Hyperbilirubinemia of Newborn

8/10/2019 Hyperbilirubinemia of Newborn

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requires protein binding with albumin.After conjugation in the liver, it is excreted

in bile.3,5-7

Newborns produce bilirubin at a rate ofapproximately 6 to 8 mg per kg per day. Thisis more than twice the production rate inadults, primarily because of relative poly-cythemia and increased red blood cell turn-over in neonates.7 Bilirubin production typi-

cally declines to the adult level within 10 to 14days after birth.2

Bilirubin Toxicity

Kernicterus refers to the neurologic con-sequences of the deposition of unconjugatedbilirubin in brain tissue. Subsequent damageand scarring of the basal ganglia and brain-stem nuclei may occur.5

The precise role of bilirubin in the develop-ment of kernicterus is not completely under-stood. If the serum unconjugated bilirubin

level exceeds the binding capacity of albumin,unbound lipid-soluble bilirubin crosses theblood-brain barrier. Albumin-bound biliru-bin may also cross the blood-brain barrier ifdamage has occurred because of asphyxia,acidosis, hypoxia, hypoperfusion, hyper-osmolality, or sepsis in the newborn.3,8

The exact bilirubin concentration associ-ated with kernicterus in the healthy terminfant is unpredictable.1 Toxicity levels mayvary among ethnic groups,with maturation ofan infant, and in the presence of hemolytic

disease. Although the risk of bilirubin toxicityis probably negligible in a healthy term new-born without hemolysis,9 the physicianshould become concerned if the bilirubin levelis above 25 mg per dL (428 mol per L).1,3,10

In the term newborn with hemolysis, a biliru-bin level above 20 mg per dL (342 mol per L)is a concern.1,3

The effects of bilirubin toxicity are oftendevastating and irreversible (Table 2).3,9

Early signs of kernicterus are subtle andnonspecific, typically appearing three to

four days after birth. However, hyperbiliru-binemia may lead to kernicterus at any timeduring the neonatal period.2 After the firstweek of life, the affected newborn begins todemonstrate late effects of bilirubin toxicity.If the infant survives the initial severe neu-rologic insult, chronic bilirubin enceph-alopathy (evident by three years of age)leads to developmental and motor delays,sensorineural deafness, and mild mentalretardation.

600 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 65, NUMBER4 / FEBRUARY 15, 2002

TABLE 1

Risk Factors for Hyperbilirubinemia in Newborns

Maternal factors

Blood type ABO or

Rh incompatibility

Breastfeeding

Drugs: diazepam

(Valium), oxytocin

(Pitocin)

Ethnicity: Asian,

Native American

Maternal illness:gestational diabetes

TORCH = toxoplasmosis, other viruses, rubella, cytomegalovirus, herpes (sim-

plex) viruses.

Information from references 2, 3, and 4.

Neonatal factors

Birth trauma: cephalohematoma, cutaneous

bruising, instrumented delivery

Drugs: sulfisoxazole acetyl with erythromycin

ethylsuccinate (Pediazole), chloramphenicol

(Chloromycetin)

Excessive weight loss after birth

Infections: TORCH

Infrequent feedings

Male genderPolycythemia

Prematurity

Previous sibling with hyperbilirubinemia

TABLE 2

Effects of Bilirubin Toxicity in Newborns

Early

Lethargy

Poor feeding

High-pitched cry

Hypotonia

Information from references 3 and 9.

Late

Irritability

Opisthotonos

Seizures

Apnea

Oculogyric crisis

Hypertonia

Fever

Chronic

Athetoid cerebral palsy

High-frequency hearing loss

Paralysis of upward gaze

Dental dysplasia

Mild mental retardation


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of physiologic hyperbilirubinemia in theneonate include an increased bilirubin loadbecause of relative polycythemia, a shortenederythrocyte life span (80 days compared withthe adult 120 days), immature hepatic uptakeand conjugation processes, and increasedenterohepatic circulation.7

JAUNDICE AND BREASTFEEDING

Early-Onset Breastfeeding Jaundice. Breast-fed newborns may be at increased risk forearly-onset exaggerated physiologic jaundice

because of relative caloric deprivation in thefirst few days of life.12 Decreased volume andfrequency of feedings may result in mild dehy-dration and the delayed passage of meco-nium.Compared with formula-fed newborns,breastfed infants are three to six times morelikely to experience moderate jaundice (totalserum bilirubin level above 12 mg per dL) orsevere jaundice (total serum bilirubin levelabove 15 mg per dL [257 mol per L]).12,13

In a breastfed newborn with early-onsethyperbilirubinemia, the frequency of feedings

needs to be increased to more than 10 per day.If the infant has a decline in weight gain,delayed stooling, and continued poor caloricintake, formula supplementation may be nec-essary, but breastfeeding should be continuedto maintain breast milk production. Supple-mental water or dextrose-water administra-tion should be avoided, as it decreases breastmilk production and places the newborn atrisk for iatrogenic hyponatremia.3,5,11

Late-Onset Breast Milk Jaundice. Breastmilk jaundice occurs later in the newborn

period, with the bilirubin level usually peak-ing in the sixth to 14th days of life. This late-onset jaundice may develop in up to one thirdof healthy breastfed infants.1 Total serumbilirubin levels vary from 12 to 20 mg per dL(340 mol per L) and are nonpathologic.

