentration are not reliable predictors of hyperbilirubinemia.64
FIGURE 53-2. Risk designation of term and near-term well newborns based on their hour-specific serum bilirubin values. The high-risk zone is designated by the 95th percentile track. The intermediate-risk zone is subdivided to upper- and lower-risk zones by the 75th percentile track. The low-risk zone has been electively and statistically defined by the 40th percentile track. (Source: Adapted from Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics 1999;103: 6-14.)
An alternative to blood sampling to determine the STB concentration is the use of a transcutaneous bilirubin (TcB) measurement. The TcB measured by newer devices that adjust for skin color can be used as a reliable surrogate for the STB measurement.86-89
EVALUATION, DIAGNOSIS, AND TREATMENT
In general, the AAP Practice Guideline sets the framework for management of hyperbilirubinemia in the healthy term newborn.70 All jaundiced newborns should have an STB or TcB level measured. The TcB or STB concentration should be referenced to an hour-specific nomogram of STB concentrations for a relevant newborn population, and serial TcB or STB concentration measurements may be indicated on the basis of hour-specific STB concentration percentile ranking (as described above; see Figure 53-2). A diagnostic evaluation is indicated for any infant whose TcB or STB concentration exceeds the 95th percentile or is predicted to exceed it based on the rate of rise. The usual laboratory testing should include a hematocrit, complete blood count, reticulocyte count, and blood smear (to assess red cell morphology), along with blood typing and a direct Coombs test as part of the initial evaluation routine. Evaluation for infection may be warranted depending on the history and physical examination.
Routine testing for G6PD deficiency is more controversial. Testing is indicated when family history or ethnic or geographic origin suggests the likelihood of G6PD deficiency. However, not all infants with G6PD deficiency have hemolysis, and G6PD levels can be high in the presence of hemolysis.90 Also, such testing is not available currently in all institutions and, when done, the results are usually not timely enough for immediate decision making. Careful follow-up is required for all discharged newborn infants who have hemolysis.
Measurement of serum albumin and use of the bilirubin-to-albumin ratio is recommended as a factor to consider in management decisions regarding treatment of hyperbilirubinemia. The ratio provides a rough measurement of unbound bilirubin.91
FIGURE 53-3. Guidelines for phototherapy in hospitalized infants of 35 or more weeks’ gestation. (Source: Adapted from Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004: 114:297-316.)
Phototherapy The standard procedures for treatment of hyperbilirubinemia are phototherapy and exchange transfusion. The criteria for application of phototherapy and exchange transfusion in healthy term newborns are described in the AAP Practice Guideline for infants of more than 35 weeks’ gestation and are shown in Figure 53-3.70 Phototherapy is effective because the yellow pigment, bilirubin, absorbs blue light mainly at the wavelength of 450 nm and is converted to lumirubin, a water-soluble isomer of bilirubin.92 The efficacy of phototherapy is determined by the dose (irradiance) and the amount of body surface area exposed. The irradiance is determined by the type of light source and the distance of the light from the infant. Intensive phototherapy is recommended for infants with high STB, rapidly rising STB, or hemolysis. It requires an irradiance in the range of 30 µW/cm2/nm at the effective wavelength range (430–490 nm) to the largest body surface area of the infant. A bank of special blue fluorescent lights is placed approximately 10 to 12 cm from the infant along with either a fiberoptic blanket or special blue fluorescent lights under the infant to increase the exposed surface area.70 Newer devices using high-intensity gallium nitride light-emitting diodes (LEDs) can generate high irradiance and have greater efficacy than conventional phototherapy. These devices may be adaptable for use in home phototherapy, which has been suboptimal because of the relatively small light-emitting surface of fiberoptic blankets.93 When phototherapy is applied, temperature and hydration status must be monitored. The infant’s eyes must be shielded during light exposure. Increased oral intake is usually sufficient, but intravenous fluids may be necessary when dehydration occurs. Unless the STB is approaching exchange transfusion levels, phototherapy can be interrupted for breast-feeding or for other brief periods of time in order to attend to the infant without compromising the effectiveness of phototherapy.
STB levels should be repeated within 2 to 4 hours after initiation and followed to ensure that the levels are decreasing. Phototherapy can be discontinued once the STB concentration has dropped below 14 mg/dL. Except in the context of hemolytic disease, rebound hyperbilirubinemia after discontinuation of phototherapy is unusual.94 Infants with elevated direct hyperbilirubinemia should be identified before instituting phototherapy in order to initiate a proper diagnostic workup and to avoid discoloration of the infant’s skin, referred to as bronze baby syndrome, which may last for weeks to months.
Exchange Transfusion Exchange transfusion was the first therapy developed for jaundice of the newborn, particularly in the context of Rh hemolytic disease.95 Exchange transfusion removes not only bilirubin but also circulating antibodies that can target the erythrocytes and the erythrocytes themselves, which might be hemolyzed later. The procedure can be conducted using one central catheter, removing small aliquots of blood from the infant, and replacing it with similar aliquots of red cells from a donor mixed with plasma, or it can be done with two central catheters in a more continuous manner. A complete exchange transfusion involves removing and replacing twice the infant’s blood volume. Sometimes, an initial or second exchange transfusion in Rh or ABO hemolytic disease may be avoided by using intravenous immune globulin therapy (500 mg/kg).96 The complications associated with exchange transfusion include hypocalcemia, thrombocytopenia, portal vein thrombosis, necrotizing enterocolitis, electrolyte imbalance, and infection.61,97 Mortality is probably less than 1%, but the complication rate may be as high as 12%.97,98 Anticipatory management of hyperbilirubinemia and intense phototherapy can avoid exchange transfusion in most cases. The AAP Practice Guideline should be followed in terms of the criteria for exchange transfusion.70
Tin-mesoporphyrin, an inhibitor of heme oxygenase, has been found to be effective in reducing bilirubin concentrations in newborns.99 This drug is not FDA approved but may have potential use in infants not responsive to phototherapy and as an alternative to exchange transfusion.100,101