Strategies to reduce bilirubin-induced complications
Kristin Melton, MD; Henry T. Akinbi, MD
VOL 106 / NO 6 / NOVEMBER 1999 / POSTGRADUATE MEDICINE
CME learning objectives
- To identify infants at risk for severe neonatal jaundice
- To optimize the benefits from phototherapy
- To select infants who could be safely managed at home
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Preview: Along with the recent trend toward shorter postdelivery hospital stays has come an increase in complications from hyperbilirubinemia. Because of this, primary care physicians need to be on the lookout for newborns at risk and may need to coordinate parent education, home phototherapy, and follow-up visits. The authors discuss the process, diagnosis, and management of hyperbilirubinemia and describe in detail risk factors that may preclude early hospital discharge or indicate that monitoring should take place after discharge.
Melton K, Akinbi HT. Neonatal jaundice: strategies to reduce bilirubin-induced complications. Postgrad Med 1999;106(6):167-78
Neonatal jaundice affects 60% of full-term infants and 80% of preterm infants in the first 3 days after birth. Although transient, the condition accounts for up to 75% of hospital readmissions in the first week after birth (1). In one Canadian study (2), shorter neonatal hospital stays correlated with an overall tripling of readmissions.
Severe hyperbilirubinemia is relatively uncommon, but infants at risk must be carefully monitored. Kernicterus, the most severe complication of hyperbilirubinemia, has increased in incidence as neonatal hospital stays have become shorter (3-5).
This article is intended to help physicians identify newborns at risk for severe hyperbilirubinemia, who may not be ideal candidates for early hospital discharge. Management, including follow-up care and home phototherapy, is also described.
Classification
Hyperbilirubinemia in newborns is primarily due to immaturity of the liver enzyme system (see box below). Jaundice can be classified as physiologic or nonphysiologic according to postdelivery timing of onset, clinical course, resolution, rate of bilirubin increases, and total serum bilirubin levels.
Physiologic jaundice
Jaundice in healthy, full-term newborns has been termed physiologic because hyperbilirubinemia occurs universally in neonates. Total serum bilirubin concentration usually peaks at 5 to 12 mg/dL on the second or third day after birth.
Nonphysiologic jaundice
Jaundice should be considered nonphysiologic, or pathologic, if it occurs less than 24 hours after birth, if bilirubin levels rise at a rate of greater than 0.5 mg/dL per hour or 5 mg/dL per day, if total bilirubin levels exceed 15 mg/dL in a full-term infant or 10 mg/dL in a preterm infant, if evidence of acute hemolysis exists, or if hyperbilirubinemia persists beyond 10 days in a full-term infant or 21 days in a preterm infant. (However, mild jaundice may persist for up to 2 weeks in breast-fed infants.)
Kernicterus
Severe hyperbilirubinemia could result in kernicterus. This condition is characterized by bilirubin staining of the basal ganglia and involves diffuse neuronal damage, which results in severe neurologic sequelae. Kernicterus rarely occurs with bilirubin levels lower than 20 mg/dL but typically occurs when levels exceed 30 mg/dL. When levels are between 20 and 30 mg/dL, concomitant conditions such as prematurity and hemolytic disease may increase the risk of kernicterus.
Clinically, bilirubin encephalopathy progresses through three phases. In the first 2 to 3 days the infant is lethargic and hypotonic and sucks weakly. Progression is marked by hypertonia (especially of the extensor muscles), arching, opisthotonic posturing, fever, seizures, and high-pitched crying. In the final phase, the patient is hypotonic for several years, then gradually becomes hypertonic. Affected children have marked developmental and motor delays in the form of choreoathetoid cerebral palsy. Mental retardation may also be present. Other sequelae include extrapyramidal disturbances, auditory abnormalities, gaze palsies, and dental dysplasias.
Risk factors for severe hyperbilirubinemia
With short neonatal hospital stays, jaundice may not be apparent–and certainly has not yet peaked–at the time of hospital discharge. Therefore infants at risk for severe hyperbilirubinemia should be identified so they can be observed closely both while in the hospital and after discharge.
Breast-feeding
Breast-feeding is an important risk factor for hyperbilirubinemia, probably owing to high levels of beta-glucuronidase in breast milk and, if maternal milk supply is not yet adequate in the first few days, decreased caloric intake and delayed passage of meconium. Jaundice is three times more likely to occur in breast-fed than in formula-fed infants, and progression to severe hyperbilirubinemia is six times more likely (6). Of 31 cases of kernicterus reported from 1990 to 1998 (7), all but one of the infants were breast-fed.
