The jaundiced newborn: Minimizing the risks

Cover story

The jaundiced newborn: Minimizing the risks

By Rajeev Dixit, MD, and Lawrence M. Gartner, MD

Vigilant monitoring and management are the keys to keepingthe healthy, full-term infant with hyperbilirubinemia healthy and headingoff the danger of brain damage.

Hyperbilirubinemia is universally present in the early newborn periodand presents as clinical jaundice in 50% to 60% of all infants. The magnitudeof concern about this problem--which can ultimately lead to bilirubin encephalopathyif not managed properly--is illustrated by the fact that it was the focusof the first practice parameter recommended by the American Academy of Pediatrics.¹Clinical jaundice appears in newborns when serum bilirubin levels reach5to 7 mg/dL. Most babies are not jaundiced at birth because unconjugatedbilirubin readily crosses the placenta and is conjugated and excreted bythe maternal liver.

Our discussion will focus on managing the jaundiced full-term infantwith unconjugated hyperbilirubinemia. Preterm infants usually receive increasedmedical attention and, often, phototherapy even at relatively low serumbilirubin levels because of the risk of bilirubin neurotoxicity at levelsconsidered safe in term infants. The full-term infant with conjugated (direct-reacting)hyperbilirubinemia poses a distinct challenge and an entirely separate differentialdiagnosis. For these reasons, we will not discuss preterm infants and terminfants with conjugated hyperbilirubinemia.

Understanding the physiologic and pathophysiologic phenomena that causeretention of unconjugated bilirubin in the circulation and other tissuesduring the newborn period greatly facilitates management of neonatal jaundice."A short course in bilirubin metabolism" on pages 168 and 169describes how bilirubin is produced, transported, and excreted.

Physiologic jaundice

For most newborns, physiologic jaundice resulting from unconjugated hyperbilirubinemiareflects a transition from an intrauterine to an extrauterine pattern ofbilirubin transport and metabolism. Neonatal jaundice progresses in a cephalocaudalmanner, appearing first at the head and neck and advancing downward towardthe feet as serum bilirubin concentrations rise. Kramer observed jaundicerelated to serum indirect bilirubin levels as follows: head and neck, 4to 8 mg/dL; upper trunk, 5 to 12 mg/dL;lower trunk and thighs, 8 to 16 mg/dL;arms and lower legs, 11 to 18 mg/dL; and palms and soles, more than 15 mg/dL.²

The regularly occurring physiologic jaundice of the newborn results froma combination of normal changes that lead to retention of unconjugated bilirubinin serum and tissues. These include:

• Increased hemolysis. Full-term newborns have a circulating red blood cell life span of about 90 days, compared to 120 days in adults. They also have a larger blood volume per unit of body weight and a higher hemoglobin concentration. As a result, the number of circulating RBCs in newborns is significantly greater than in adults.
• Decreased rate of hepatic uptake of bilirubin.
• Decreased hepatic conjugation of bilirubin. Glucuronyl transferase activity at birth is approximately 5% of adult activity, and the predominant conjugate formed is monoglucuronide rather than diglucuronide as in the older child and adult.
• Increased enterohepatic circulation of bilirubin. Enterohepatic circulation of bilirubin is severalfold greater in newborns than older children and adults. The monoglucuronide conjugate of bilirubin is more rapidly hydrolyzed to unconjugated bilirubin in the intestine than diglucuronide. b-glucuronidase, a mucosal enzyme that cleaves glucuronide from bilirubin and other conjugates, is present in the infant's gastrointestinal tract at concentrations around 10 times greater than in older children and adults.

Because infants do not have the bacterial flora necessary to convertbilirubin to urobilinogen and stercobilin, unconjugated bilirubin persiststhroughout the entire intestinal tract. Only unconjugated bilirubin canbe absorbed across the intestinal mucosa and the newborn has a far greaterconcentration of intestinal unconjugated bilirubin than the older childor adult.

Meconium contains large amounts of unconjugated bilirubin, which contributesto the circulating bilirubin pool through enteric reabsorption. Failureto clear meconium promptly enhances enteric reabsorption and increases serumbilirubin concentrations. The laxative effect of colostrum hastens the evacuationof meconium and reduces the enterohepatic circulation of bilirubin.