The underlying cause of breast milk jaun-dice is not entirely understood. Substances inmaternal milk, such as -glucuronidases, andnonesterified fatty acids, may inhibit normalbilirubin metabolism.5,7,14,15 The bilirubin

level usually falls continually after the infant istwo weeks old, but it may remain persistentlyelevated for one to three months.

If the diagnosis of breast milk jaundice is indoubt or the total serum bilirubin level becomesmarkedly elevated, breastfeeding may be tem-porarily interrupted, although the mothershould continue to express breast milk to main-tain production.With formula substitution, thetotal serum bilirubin level should declinerapidly over 48 hours (at a rate of 3 mg per dL[51 mol per L] per day),1 confirming the diag-

nosis. Breastfeeding may then be resumed.

PATHOLOGIC JAUNDICE

All etiologies of jaundice beyond physio-logic and breastfeeding or breast milk jaun-dice are considered pathologic. Features ofpathologic jaundice include the appearance ofjaundice within 24 hours after birth, a rapidlyrising total serum bilirubin concentration(increase of more than 5 mg per dL per day),and a total serum bilirubin level higher than17 mg per dL in a full-term newborn.3,5 Other

features of concern include prolonged jaun-dice, evidence of underlying illness, and eleva-tion of the serum conjugated bilirubin level togreater than 2 mg per dL or more than 20 per-cent of the total serum bilirubin concentra-tion. Pathologic causes include disorders suchas sepsis, rubella, toxoplasmosis, occult hem-orrhage, and erythroblastosis fetalis.

Diagnosis

PHYSICAL EXAMINATION

The presence of jaundice can be deter-

mined by examining the infant in a well-litroom and blanching the skin with digitalpressure to reveal the color of the skin andsubcutaneous tissue. Neonatal dermal icterusis not noticeable at total serum bilirubin lev-els below 4 mg per dL (68 mol per L).16

Increasing total serum bilirubin levels areaccompanied by the cephalocaudal progres-sion of dermal icterus, predictably from theface to the trunk and extremities, and finally tothe palms and soles.16,17 The total serum biliru-



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bin level can be estimated clinically by thedegree of caudal extension: face, 5 mg per dL;upper chest, 10 mg per dL (171 mol per L);abdomen, 12 mg per dL; palms and soles,

greater than 15 mg per dL.The only consistently reliable estimation of

total serum bilirubin occurs when dermalicterus is confined to above the nipple line. Inthis situation, the bilirubin level is invariablybelow 12 mg per dL.As jaundice extends belowthe middle of the chest, the correlationbetween physical signs and measured bilirubinlevels becomes increasingly unreliable. Differ-ences in skin color among races, delays in der-mal deposition with rapidly rising bilirubin

levels, interobserver variability, and other fac-tors contribute to the difficulty of accuratelypredicting the total serum bilirubin concentra-tion based on caudal progression alone.18

The physical examination should focus onidentifying one of the known causes of patho-logic jaundice. The infant should be assessedfor pallor, petechiae, extravasated blood, ex-cessive bruising, hepatosplenomegaly, weightloss, and evidence of dehydration.

LABORATORY EVALUATION

The initial evaluation of jaundice dependson the age of the newborn (Figure 1).2 If theserum conjugated bilirubin level is above

FEBRURARY 15, 2002 / VOLUME 65, NUMBER4 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 603

Laboratory Evaluation of Term Newborn with Jaundice

Age of newborn

2 weeks

Conjugated bilirubin level

>2mg per dL (34 mol per L)


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2 mg per dL, the infant should be evaluatedfor possible hepatocellular disease or biliaryobstruction.

Management

Studies on the toxic effects of hyperbiliru-

binemia historically involved infants withhemolytic disease. An increased incidence ofkernicterus was found to be associated withtotal serum bilirubin levels above 20 mg perdL in the presence of hemolysis.19,20 Thisobservation was the basis for aggressive guide-lines recommending the use of exchangetransfusion in all infants with significant

hyperbilirubinemia. More recently, term in-fants without hemolysis have been found totolerate higher total serum bilirubin levels,21

and management guidelines now focus pri-marily on phototherapy as initial treatment.1

Recommendations for the management ofhyperbilirubinemia in healthy term newbornshave been outlined by the American Academyof Pediatrics (Table 4).1 Jaundice in a termnewborn fewer than 24 hours old is alwayspathologic: it should be investigated thor-oughly and treated appropriately. Depending

on the rate at which the bilirubin level rises, anewborns risk of developing significanthyperbilirubinemia can be classified as low,intermediate, or high (Figure 2).22 With theassumption that the bilirubin level will con-tinue to rise at the same rate, the physician canpredict the potential further progression ofthe rise and calculate the number of days thatthe infant may be at risk for bilirubin toxicity.

