Hyperbilirubinemia in the Healthy Term Newborn
The Nurse Practitioner April 1999
M. COLLEEN AUGUSTINE, RN, CRNP-C, MSN
Family Nurse Practitioner
Mercy Hospital, Pittsburgh, Pa.
ABSTRACT
Jaundice is a common clinical problem in newborns. Although the need to diagnose and treat hyperbilirubinemia in the healthy term newborn has been controversial, recent reports of detrimental neurologic effects from elevated serum bilirubin levels in the healthy newborn make such scrutiny prudent.
Until 1994, when the American Academy of Pediatrics developed guidelines for managing hyperbilirubinemia in the healthy term newborn, no standard of care was defined.
Healthy term newborns are now routinely discharged less than 48 hours after birth. The presence of significant jaundice is the most common reason for infant readmission to the hospital during the first week of life. Clinicians should recognize the risk factors for significant jaundice, make sure babies are appropriately followed and treated, and provide adequate support and education to caregiver (see Patient Education). This article outlines the etiology and clinical manifestations, differential diagnosis, and current recommendations for the management of neonatal jaundice.
Jaundice is the most common clinical problem in newborns, observed during the first week of life in approximately 60% of term infants and in 80% of preterm infants.1,2 Much debate has surrounded the evaluation and treatment of jaundice, particularly due to the potential deleterious neurologic effects from elevated serum bilirubin levels.1-10 Documentation of kernicterus in healthy term newborns with no evidence of hemolysis and no cause for hyperbilirubinemia other than breast-feeding has raised concern among those in the pediatric and primary care community.4,5,10,11
With the advent of early discharge from the hospital, care of neonatal jaundice has been transformed to an outpatient problem. It has become the responsibility of the outpatient medical community to provide early detection and treatment of neonatal hyperbilirubinemia to ensure optimal management of infants.12 Recognizing that practices were changing and that no attempt had been made to use evidence-based practice to recommend strategies for managing jaundiced infants, the American Academy of Pediatrics (AAP) developed guidelines for the management of hyperbilirubinemia in the healthy term infant and published them in 1994.2 aap.org
Etiology and Clinical Manifestations
Bilirubin is largely produced by the breakdown of red blood cells (RBCs). In the fetus, the placenta eliminates most of the lipid-soluble bilirubin. In the newborn, bilirubin must be conjugated, or chemically changed, in the liver to a water-soluble form before it can be excreted in the bile.13 In the adult, bilirubin passes into the small bowel where bacteria reduces or converts it to urobilinogen. Urobilinogen is excreted in the stool; virtually no bilirubin is absorbed from the gastrointestinal tract.10
The fetal gut is sterile, however, and although bacteria form after delivery, they do not reduce bilirubin to urobilinogen. Conjugated bilirubin cannot pass through the intestinal mucosa, but because it is not reduced to urobilinogen and remains in the bowel, it is deconjugated and becomes available for resorption.10
Jaundice refers to the yellow color of the skin, sclera, mucous membranes, and body fluids when bile pigment (bilirubin) is present as a result of excess bilirubin in the blood.13 Jaundice is first seen on the face and progresses caudally to the trunk and extremities.1,10,13 In newborns, jaundice is detected by digitally blanching the skin, which reveals the underlying color of the skin and subcutaneous tissue.1,10 (See Using Body Zones to Estimate the Degree of Jaundice.)
Bilirubin Toxicity
Bilirubin appears to be poisonous to cells, although the exact mechanism of its toxic effect is unknown.10 Toxic levels of unconjugated bilirubin may cause infants to develop kernicterus, a condition characterized by encephalopathy, opisthotonos, hearing loss, and in many cases death.14 Signs and symptoms of bilirubin toxicity include vomiting, lethargy, poor feeding, high-pitched crying, hypotonic state, respiratory distress, and temperature instability.1,9,11
Conditions that may make the infant's brain more susceptible to toxic levels of unconjugated bilirubin include factors that allow bilirubin to leave the circulation, such as hypoalbuminemia; displacement of bilirubin (by drugs or other anions) from its binding sites on albumin; and factors that increase the permeability of the blood-brain barrier.1,2,10
RAPID READ
Jaundice is the most common clinical problem in newborns, observed during the first week of life in approximately 60% of term infants and in 80% of preterm infants. Jaundice is first seen on the face and progresses caudally to the trunk and extremities. In newborns, jaundice is detected by digitally blanching the skin, which reveals the underlying color of the skin and subcutaneous tissue. Toxic levels of unconjugated bilirubin may cause infants to develop kernicterus, a condition characterized by encephalopathy, opisthotonos, hearing loss, and in many cases death. Conditions that may make the infant's brain more susceptible to toxic levels of unconjugated bilirubin include factors that allow bilirubin to leave the circulation, such as hypoalbuminemia; displacement of bilirubin (by drugs or other anions) from its binding sites on albumin; and factors that increase the permeability of the blood-brain barrier.