The intensity and duration of physiologic jaundice in newborns varieswidely. Black infants have slightly lower levels of serum bilirubin thanwhite infants, but both reach their mean peak level of approximately 5 to6 mg/dL on the third day of life. In contrast, Asian infants peak on thefourth or fifth day of life at mean levels of approximately 9 to 12 mg/dLand sustain higher bilirubin levels for a longer period than black and whiteinfants. The mechanism of these apparently inherited differences is notclear but may relate to an increase in bilirubin production or enterohepaticcirculation rates in Asian infants.

Jaundice in the breastfed infant

Both normal and abnormal increasesin neonatal jaundice are associatedwith breastfeeding. Distinguishing the two types is important to avoid overtreatmentof normalinfants and prevent excessive hyperbilirubinemia.

Breastfeeding jaundice, also known as early-onset exaggeration of physiologichyperbilirubinemia, is an abnormal type of jaundice in breastfed newborns.A study of 2,416 infants by Maisels and Gifford revealed that nearly 9%of breastfed infants had serum bilirubin levels above 12.9 mg/dL on thesecond and third days of life, compared to only 2.4% of artificially fedinfants.³ Average weight loss in the breastfed infants was alsohigher (6.9% vs. 4.2%). This suggested that suboptimal frequency and volumeof breastfeeding might be a significant factor in increased jaundice amongbreastfed infants during the first five days of life. A large retrospectiveAustralian study in which greater weight loss and reduced stooling weresignificantly associated with higher serum bilirubin levels substantiatedthis hypothesis.⁴

DeCarvalho and colleagues defined the critical role of frequency of breastfeedingand jaundice.⁵ They found that increasing frequency of nursingfrom 6 to 12 times per day during the first three days of life was associatedwith lower bilirubin levels on the third day. There is no apparent differencein bilirubin conjugation or synthesis that could account for this phenomenon.

Early exaggerated unconjugated hyperbilirubinemia caused by insufficientintake of milk is considered to be the neonatal equivalent of adult starvationjaundice, which results from increased enterohepatic circulation of bilirubin.The majority of infants admitted for significant hyperbilirubinemia areadmitted in the latter half of the first week, and they are often breastfedand have excessive weight loss.⁶ Exaggerated hyperbilirubinemiain the early days of life is not always associated with excessive weightloss, however, even though it is related to deficient milk intake and reducedfrequency of nursing.

Breastmilk jaundice, also known as late-onset prolonged unconjugatedhyperbilirubinemia, is a naturally occurring extension of physiologic jaundicein the newborn. It is probably caused by an as yet unidentified factor inmilk that enhances the enterohepatic circulation of bilirubin. While colostrumdoes not enhance the enterohepatic circulation, transitional and maturebreast milk increases intestinal bilirubin absorption.

Around two-thirds of all healthy, full-term breastfed infants duringthe third week of life have serum unconjugated bilirubin concentrationsgreater than the adult normal upper limit of 1.5 mg/dL. Half of these infantsare clinically jaundiced and have serum bilirubin concentrations above 5.0mg/dL.⁷ In contrast, all normal artificially-fed infants haveserum bilirubin levels in the third week of life that are in the adult normalrange of less than 1.5 mg/dL.

Elevated unconjugated bilirubin concentrations may persist for up tothree months, although they decline gradually over that period. The majorityof clinically jaundiced breastfed infants are anicteric by 4 to 6 weeksof age. The major differential diagnosis for prolonged unconjugated hyperbilirubinemiais continuing hemolysis, hypothyroidism, maternal diabetes, and congenitalhepatic conjugating deficiency (Crigler-Najjar and Arias-Type II syndrome).

Prevention and management

Breastfeeding jaundice is a preventable disorder. This early exaggerationof physiologic jaundice can be reduced or even eliminated by an effectivematernal breastfeeding education program that encourages early, frequentbreastfeeding--10 times or more per day--during the first weeks of life,and avoiding all water and formula supplementation. The AAP recommends that"formal evaluation of breastfeeding performance be undertaken duringthe first 24 to 48hours after delivery and again at the early follow-upvisit, which should occur 48 to 72 hours after hospital discharge."⁸

Weight loss of more than 7% suggests insufficient milk intake and indicatesa need for detailed evaluation of breastfeeding performance and correctionof problems. During the first month of life, after the third day of life,adequate milk intake is indicated by at least six urines and three stoolsper day. Maintaining breastfeeding is paramount for the benefit of infantand mother, but in some cases temporary supplementation with infant formulamay be required to assure adequate nutrition.