Low birth weight and prematurity
Infants born at 35 to 37 weeks’ gestation–who are often treated as full-term infants–are more likely to breast-feed poorly and to have significant weight loss than their full-term counterparts. They are four times more likely than full-term infants to have a bilirubin level greater than 13 mg/dL (8). In the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke (9), in which more than 50,000 infants were studied prospectively, 10% to 20% of infants weighing less than 2,500 g (5.5 lb) at birth had total serum bilirubin levels higher than 15 mg/dL in the first week after birth. Poor caloric intake and excessive weight loss have also been correlated with an increased risk of jaundice in full-term infants.
Ethnicity
Infants of East Asian and Native American descent have higher levels of bilirubin than white infants, who in turn have higher bilirubin levels than infants of African descent. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is more prevalent in infants of East Asian, Greek, and African descent.
Sickle cell anemia does not predispose newborn infants to jaundice.
Hemolytic conditions
Hemolysis from blood-type incompatibilities plays a significant role in neonatal hyperbilirubinemia, and moderate jaundice usually develops in infants with ABO incompatibilities. Many hospitals routinely perform blood type and Coombs’ tests on infants of mothers who have blood type O.
Development of severe hyperbilirubinemia, often requiring treatment, is classic in infants with Rh isoimmunization. These infants appear to be at much higher risk for kernicterus and neurologic sequelae than those with nonhemolytic hyperbilirubinemia. The incidence of severe Rh isoimmunization decreased dramatically following the introduction of Rho(D) immune globulin (Gamulin Rh, HypRho-D, RhoGAM) to 0.17% of offspring of Rh-negative mothers (10).
Hemolysis can result from other inherited or congenital causes. Hereditary spherocytosis or elliptocytosis can be present in the newborn. G6PD deficiency is often overlooked, difficult to recognize, and unique because jaundice may not develop until after the fourth day postdelivery.
Polycythemia contributing to hyperbilirubinemia is seen in infants who are large or small for their gestational age, as well as in trisomic syndromes, placental transfusion syndrome (twin-to-twin transfusion) and maternal-fetal transfusion.
Newborn infants with a sibling who had jaundice are at increased risk of severe hyperbilirubinemia. Boys are also at increased risk.
Infants of diabetic mothers often have macrosomia, polycythemia, ineffective erythropoiesis, and increased levels of hemoglobin F contributing to bilirubin elevations.
Extravasated blood in ecchymosis, cephalohematomas, subgaleal hemorrhage, intraventricular or intracranial hemorrhage, pulmonary hemorrhage, or adrenal hemorrhage can predispose a newborn infant to severe hyperbilirubinemia resulting from breakdown of the blood.
Finally, sepsis, hypothyroidism, and galactosemia are neonatal conditions that may cause jaundice. Jaundice is rarely the only manifestation of these disorders, however, and the clinical presentation often suggests the diagnosis.
Diagnosis
Jaundice usually becomes apparent when total bilirubin levels exceed 5 mg/dL. Neonatal jaundice progresses in a cephalopedal direction. However, estimates of total serum bilirubin levels based on visual evaluation are often inaccurate because of interobserver variability, especially in dark-skinned infants.
Laboratory testing should be reserved for infants with nonphysiologic jaundice. Routine measurement of total serum bilirubin levels in infants who do not meet the criteria for nonphysiologic jaundice is not warranted. Laboratory evaluation should be fairly minimal because test results are often nonrevealing, even in the presence of hemolysis. In up to 50% of infants with severe jaundice, breast-feeding and lower gestational age are the only causes identified despite extensive workups (11). No data on the sensitivity and specificity of routine testing for hyperbilirubinemia are available.
Hematocrit, reticulocyte count, and peripheral blood smear results may be informative, but these do not always correlate with the degree of hemolysis. Evaluation for G6PD deficiency and pyruvate kinase deficiency should be considered, especially for infants who are older than 4 days, who have a significant family history, or who are of Asian, Mediterranean, or African descent and have severe hyperbilirubinemia. A direct (conjugated) bilirubin level should be obtained for infants with jaundice that persists longer than 2 weeks or with dark urine or acholic stools. Blood type, Rh factor, and nonagglutinating antibody level (by a Coombs’ test) should be determined for infants of mothers who have O or Rh-negative blood type or who have had no prenatal care, because of the potential for isoimmunization.