Although nonhemolytic jaundice in healthy term newborns has generally been thought to be benign, case reports have appeared of healthy term newborns having no risk factors, other than breast-feeding, who developed kernicterus.4,5 Because newborns are now routinely discharged before the bilirubin peak, primary care providers may see infants on days 4 through 7 with serum bilirubin levels greater than 25 to 30 mg/dl.10
Debate surrounds the question of whether neurotoxicity occurs at lower bilirubin levels without abnormal clinical signs and symptoms during the newborn period.6,10 In the late 1960s and throughout the 1970s, reports from the Collaborative Perinatal Project, a study of 53,000 pregnant women and their offspring, linked moderate increases in serum bilirubin to increased neurologic abnormalities and decreased developmental and IQ scores.15-17 This large study was not restricted to healthy or term newborns.10
A recent reanalysis of the study data showed that elevated neonatal bilirubin levels seem to have little effect on IQ, hearing loss, or definite neurologic abnormalities. An association between higher bilirubin levels and mild, nonspecific motor abnormalities may exist.7
The effects of moderately elevated bilirubin levels are not known. Recent literature suggests that bilirubin may have protective properties as a physiologic antioxidant.12
Physiologic Jaundice
Normally, the level of indirect bilirubin in umbilical cord blood is 1 to 3 mg/dl and rises at a rate of less than 5 mg/dl/24 hours. Jaundice becomes apparent between the second and fourth days of life, when bilirubin usually peaks (or in breast-fed infants, between the third and fifth days)11 at 5 to 6 mg/dl; it decreases to 2 mg/dl between the fifth and seventh days.1 It is hypothesized that this normal appearance of jaundice, called physiologic jaundice, results from several processes: the breakdown of fetal RBCs; increased enterohepatic circulation of bilirubin, which causes increased bilirubin load on liver cells; decreased uptake of bilirubin from plasma; a decrease in the liver's ability to conjugate bilirubin; and defective bilirubin excretion.1,10
Some 6% to 7% of full-term infants have total bilirubin levels above 12.9 mg/dl. Less than 3% have levels greater than 15 mg/dl.1 Breast-fed infants are three times more likely than formula-fed infants to have serum bilirubin levels above 12 mg/dl during the first few days of life.11
Idiopathic or breast-feeding associated jaundice is far more common than jaundice of any pathologic cause. Bilirubin production in breast-fed infants is no greater than in formula-fed infants.18 Suggested causes of jaundice associated with breast-feeding include decreased bilirubin clearance by the liver and increased intestinal resorption of bilirubin. Decreased bilirubin clearance is affected by the decreased caloric intake in early breast-feeding and by weight loss in the first few days after birth, both of which are associated with elevated bilirubin levels.19,20 The breast milk of some mothers is believed to contain inhibitory substances. Genetic factors may also play a role.
The increased intestinal resorption of bilirubin is most responsible for breast-feeding associated jaundice. Factors include delayed passage of meconium and decreased formation of urobilinogen, both of which enhance the resorption of bilirubin in the intestine. An increase in beta-glucuronidase, an enzyme that reduces bilirubin to an unconjugated (absorbable) form, may be a contributing factor in breast-feeding associated jaundice. Bile acid abnormalities may also play a role in the intestinal resorption of bilirubin.10
Differential Diagnosis
Jaundice can have many causes, and the time of onset is important in determining etiology. Jaundice that appears within the first 24 hours of life may be caused by erythroblastosis fetalis (Rh incompatibility) or other hemolytic anemia, including ABO incompatibility. It may also be caused by concealed hemorrhage, congenital viral infection, or sepsis. Early jaundice can be significant in the diagnosis of sepsis.