Decisions regarding intervention in the otherwise healthy full-term infantwith hyperbilirubinemia, especially when bilirubin levels rise above 20mg/dL, must take into account the rate of rise, absolute serum bilirubinlevel, and age of the infant. The AAP practice parameter on neonatal jaundiceprovides guidance.¹

After the first 48 hours of life, healthy full-term infants without hemolysisdo not require phototherapy or interruption of breastfeeding until totalserum bilirubin concentrations exceed 18 to 20 mg/dL. Exchange transfusionsare not indicated until serum bilirubin levels rise above 25 to 30 mg/dL.Management options for infants with bilirubin levels above 18 to 20 mg/dLbut below exchange transfusions levels include:

• observation alone while continuing to monitor bilirubin levels
• continuation of breastfeeding supplemented by expressed breast milk or formula with or without phototherapy
• temporary interruption of breastfeeding and substitution of formula with or without phototherapy.

Substituting infant formula for breastfeeding for 24 to 48 hours causesbilirubin levels to decline rapidly by half in infants with breastfeedingand breastmilk jaundice. Resuming breastfeeding results in a small risein bilirubin, rarely, if ever to original levels. Careful monitoring ofserum bilirubin levels after resuming breastfeeding is advised.

Clinical evaluation of jaundice

It is important that the pediatrician and neonatologist identify babieswho are likely to develop significantly elevated serum bilirubin concentrationsand distinguish them from the vast majority of infants with low to moderateelevations, which are entirely normal. Failure to identify infants at riskcan result in undertreatment of severe potentially toxic hyperbilirubinemia.On the other hand, overly aggressive labeling of jaundiced infants as havingpathologic hyperbilirubinemia can result in overtreatment of normal infants.It can even lead to inappropriate lowering of bilirubin levels and lossof what some investigators have postulated to be a physiologically importantantioxidant effect of bilirubin.^9­11

The challenge for the clinician is to identify the infant likely to develophyperbilirubinemia that may cause brain damage. This has become increasinglydifficult in recent years because of early discharge of newborns from thehospital, which reduces the period for observation and, in the case of breastfedinfants, the opportunity to evaluate the adequacy and competency of breastfeeding.

The physician should assess the extent of jaundice in a well-lit area,preferably in natural daylight, with the baby undressed. Bruising or cephalhematomas,petechiae, hepatosplenomegaly, and signs of sepsis suggest pathologic causesof hyperbilirubinemia, which increase the risks of rapid rises in serumlevels and complications, including kernicterus. With experience, physicians,nurses, and even parents can be trained to assess whether jaundice is severeenough to require laboratory evaluation. Untrained parents, however, oftenfail to recognize even severe degrees of jaundice, making it essential toarrange adequate professional evaluation of infants in the early days oflife.

Laboratory evaluation of jaundice

Considering that more than half of all full-term newborns develop clinicaljaundice sometime in the first week of life, the temptation to perform serumbilirubin determinations on all jaundiced babies must be tempered by clinicaljudgment.^12,13 Decisions should be based on the physician's suspicionof risk. A history of significant jaundice or anemia in the family, an Oor Rh-negative blood type in the mother, poor feeding, and onset of clinicaljaundice in the first 24hours of life all indicate a need for greater surveillance.

All infants with onset of jaundice in the first 24 hours and any beyondthat period in whom clinical assessment of jaundice--based on caudal progressionand skin and mucous membrane intensity--suggests moderately severe hyperbilirubinemia(greater than 8 to 10 mg/dL) should have a serum bilirubin determinationbefore leaving the hospital or at evaluation after discharge. Many hospitalsnow require routine clinical evaluation of all newborns 48 to 72 hours afterdischarge either at home or in the office, providing an opportunity to assessseverity of jaundice and need for bilirubin determination by the third tofifth days of life.