The clinical significance of bilirubin levels depends on postnatal age, in hours. A bilirubin level of 12 mg/dL may be pathologic in an infant younger than 48 hours, but is benign in an infant older than 72 hours.
Treatment
To address the controversy and confusion regarding levels of hyperbilirubinemia that require treatment, the American Academy of Pediatrics (AAP) has developed a practice parameter for management of hyperbilirubinemia in the healthy, full-term newborn (table 1) (12). With severe hyperbilirubinemia, intense phototherapy consisting of at least double phototherapy using a fiberoptic blanket and one or two banks of phototherapy light should be initiated while preparations for exchange transfusion are being made. If phototherapy fails to produce a change of 1 to 2 mg/dL in 4 to 6 hours, initiation of exchange transfusion is recommended. Infants with any of the previously mentioned risk factors (eg, a hemolytic condition, breast-feeding, prematurity, diabetes in the mother) are at increased risk for severe hyperbilirubinemia, and the method of treatment should be carefully considered.
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Table 1. Guidelines for management of hyperbilirubinemia in healthy, full-term infants
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Age (hr)
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Total serum bilirubin level (mg/dL)
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Consider phototherapy
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Initiate phototherapy
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Initiate exchange transfusion if intense phototherapy* fails
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Initiate exchange transfusion
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25-48**
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>12
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>15
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>20
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>25
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49-72
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>15
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>18
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>25
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>30
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>72
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>17
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>20
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>25
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>30
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*At least double phototherapy using two banks of phototherapy lights or a fiberoptic blanket and a bank of lights.
**Full-term infants who are clinically jaundiced at <24 hours old are not considered healthy and require further evaluation.
Adapted, with permission, from the American Academy of Pediatrics (12).
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Full-term infants who have normal findings on physical examination, no underlying serious illness or feeding difficulties, and no potential for blood incompatibility can be safely managed at home by following recommendations proposed by the AAP (12).
Phototherapy
The mainstay in treatment of hyperbilirubinemia is phototherapy, which is safe and widely available. Its effectiveness was demonstrated in a study by the National Institute of Child Health and Human Development of a cohort of 1,339 infants (13). Only 4% of those treated with phototherapy required exchange transfusion, compared with 24.4% of those who did not receive phototherapy. Light emitted at a wavelength of 425 to 475 nm converts bilirubin to a water-soluble form that can be excreted in the bile or urine without glucuronidation.
Multiple factors can influence the effectiveness of phototherapy, including the type and intensity of the light and the extent of skin surface exposure. “Special blue” fluorescent light has been shown to be most effective, although many nurseries use a combination of daylight, white, and blue lamps. Recently, fiberoptic blankets have been developed that emit light in the blue-green spectrum. These are effective, convenient forms of phototherapy. The intensity of light delivered is inversely related to the distance between the light source and the skin surface.
Phototherapy acts by altering the bilirubin that is deposited in the subcutaneous tissue. Therefore, the area of the skin exposed to phototherapy should be maximized. This has been made more practical with the development of fiberoptic phototherapy blankets that can be wrapped around an infant. Double phototherapy can reduce bilirubin levels twice as fast as single phototherapy (14) and can be accomplished by using the combination of a blanket and a bank of lights or by using two banks of lights.
Home-based care for neonatal jaundice has become more prevalent than hospital care, and the availability of fiberoptic blankets has made it convenient. The benefits of home phototherapy include decreased cost, less disruption of the parent-child relationship, and better maintenance of breast-feeding. It has been shown to be as effective as hospital-based therapy when used appropriately in situations where intense phototherapy is not required (15). Parents must be carefully instructed about use of the phototherapy blanket, because the primary problem has been inconsistent or inadequate application. Infants should remain in the blanket at all times, including during feedings.
Infants receiving home phototherapy need daily follow-up visits by a nurse, who performs a physical examination and measures the total serum bilirubin level. If bilirubin levels continue to rise, hospital readmission should be considered. Discontinuation of home phototherapy is safe once the total serum bilirubin level has decreased to less than 15 mg/dL in healthy full-term infants older than 4 days. Office evaluation within 2 to 3 days of discontinuing home phototherapy is recommended.
Potential side effects of phototherapy, when used in the presence of elevated direct bilirubin levels, include watery diarrhea, increased insensible water loss, skin rash, and transient bronzing of the skin. The possibility of increased insensible water loss underscores the importance of appropriate hydration. Many infants who are readmitted because of hyperbilirubinemia are mildly to moderately dehydrated. Breast-feeding should be increased to every 2 to 2 1/2 hours. Increased feedings can increase peristalsis and meconium passage, decreasing bilirubin resorption into the enterohepatic circulation.