Hemolytic anemia caused by Rh incompatibility is rare since the advent of Rho(D) immune globulin (RhoGAM). ABO incompatibility is more common. Some 20% of all pregnancies are associated with mother-fetus ABO incompatibility, but the incidence of severe hemolytic disease is low. ABO hemolytic disease results from the action of anti-A or anti-B antibodies of the mother with type O blood on the fetal type A or type B erythrocyte.
Immunoglobulin (Ig) A, IgM, and IgG fractions of plasma contain the anti-A and anti-B antibodies, but only the anti-G antibodies cross the placenta and produce disease. Newborns of mothers with high levels of IgG anti-A or anti-B titers tend to have ABO hemolytic disease. The diagnosis of ABO hemolytic disease is supported by indirect hyperbilirubinemia, jaundice during the first 24 hours of life, a type A or type B baby born to a type O mother, an increased number of spherocytes in the blood, and increased erythrocyte production as evidenced by reticulocytosis or an elevated erythrocyte creatine concentration.21
Other maternal minor group antibodies such as anti-E, anti-C, and anti-Kell can cause hemolytic disease. Anti-Kell antibodies can cause severe hemolytic disease and neonatal death.22 Management of ABO incompatibility is directed primarily toward preventing hyperbilirubinemia. Phototherapy reduces the need for exchange transfusion.23
Physiologic jaundice usually appears on the second or third day of life. Hyperbilirubinemia of the newborn occurs when physiologic bilirubin levels are exceeded. Jaundice that appears in the first week is usually physiologic, associated with breast-feeding, or caused by increased bilirubin production from bruising or a cephalhematoma. Jaundice noted initially after the first week of life may be caused by septicemia, congenital atresia of the bile ducts, congenital viral infections, metabolic disorders such as hypothyroidism or galactosemia, hemolytic anemias, or congenital deficiencies of enzymes glucose-6-phosphate dehydrogenase, glutathione synthetase, reductase, or peroxidase.1
In infants with jaundice that persists beyond the second or third week of life, a direct bilirubin level must be obtained to rule out the possibility of cholestatic (obstructive) jaundice. Parents or caretakers must be asked whether the child has dark urine or light-colored stools.
RAPID READ
Jaundice can have many causes, and the time of onset is important in determining etiology. Jaundice that appears within the first 24 hours of life may be caused by two forms of hemolytic anemia: erythroblastosis fetalis (Rh incompatibility) or ABO incompatibility. It may also be caused by concealed hemorrhage, congenital viral infection, or sepsis. Early jaundice can be significant in the diagnosis of sepsis. Physiologic jaundice usually appears on the second or third day of life. Jaundice that appears in the first week is usually physiologic, associated with breast-feeding, or caused by increased bilirubin production from bruising or a cephalhematoma. Jaundice noted initially after the first week of life may be caused by septicemia, congenital atresia of the bile ducts, congenital viral infections, metabolic disorders, or congenital deficiencies. In infants with jaundice that persists beyond the second or third week of life, a direct bilirubin level must be obtained to rule out the possibility of cholestatic (obstructive) jaundice.
Diagnosing the cause of hyperbilirubinemia requires careful consideration of the maternal and infant history, the physical examination, and laboratory findings. Table 1 lists factors that warrant further assessment of the jaundiced infant.1,2,10,24
Risk Factors for Indirect Hyperbilirubinemia
Indirect hyperbilirubinemia has numerous risk factors (see Table 2).1,2,6,10 Infants with multiple risks are more likely to have elevated indirect bilirubin levels. Infants without risk factors rarely develop levels greater than 12 mg/dl.1
Significant jaundice is the most common reason for an infant to be readmitted to the hospital in the first week of life.25 Identifying infants who are at higher risk for hyperbilirubinemia and predicting the ideal time to institute treatment (such as phototherapy to prevent high bilirubin levels), potential detrimental sequelae, and to avoid the need for exchange transfusion is difficult even for health care providers who are knowledgeable about risk
factors.26
Management
The main treatment modalities that have been advocated for hyperbilirubinemia in the newborn are exchange transfusion, phototherapy, and, in cases in which breast-feeding was thought to contribute to jaundice, nursing cessation.1,2,10,24
Exchange transfusion was developed in the 1950s as a method for reducing the risk of death or injury in infants born with hemolytic disease.27 In hemolytic disease, the sensitized RBCs and bilirubin are removed and replaced with group O Rh-negative (bilirubin-free) blood.13
Phototherapy, first described in 1958,28 reduces serum bilirubin concentration in the newborn via exposure to sunlight (for mildly jaundiced infants) or artificial blue light, which alters bilirubin to a readily excreted form.13 Refinements in phototherapy in the late 1980s brought about the fiberoptic delivery of blue light. This form of delivery, commonly used in the home setting, is equally effective if used properly. Other advantages include low cost, reduction of parent-child separation, and reduction of breast-feeding cessation.10
RAPID READ