Noninvasive transcutaneous reflectance spectrophotometry using one ofseveral new devices may improve clinical assessment of the intensity ofjaundice, especially when the observer is inexperienced or lighting is lessthan optimal.^14,15 Such devices can theoretically reduce theneed to draw blood, avoiding discomfort to the infant and lowering costs.

Maternal blood type and family history can help identify infants at riskfor hemolysis and increased serum bilirubin concentrations, but using thesecriteria alone misses many infants with increased bilirubin production.Another new device, the expired carbon monoxide monitor, permits noninvasiveinstantaneous assessment of hemolysis with reasonable accuracy. Infantswho have elevated serum bilrubin concentrations or increased expired carbonmonoxide concentrations need additional laboratory studies as well as verycareful follow-up with repeat serum bilirubin determinations (Table 1).

The only blood tests needed for most babies are a major blood group andRh type and direct Coombs test. (The results from the mother's blood typeand Rh should also be available.) Some hospitals have eliminated routinetesting of newborn blood for type, Rh, and Coombs except for babies bornto Rh-negative mothers. Instead they hold cord blood specimens in the laboratoryuntil the infant develops clinically significant jaundice. While this mayreduce laboratory costs, it can also increase the risk of missing an infantwith ABO or minor blood group erythroblastosis.

Infants with serum bilirubin concentrations greater than 5 mg/dL in thefirst 24 hours of life and older newborns with serum bilirubin concentrationsgreater than 12 to 14 mg/dL need additional studies.¹⁶ A redcell smear for morphology and an hemocrit or hemoglobin suffices as theinitial workup for hemolysis. Reticuloyte counts and measurement of glucose-6-phosphatedehydrogenase are rarely useful in the absence of anemia and can be performedselectively. Routine neonatal screening studies help identify hypothyroidismand galactosemia, while a direct-reacting serum bilirubin fraction can helpidentify liver or biliary disease.

Routine testing for sepsis, including white count, differential, bloodculture, and urinalysis, is unwarranted in the absence of other suggestivesigns of sepsis.¹⁷ Transaminases and other liver tests are indicatedonly when significant direct-reacting bilirubin elevations (greater than2.0 mg/dL) and clinical signs of liver disease are present.

Monitoring of serum bilirubin levels should include at least one measurementof direct-reacting serum bilirubin per day. The frequency of bilirubin determinationsmust be based on rate of rise, previous patterns of rise and fall, and closenessof the previous value to a predetermined treatment level.

Soon after determining the probable cause of excessive jaundice and takinginto account the various risk factors for kernicterus in a particular infant,the physician should determine at what serum bilirubin levels various therapieswill be instituted for that infant. These "critical points" helpguide management and provide consistency among caregivers in the hospitalor clinic.

Treating neonatal jaundice

Treatment generally aims at managing the hyperbilirubinemia itself, althoughstable physiologic parameters and good nutrition can reduce risks and evenreduce excessive hyperbilirubinemia. Therapy may include phototherapy, pharmacologicalinterventions, interruption of the enterohepatic circulation, and exchangetransfusion used alone or in combination.

The AAP's practice parameter on management of hyperbilirubinemia providesguidance on treatment at different bilirubin levels (Table 2).^1,18These guidelines apply only to full-term, healthy infants without hemolysis.

Infants with hemolytic disease of any cause must be treated aggressively,both because they are at greater risk for rapid rises in serum bilirubinto potentially toxic levels and because they appear to be more likely todevelop kernicterus at lower serum bilirubin levels than infants withouthemolysis. The same is true for infants with bacterial sepsis, prior hypoxia,hypoglycemia, and prematurity. The levels at which phototherapy and exchangetransfusions should be instituted in these high-risk infants are quite variable,but are generally 2 mg/dL to as much as 15 or 20 mg/dL lower than in healthyterm infants.

Phototherapy. Phototherapy prevents serum bilirubin from reaching levelsrequiring exchange transfusion in all but a few infants with ongoing hemolysisand severe hyperbilirubinemia. Effective phototherapy depends on optimalchoice of light, intensity of light, and surface area exposed. The colorof the light is important because bilirubin only absorbs some colors. Lightpredominantly in the blue-green spectrum (wavelength in the 425­475nm range) is most effective.