Formula supplements should be considered if adequate lactation has not been established. Supplementation with plain water or dextrose water has been associated with increased bilirubin levels and carries the risk of iatrogenic hyponatremia (16). Intravenous fluids are indicated only in infants who are unable to take oral nutrition.
Exchange transfusion
Full-term infants rarely require exchange transfusion if intense phototherapy is initiated in a timely manner (17). Exchange transfusion should be considered if the total serum bilirubin level is higher than 25 mg/dL and continues to rise despite intense in-hospital phototherapy. Exchange transfusion corrects anemia associated with hemolysis and is effective in removing sensitized red blood cells before they are hemolyzed. It also removes about 60% of bilirubin from the plasma, resulting in a clearance of about 30% to 40% of the total bilirubin as it equilibrates with the extravascular tissues.
Exchange transfusion is associated with more complications than phototherapy. It carries a 5% risk of major morbidity and a risk of 2 to 3 deaths per 1,000 procedures (18). Along with the risks associated with blood exposure, infants receiving exchange transfusion have increased risks of infection, necrotizing enterocolitis, acidosis, hypocalcemia, hypoglycemia, electrolyte abnormalities, and air embolism.
Guidelines for follow-up
To minimize the complications from neonatal jaundice, parental education and a patient tracking system are critical. The AAP recommends that infants discharged from the hospital within 48 hours of birth receive follow-up care within 2 to 3 days by their primary care physician (12). Infants at risk for severe hyperbilirubinemia should receive follow-up care within 48 hours of discharge. The recommendations leave follow-up specifics at the discretion of the physician. Appropriate follow-up for breast-fed infants may simply be a home health visit, while those with other risk factors may require an office visit.
Summary
Neonatal hyperbilirubinemia is the most common reason for hospital readmission in the first 2 weeks of life. Kernicterus is still relatively uncommon but has been on the rise with the institution in the 1990s of aggressive early postnatal discharge policies. Bilirubin-induced complications can be prevented by instituting a neonatal jaundice protocol to identify infants at risk for significant hyperbilirubinemia, by ensuring adequate parental education and preparedness, and by implementing a good neonatal tracking system for follow-up care. Hyperbilirubinemia is easily treated with phototherapy, which can be administered at home in selected infants.
References
- Britton JR, Britton HL, Beebe SA. Early discharge of the term newborn: a continued dilemma. Pediatrics 1994;94(3):291-5
- Lee KS, Perlman M, Ballantyne M, et al. Association between duration of neonatal hospital stay and readmission rates. J Pediatr 1995;127(5):758-66
- Catz C, Hanson JW, Simpson L, et al. Summary of workshop: early discharge and neonatal hyperbilirubinemia. Pediatrics 1995;96(4 Pt 1):743-5
- Maisels MJ, Newman TB. Kernicterus in otherwise healthy, breast-fed term newborns. Pediatrics 1995;96(4 Pt 1):730-3
- Brown AK, Johnson L. Loss of concern about jaundice and the reemergence of kernicterus in full-term infants in the era of managed care. In: Fanaroff AA, Klaus MH, eds. The year book of neonatal and perinatal medicine. St Louis: Mosby-Year Book, 1996:17-28
- Schneider AP 2d. Breast milk jaundice in the newborn: a real entity. JAMA 1986;255(23):3270-4 [Erratum, JAMA 1986;256(23):3218]
- Johnson L, Bhutani VK. Guidelines for management of the jaundiced term and near-term infant. Clin Perinatol 1998;25(3):555-74
- Gale R, Seidman DS, Dollberg S, et al. Epidemiology of neonatal jaundice in the Jerusalem population. J Pediatr Gastroenterol Nutr 1990;10(1):82-6
- Hardy JB, Drage JS, Jackson EC. The Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke. Baltimore: Johns Hopkins University Press, 1979:104
- McMaster conference on prevention of Rh immunization: 28-30 September, 1977. Vox Sang 1979;36(1):50-64
- Newman TB, Easterling MJ, Goldman ES, et al. Laboratory evaluation of jaundice in newborns: frequency, cost, and yield. Am J Dis Child 1990;144(3):364-8 [Erratum, Am J Dis Child 1992;146(2):1420-1]
- Practice parameter: management of hyperbilirubinemia in the healthy term newborn. American Academy of Pediatrics. Provisional Committee for Quality Improvement and Subcommittee on Hyperbilirubinemia. Pediatrics 1994;94(4 Pt 1):558-65 [Erratum, Pediatrics 1995;95(3):458-61]