Normally, the level of indirect bilirubin in umbilical cord blood is 1 to 3 mg/dl and rises at a rate of less than 5 mg/dl/24 hours. Jaundice becomes apparent between the second and fourth days of life (or in breast-fed infants, between the third and fifth days) when bilirubin usually peaks at 5 to 6 mg/dl; it decreases to 2 mg/dl between the fifth and seventh days. Some 6% to 7% of full-term infants have total bilirubin levels above 12.9 mg/dl. Less than 3 have levels greater than 15 mg/dl. Breast-fed infants are three times more likely than formula-fed infants to have serum bilirubin levels above 12 mg/dl during the first few days of life. Idiopathic or breast-feeding associated jaundice is far more common than jaundice of any pathologic cause. Bilirubin production in breast-fed infants is no greater than in formula-fed infants. Suggested causes of jaundice associated with breast-feeding include decreased bilirubin clearance by the liver and increased intestinal resorption of bilirubin. Decreased bilirubin clearance is affected by the decreased caloric intake in early breast-feeding and by weight loss in the first few days after birth, both of which are associated with elevated bilirubin levels.
The AAP recommends not interrupting breast-feeding for jaundiced healthy term newborns and encourages continued frequent breast-feeding--at least 8 to 10 feedings every 24 hours. Supplementation with water or glucose water does not lower the bilirubin level in jaundiced, healthy breast feeding infants. Other options include supplementing breast-feeding with formula or interrupting breast-feeding temporarily and substituting it with formula. Either option can be accompanied by phototherapy.2 A recent study compared newborns who developed nonhemolytic hyperbilirubinemia and feeding methods. This study consisted of three groups including infants who were formula-fed, breast-fed, and primarily breast-fed with formula supplementation. All three groups received phototherapy. The infants who were breast-fed and supplemented with formula reduced their bilirubin concentration faster than the other two groups. This study supports the theory that breast-feeding with formula supplementation in addition to phototherapy is efficacious in treating hyperbilirubinemia.29
The AAP has issued guidelines for treating hyperbilirubinemia in the healthy term newborn. The group recommends including ABO and Rh typing and a blood screen for unusual isoimmune antibodies in prenatal screening. If the mother has not undergone prenatal blood grouping or is Rh negative, tests from the infant's cord blood should include a direct Coombs' test, blood type, and Rh type.
Institutions are encouraged to save cord blood for future testing, especially when the mother's blood type is O. Infants who develop jaundice in the first 24 hours of life should undergo a total serum bilirubin evaluation. The pattern of early newborn discharge from the hospital makes it prudent that all neonates discharged within 48 hours of birth receive follow-up care by a health care professional in an office or clinic or at home within 2 to 3 days
of discharge. (See Figure Part 1 and Figure Part 2.)
The AAP guidelines for management of hyperbilirubinemia in the healthy term infant, written as an algorithm and as a table, offer a range of acceptable evaluation and treatment practices based on the infant's age as measured in hours(see Figure and Table 3).2
The rate of total serum bilirubin rise and the infant's age help determine how often to monitor bilirubin levels and whether to begin phototherapy. The provider may appropriately choose to observe rather than to treat with repeated phototherapy and total serum bilirubin testing. If the infant requires intensive phototherapy, this can be achieved by using special blue tubes in standard fluorescent phototherapy units or increasing the infant's body surface area exposure by placing him or her on a fiberoptic blanket ohmedamedical.com while also using a standard phototherapy system. A decline in the total serum bilirubin of 1 to 2 mg/dl within 4 to 6 hours of intensive phototherapy can be expected; the level should continue to decline. When the total serum bilirubin level falls to 14 to 15 mg/dl, phototherapy may be discontinued.2
While receiving phototherapy, infants should be monitored for fluid and weight loss and for hyperthermia. Insensible water loss is increased in the full-term infant during phototherapy.30 Skin temperature increases significantly as well; however, these complications can be avoided by using servocontrolled incubators. Weight gain is less in infants who receive phototherapy during the first week of life than in those who do not, but their growth catches up during the next 2 weeks.10
Newer Treatments for Severe Hyperbilirubinemia
Less commonly used pharmacologic treatment for severe hyperbilirubinemia includes the administration of phenobarbital, which accelerates the normal metabolic pathways for bilirubin clearance, and the administration of agar, which inhibits the enterohepatic circulation of bilirubin. Synthetic metalloporphyrins, still in experimental use only, inhibit the production of bilirubin. The use of high-dose I.V. immunoglobulin is being studied to reduce the need for exchange transfusion in infants with isoimmune hemolytic disease.11 These treatments, which require consultation with or referral to a physician, are not indicated for the healthy term newborn without hemolytic disease.