Various phototherapy units, including special blue lamps (labeled F20/T12/BBfor the type of tube and phosphor used), halogen lamps, and combinationsare available, and are probably equally efficient if the light is placedas close to the infant as safely possible.¹⁹ Fiberoptic padsare also safe and efficient and permit greater maternal-infant bonding thanother lights by avoiding the need for blindfolding the baby.

Since phototherapy increases excretion of unconjugated bilirubin, thetype that is readily absorbed in the intestine, it is more effective whencombined with continued milk feeding at frequent intervals to reduce intestinalbilirubin absorption. Giving intravenous fluids to jaundiced neonates, especiallythose undergoing phototherapy, is not necessary and may be counterproductivein the absence of dehydration since it reduces milk intake. Oral intakereadily compensates for the increase in insensible water loss during phototherapy.

Complications of phototherapy are rare and generally mild.^20,21It should not be initiated without prior diagnostic evaluation of the causeof the jaundice, however. Home phototherapy appears to be gaining support^22,23but must be viewed with caution because, under current guidelines, phototherapyis administered to full-term healthy infants only at relatively high serumbilirubin concentrations. Such levels require close monitoring of the infantand prompt exchange transfusion if phototherapy fails.

Pharmacologic interventions. Phenobarbital and other inducers of microsomalenzymes, including the bilirubin conjugating enzyme hepatic glucuronyl transferase,have proved effective in reducing serum bilirubin levels in newborns. Theyhave been used very little, however, primarily because they require up tosix days of treatment for maximum effect. There is no advantage in combiningphenobarbital and phototherapy.

Various substances including agar, cholestyramine, charcoal, and bilirubinoxidase have been used to interrupt gastrointestinal reabsorption of bilirubinwith varying degrees of success, but such treatments are not generally accepted.Inhibiting heme oxygenase with metalloporphyrins to reduce heme degradationto bilirubin has shown some early promise, but much work remains to be donewith regard to safety, efficacy and clinical dosing.²⁴ Metalloporphyrinsare not approved by the Food and Drug Administration for use in humans.

Bilirubin toxicity

The term kernicterus was coined at the turn of the century by Schmorlto describe the yellow staining of basal ganglia in six infants with neonataljaundice who died.²⁵ Experts generally prefer to distinguishkernicterus, a pathologist's term describing the anatomic pattern of neurologicinjury, from bilirubin encephalopathy, a more general term encompassingthe clinical disorder.

Bilirubin accumulates in the basal ganglia, hippocampus, cranial nervenuclei (oculomotor, vestibular, cochlear, and facial), inferior olivarynuclei, and cerebellar nuclei. Yellow deposits in these parts of the braingradually fade leaving dead neurons in their place. Loss of neuronal cellsresults in permanent brain injury. The progression of this disorder is describedby Van Praagh as beginning with three clinical stages of acute encephalopathyin the newborn period:²⁶

• stupor, hypotonia, and poor sucking
• extensor hypertonia and fever
• improvement of hypertonia and other symptoms (the "honeymoon"phase), which may persist for weeks or months.

Chronic postkernicteric encephalopathy includes cerebral palsy, oftenaccompanied by paralysis of upward gaze, and high-frequency hearing losscaused by injury to cochlear nuclei. Athetosis may develop as early as 18months but may be delayed until 8 to 9 years of age. Visual motor and auditorylosses also may occur as isolated findings.

Bilirubin encephalopathy is a potentially preventable disease. Interventionssuch as preventive and therapeutic management of Rh erythroblastosis, improvedintensive care of premature infants, and generally improved surveillanceof neonatal jaundice have led to a significant decline in kernicterus. Recently,however, reported cases of severe hyperbilirubinemia and kernicterus haveincreased.²⁷Factors contributing to these unfortunate outcomesmay have included early postnatal discharge from hospital, delay in medicalfollow-up visits, minimal laboratory testing, failure to prepare mothersto breastfeed, failure to assess breastfeeding adequately,²⁸professional inexperience with severe jaundice, and the mistaken beliefthat jaundice in breastfed babies does not cause bilirubin encephalopathy.