- Brown AK, Kim MH, Wu PY, et al. Efficacy of phototherapy in prevention and management of neonatal hyperbilirubinemia. Pediatrics 1985;75(2 Pt 2):393-400
- Holtrop PC, Ruedisueli K, Maisels MJ. Double versus single phototherapy in low birth weight newborns. Pediatrics 1992;90(5):674-7
- Slater L, Brewer MF. Home versus hospital phototherapy for term infants with hyperbilirubinemia: a comparative study. Pediatrics 1984;73(4):515-9
- de Carvalho M, Hall M, Harvey D. Effects of water supplementation on physiological jaundice in breast-fed babies. Arch Dis Child 1981;56(7):568-9
- Jackson JC. Adverse events associated with exchange transfusion in healthy and ill newborns. Pediatrics 1997;99(5):E7
- Keenan WJ, Novak KK, Sutherland JM, et al. Morbidity and mortality associated with exchange transfusion. Pediatrics 1985;75(2 Pt 2):417-21
How bilirubin is metabolized
Bilirubin is a product of heme catabolism. In the neonate, destruction of senescent erythrocytes accounts for 75% of the bilirubin produced. Almost completely insoluble in water, bilirubin must be bound to albumin for transport in the plasma. Bound bilirubin coexists with a small unbound fraction determined by both the molar ratio of albumin to bilirubin and the binding affinity of albumin.
Prenatal clearing
Unbound fetal bilirubin continuously crosses the placenta to the mother because of the greater albumin-binding capacity of maternal serum. Bilirubin from the fetus is conjugated to glucuronic acid in the maternal liver in a reaction catalyzed by uridine diphosphate glucuronosyltransferase (UDPGT). In healthy adults, this enzyme is present in great excess so that even the by-products of major hemolytic events do not exceed the UDPGT needed to convert bilirubin to its glucuronide form. In the mother, the bilirubin glucuronide, which is water-soluble, is secreted by active transport into the bile canaliculi and becomes concentrated in the gallbladder before excretion into the intestinal tract. In the intestine, some of the bilirubin glucuronide can be deconjugated to water-insoluble unbound bilirubin, which readily enters the enterohepatic circulation. Deconjugation and resorption of bilirubin is minimal in adults, however, because of the action of intestinal bacteria, which progressively convert the bilirubin glucuronide into water-soluble stercobilins and urobilins that are excreted in the stool.
Neonatal metabolism
In the liver of the fetus and newborn, the activity of UDPGT is limited because of immaturity of the liver enzyme system. At birth, the UDPGT activity level is only 0.1% to 1% that of the adult (1). Activity increases over time but does not reach adult levels until 6 to 14 weeks after birth. As a result, bilirubin accumulates in the bloodstream of all newborns.
Not only is the liver of the newborn deficient in its enzyme activity levels, the daily load of bilirubin excretion is disproportionately large. A twofold increase in neonatal bilirubin production occurs as a result of both a higher circulating erythrocyte volume and an erythrocyte life span shortened from 120 to 90 days. Newborns also have higher levels of intestinal beta glucuronidase than adults, resulting in much greater resorption of unconjugated bilirubin through the enterohepatic circulation. This is especially true of breast-fed babies, who receive additional beta-glucuronidase in breast milk. Also, since infants lack intestinal bacterial flora, very little bilirubin glucuronide is converted to stercobilins and urobilins, with the result that both conjugated and unconjugated bilirubins are excreted as the golden-yellow pigment characteristic of the stools of the newborn.
Reference
- Kawade N, Onishi S. The prenatal and postnatal development of UDP-glucuronyltransferase activity towards bilirubin and the effect of premature birth on this activity in the human liver. Biochem J 1981;196(1):257-60
The authors are indebted to Lois Johnson, MD, and Edward Donovan, MD, for their helpful input, and to Ann Maher for her secretarial help.
Dr Melton is a fellow and Dr Akinbi is assistant professor, divisions of neonatology and pulmonary biology, Children’s Hospital Medical Center, Cincinnati, Ohio. Correspondence: Henry T. Akinbi, MD, Children’s Hospital Medical Center, Division of Pulmonary Biology, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail: akinh0@chmcc.org.
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