A simple, noninvasive method to measure increased RBC destruction in newborns has had promising results. Clinically important hemolysis has been identified before the development of anemia or hyperbilirubinemia by measuring carbon monoxide production, an index of bilirubin production.10 The device determines the end-tidal carbon monoxide concentration by sampling expired air with a small nasal catheter.12
RAPID READ
The main treatment modalities that have been advocated for hyperbilirubinemia in the newborn are exchange transfusion, phototherapy, and, in cases in which breast-feeding was thought to contribute to jaundice, nursing cessation. The rate of total serum bilirubin rise and the infant's age help determine how often to monitor bilirubin levels and whether to begin phototherapy. The provider may appropriately choose to observe rather than to treat with repeated phototherapy and total serum bilirubin testing. A decline in the total serum bilirubin of 1 to 2 mg/dl within 4 to 6 hours of intensive phototherapy can be expected; the level should continue to decline. When the total serum bilirubin level falls to 14 to 15 mg/dl, phototherapy may be discontinued. While receiving phototherapy, infants should be monitored for fluid and weight loss and for hyperthermia. Weight gain is less in infants who receive phototherapy during the first week of life than in those who do not, but their growth catches up during the next 2 weeks.
Case Study
K.A. was a well newborn delivered vaginally and without complications to a healthy woman. Born at 39 weeks and 1 day on March 31, 1996, 12:25 a.m., he weighed 7 lbs 1 oz and was 20 inches long. He was breast-fed and had a 22-month-old sibling who had mild jaundice in the newborn period that did not require treatment.
The initial assessment, conducted by a staff pediatrician 12 hours after birth, was normal. An evaluation on day 2 of life, 32 hours after birth, and just before hospital discharge, revealed jaundice. Follow-up with health care provider in 2 to 3 days was recommended.
Upon follow-up check on April 4, 1996, the infant was noted to be significantly jaundiced with icterus. Record review showed that the mother had O+ blood and the infant had A+ blood. A Coombs' test performed on cord blood was negative. Stat total bilirubin level was obtained and found to be 21.4. A home phototherapy blanket was instituted later that evening.
On April 5, 1996, bilirubin had decreased to 19 mg/dl. Phototherapy was continued and the bilirubin level on April 6 was 15 mg/dl. Phototherapy was continued for another 24 hours and discontinued when total bilirubin level reached 12.4 mg/dl.
Conclusion
Jaundice in the healthy term newborn is common. In rare cases, bilirubin reaches toxic levels within the first week of life.1,4,5,10,11 Untreated infants may develop kernicterus.4,5,11 Lower levels of hyperbilirubinemia may place infants at risk for mild, nonspecific neurologic abnormalities. Even those who are knowledgeable about risk factors for hyperbilirubinemia may find it difficult to predict which infants are at increased risk.5
The need for research to determine the effects of moderate increases in bilirubin on the healthy infant's developing neurologic system persists. Breast-feeding associated jaundice or idiopathic jaundice is far more common than jaundice with pathologic causes. On an ongoing basis, it is necessary for clinical practitioners to recognize risk factors for the development of significant jaundice, to provide thorough follow-up for newborns discharged from the hospital, and to support and educate caregivers.
REFERENCES
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22. Pepperell RJ, Barrie JU, Fliegner JR: Significance of red cell irregular antibodies in the obstetric patient. Med J Aust 1977;2(14):453-56.
23. Kaplan E, Herz F, Scheye E, et al.: Phototherapy in ABO hemolytic disease of the newborn. J Pediatr 1971;79(6):911-14.
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