All but one of the recently reported infants with severe hyperbilirubinemiawere breastfed, and all were discharged by the second day of life. Theymanifested severe unconjugated hyperbilirubinemia in association with severeweight loss, hypernatremia, and dehydration, suggesting that they suffereda prolonged period of inadequate milk intake that went unrecognized. TheAAP recommends formal evaluation of breastfeeding before hospital discharge,again at 3 to 5 days of age, and at the regularly scheduled well-baby visittwo to four weeks after birth. All of the reported cases of kernicterusappear to have been preventable, although sepsis and occult hemolysis mayhave also contributed to its development.

The risk of encephalopathy in the otherwise healthy full-term infantis unclear. While the literature supports the notion that very high totalserum bilirubin levels (above 35 mg/dL) correlate with a 90% chance of adverseoutcome, many studies support the conclusions of experts in this field thatthe healthy full-term newborn without hemolysis and with levels below 25mg/dL or even 30 mg/dL is at very low risk for encephalopathy.¹⁸This was the basis for the AAP's recommendation to use higher serum bilirubinlevels as indications for both phototherapy and exchange transfusion.

Factors that increase the risk of kernicterus include displacement ofbilirubin from albumin binding by medications or endogenous substances anddisruption of the blood-brain barrier by hypoxia. Little is known, however,about the mechanisms by which bilirubin gains entry into the brain or howit produces permanent injury to certain neurons, especially those in thebasal ganglia and cerebellum.

Conflicting data exist supporting as well as rejecting the notion ofa continuum of bilirubin neurotoxicity.²⁹ Controversy remainsregarding the risks of low to moderate elevations of bilirubin in pretermand high-risk full-term infants. Even at bilirubin levels in the physiologicrange, bilirubin may be crossing into the brain.

Neurologic changes, including auditory evoked potentials (BAER), cryanalysis, and somatosensory-evoked responses have been documented at levelsbetween 15 and 20 mg/dL in term infants.^30­32These earlychanges have not been associated with permanent brain injury, however. Thissuggests that an initial stage of bilirubin encephalopathy may be reversibleand that starting therapy early may prevent permanent damage. It also suggeststhat even minimal neurologic and behavior changes in moderately to severelyjaundiced infants should be considered to be early signs of potential bilirubinencephalopathy requiring immediate attention.

Heading off trouble

A well-grounded understanding of both bilirubin metabolism and breastfeedingphysiology can help minimize the risks of extreme hyperbilirubinemia andbilirubin encephalopathy. Similarly, attention to the potential for hemolysisand other diseases combined with surveillance techniques that identify significantjaundice at its earliest stages allows timely therapy to reduce the potentialfor brain damage. Good medical judgment can balance the need for such earlyidentification by promoting effective breastfeeding, optimal nutrition,and parent-infant bonding.

REFERENCES

1. American Academy of Pediatrics, Provisional Committee for QualityImprovement and Subcommittee on Hyperbilirubinemia: Practice parameter:Management of hyperbilirubinemia in the healthy term newborn. Pediatrics1994;94:558

2. Kramer LI: Advancement of dermal icterus in the jaundiced newborn.Am J Dis Child 1969;118:454

3. Maisels MJ, Clifford K: Normal serum bilirubin levels in the newbornand the effect of breastfeeding. Pediatrics 1986;78:837

4. Tudehope C, Bayley G, Munro D, et al: Breast feeding practices andsevere hyperbilirubinemia. J Pediatr Child Health 1991;27:240

5. DeCarvalho M, Klaus MH, Merkatz MB: Frequency of breast feeding andserum bilirubin concentration. Am J Dis Child 1982;136:747

6. Edmonson MB, Stoddard JJ, Ownes LM: Hospital readmission with feedingrelated problems after early postpartum discharge of normal newborns. JAMA1997;278:299

7. Alonso EM, Whitington PF, Whitington S, et al: Enterohepatic circulationof nonconjugated bilirubin in rats fed with human milk. J Pediatr 1991;118:425

8. American Academy of Pediatrics, Work Group on Breast-feeding: Breast-feedingand the use of human milk. Pediatrics 1997;100:1035

9. McDonagh AF: Is bilirubin good for you? Clin Perinatol 1990;17:359

10. Stocker R, Yamamoto Y, McDonagh AF, et al: Bilirubin is an antioxidantof possible physiologic importance. Science 1987;235:1043

11. Hegyi T, Goldie E, Hiatt M: The protective role of bilirubin in oxygenradical diseases of the preterm infant. J Perinatol 1994;14:296

12. Rosenthal P, Sinatra F: Jaundice in infancy. Pediatr Rev 1989;11:79

13. Johnson L, Bhutani VK: Guidelines for management of the jaundicedterm and near-term infant. Clin Perinatol 1998;25:555

14. Schumacher RE: Non-invasive measurements of bilirubin in the newborn.Clin Perinatol 1990;17:417

15. Yamauchi Y, Yamanouchi I: Clinical application of transcutaneousbilirubinometry: A comparison of old and new methods. Pediatrics 1985;76:10

16. Newman TB, Easterling MJ, Goldman ES, et al: Laboratory evaluationof jaundice in newborns: Frequency, cost, and yield. Am J Dis Child 1990;144:364

17. Maisels MJ, Kring E: Full-term infants with severe hyperbilirubinemia:Do they need a septic workup? Pediatr Res 1991;29:224A

18. Newman TB, Maisels MJ: Evaluation and treatment of jaundice in theterm newborn: A kinder, gentler approach. Pediatrics 1992;89:809

19.Maisels MJ: Why use homeopathic doses of phototherapy? Pediatrics1996;98:283

20. Drew JH, Marriage KJ, Bayle V: Phototherapy. Short- and long-termcomplications. Arch Dis Child 1976;51:454

21. De Curtis M, Guandalini S, Fasano A, at al: Diarrhea in jaundicedneonates treated with phototherapy: A role of intestinal secretion. ArchDis Child 1989;64:1161

22. Grabert BE, Wardwell C, Harburg SK: Home phototherapy. An alternativeto prolonged hospitalization of the full-term well newborn. Clin Pediatr1986;25:291

23. Ludwig MA: Phototherapy in the home setting. J Pediatr Health Care1990;4:304

24. Martinez JC, Garcia HO, Otheguy LE, et al: Control of severe hyperbilirubinemiain full-term newborns with the inhibitor of bilirubin production Sn-mesoporphyrin.Pediatrics 1999;103:1

25. Schmorl G: Zur kenntis des icterus neonatorum. Verh Dtsch Ges Pathol1903;6:109

26.Van Praagh R: Diagnosis of kernicterus in the neonatal period. Pediatrics1961;28:870

27. Brown AK, Johnson L: Loss of concern about jaundice and the reemergenceof kernicterus in full-term infants in the era of managed care, in FanaroffAA, Klaus MH (eds): The Yearbook of Neonatal and Perinatal Medicine. StLouis, Mosby-Year Book, 1996, pp 17­28

28. Lawrence RA: Early discharge alert. Pediatrics 1995;96:966

29.Scheidt PC, Mellits ED, Hardy JB, et al: Toxicity to bilirubin inneonates: Infant development during first year in relation to maximum neonatalserum bilirubin concentration. J Pediatr 1977;91:293

30. Nakamura H, Takada S, Shimbuku R, et al: Auditory nerve and brainstemresponses in newborn infants with hyperbilirubinemia. Pediatrics 1985;75:703

31.Vohr BR, Lester B, Rapisardi G, et al: Abnormal brainstem functioncorrelates with acoustic cry features in term infants with hyperbilirubinemia.J Pediatr 1989;115:303

32. Bongers-Schokking JJ, Colon EJ, Hoogland RA, et al: Somatosensoryevoked potentials in neonatal jaundice. Acta Pediatr Scand 1990;79:148

DR. DIXIT is a Fellow in Neonatology at the University of Chicago.

DR. GARTNER is Professor Emeritus, Departments of Pediatrics and Obstetrics/Gynecologyat the University of Chicago. He is also Chair of the Work Group on Breastfeedingof the American Academy of Pediatrics and President of the Academy of BreastfeedingMedicine.

(Sidebar) A short course in bilirubin metabolism

Bilirubin is a catabolic product of heme, mostly from hemoglobin of senescentcirculating erythrocytes, with lesser contributions from erythropoiesis,muscle myoglobin, cytochromes, and other heme proteins. Heme degradationoccurs primarily in cells in the reticuloendothelial system.

Heme oxygenase cleaves the tetrapyrrole ring of heme at the alpha carbonbridge after first removing the protein coat (globin) and iron. This reactiongenerates one molecule each of the linear tetrapyrrole biliverdin IXa andcarbon monoxide. It is the predominant source of endogenous carbon monoxide.Carbon monoxide is excreted unchanged by the lungs in expired air. Measuringthe amount excreted provides an index of heme breakdown and bilirubin production.In mammals, virtually all biliverdin is rapidly reduced by the enzymebiliverdinreductaseto bilirubin 9 alpha zz.

Bilirubin production averages 6 to 8 mg/kg/day in healthy term infantsand 3 to 4 mg/kg/day in adults. Newborns produce more bilirubin than adultsbecause they have a larger circulating pool of erythrocytes with shorterlife spans and more erythropoietic tissue. Nearly all of this tissue ceasesto mature, and the hemoglobin in it undergoes catabolic conversion to bilirubin.

Transport. Bilirubin is nonpolar, lipophilic, and poorly soluble in aqueoussolvents. It must be transported in the circulation bound to serum albumin.Albumin binding of bilirubin appears to be weaker in both affinity and capacityin the newborn period, perhaps increasing the risk of bilirubin encephalopathy.Albumin binding measurements have not proved useful in defining the riskfor kernicterus and are not in general clinical use.

Circulating bilirubin is rapidly taken up by hepatocytes in a free bidirectionalflux across the sinusoidal-hepatocyte interface, a process known as uptake(see figure). In the aqueous environment of the hepatocyte cytoplasm, bilirubinis bound to several cytosolic proteins, one of which is ligandin.

Each ligandin molecule binds one molecule of bilirubin. Ligandin is believedto play a role in preventing bilirubin and its conjugates from fluxing backinto the circulation and in transferring bilirubin to the smooth endoplasmicreticulum for conjugation. Reduced ligandin concentrations and limited transferacross the liver cell membrane in the newborn contribute to physiologicjaundice by restricting clearance of bilirubin from blood into the liver.

Conjugation and excretion. Nonpolar bilirubin must become soluble inorder to be excreted from the liver cell. This is accomplished by conjugatingbilirubin with glucuronic acid within the endoplasmic reticulum under theinfluence of the enzyme bilirubin glucuronosyltransferase (glucuronyl transferase).The first conjugate formed is a monoglucuronide, the predominant conjugatein newborns. In adults and older infants and children, a second glucuronicacid is added to the molecule to form bilirubin diglucuronide.

Bilirubin itself and drugs such as phenobarbital and narcotics can inducebilirubin glucuronyl transferase activity, while protein and calorie restrictioncan decrease its activity. At birth, bilirubin glucuronyl transferase activityis much less than in the adult liver, but it increases rapidly during thefirst week.

The hepatocytes excrete conjugated bilirubin into bile canaliculi byan active transport process that concentrates the pigment by approximately100-fold. After the newborn period, excretion by the hepatocyte is the rate-limitingstep in bilirubin clearance. Once transported into the intestinal lumenin bile, conjugated bilirubin is hydrogenated to produce colorless urobilinogens,which are either excreted in feces or absorbed and excreted in urine.

Most urobilinogen is oxidized to brown urobilins (stercobilin) and excretedin stool contributing to its normal mature color. These steps are carriedout by normal intestinal bacteria, particularly clostridial organisms.

Bilirubin glucuronide is also hydrolyzed (removal of glucuronide) tounconjugated bilirubin spontaneously or by bacterial or endogenous intestinalb-glucuronidase. Unconjugated bilirubin in the intestine that escapes reductionto urobilinogens can be reabsorbed by the mucosa, returning the pigmentto the circulation and to the liver via portal blood flow. This is knownas the enterohepatic circulation of bilirubin. In newborns, enterohepaticcirculation is markedly increased, returning large amounts of bilirubinto the circulation and adding to the load of bilirubin that must be clearedby the liver.

(End of Sidebar)