Conjugated hyperbilirubinemia is neverphysiologic,and it may indicate the presence ofa potentially serious underlying disorder. How-

ever, elevated conjugated bilirubin levels arenot directly toxic to brain cells in the neonate.2

If jaundice persists for more than twoweeks in a formula-fed infant and more thanthree weeks in a breastfed infant, further eval-uation is warranted.1,7 Laboratory studiesshould include a fractionated bilirubin level,thyroid studies,evaluations for metabolic dis-orders or hemolytic disease, and an assess-ment for intestinal obstruction.

Treatment

Before treatment is initiated, the minimumevaluation should include the infants age andpostnatal course, a maternal and gestationalhistory,physical examination of the infant, anddetermination of the total serum bilirubin leveland the rate at which it is rising (Figure 2).22

PHOTOTHERAPY

Phototherapy employs blue wavelengths oflight to alter unconjugated bilirubin in theskin. The bilirubin is converted to less toxic


TABLE 4

Management of Hyperbilirubinemia in Healthy Term Newborns

The Authors

MEREDITH L. PORTER, CPT, MC, USA, is a staff family physician at Vicencza ArmyHealth Clinic, Italy. Dr. Porter received her medical degree from Virginia Common-wealth University School of Medicine, Richmond, and completed a family practice res-idency at Dewitt Army Community Hospital, Fort Belvoir, Va.

BETH L. DENNIS, MAJ, MC, USA, is a staff family physician and clinic director at DewittArmy Community Hospital. She also serves as assistant professor of medicine at theUniformed Services University of Health Sciences F. Edward Hbert School of Medicine,Bethesda, Md. Dr. Dennis received her medical degree from the University of VirginiaSchool of Medicine, Charlottesville, and completed a family practice residency atTripler Army Medical Center, Honolulu.

Address correspondence to Meredith L. Porter, CMR 427, Box 3389, APO,

AE 09630 (e-mail: [email protected]). Reprints are not avail-

able from the authors.

The rightsholder did not

grant rights to reproducethis item in electronicmedia. For the missingitem, see the original printversion of this publication.


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tial bilirubin level is meets defined critical levelsbased on the infants age (Table 4),1 prepara-tions should be made for exchange transfusion.

EXCHANGE TRANSFUSION

Exchange transfusion is the most rapidmethod for lowering serum bilirubin concen-trations. This treatment is rarely neededwhen intensive phototherapy is effective.1,26,27

The procedure removes partially hemolyzedand antibody-coated erythrocytes andreplaces them with uncoated donor red blood

cells that lack the sensitizing antigen.In the presence of hemolytic disease, severeanemia,or a rapid rise in the total serum biliru-bin level (greater than 1 mg per dL per hour inless than six hours),exchange transfusion is therecommended treatment. Exchange transfu-sion should be considered in a newborn withnonhemolytic jaundice if intensive photother-apy fails to lower the bilirubin level.1

Complications of exchange transfusion caninclude air embolism, vasospasm, infarction,infection,and even death.Because of the poten-

tial seriousness of these complications, intensivephototherapy efforts should be exhaustedbefore exchange transfusion is initiated.26

The authors indicate that they do not have any con-

flicts of interest. Sources of funding: none reported.

The opinions and assertions contained herein are the

private views of the authors and are not to be con-

strued as official or as reflecting the views of the U.S.

Army Medical Department or the U.S. Army at large.

REFERENCES

1. Practice parameter: management of hyperbiliru-binemia in the healthy term newborn. Pediatrics1994;94(4 pt 1):558-62.

2. Jaundice and hyperbilirubinemia in the newborn.In: Behrman RE, Kliegman RM, Jenson HB, eds.Nelson Textbook of pediatrics. 16th ed. Philadel-phia: Saunders, 2000:511-28.

3. Dennery PA, Seidman DS, Stevenson DK. Neonatalhyperbilirubinemia. N Engl J Med 2001;344:581-90.

4. Clemons RM. Issues in newborn care. Prim Care2000;27:251-67.

5. Melton K, Akinbi HT. Neonatal jaundice. Strategiesto reduce bilirubin-induced complications. Post-grad Med 1999;106:167-8,171-4,177-8.

6. Wintrobe MM, Lee GR. Wintrobes Clinical hema-tology. 10th ed. Baltimore: Williams & Wilkins,1999:267-89.

7. Gartner LM, Herschel M. Jaundice and breastfeed-ing. Pediatr Clin North Am 2001;48:389-99.

8. Ravel R. Clinical laboratory medicine: clinical appli-cation of laboratory data. 6th ed. St. Louis: Mosby,1999:309-27.

9. Maisels MJ, Newman TB. Kernicterus in otherwisehealthy, breast-fed term newborns. Pediatrics1995;96(4 pt 1):730-3.

10. Newman TB, Maisels MJ. Evaluation and treatmentof jaundice in the term newborn: a kinder, gentlerapproach. Pediatrics 1992;89(5 pt 1):809-18.

11. Siberry GK, Iannone R, eds. The Harriet Lane hand-book: a manual for pediatric house officers. 15th

ed. St. Louis: Mosby, 2000:257-8.12. Osborn LM, Reiff MI, Bolus R. Jaundice in the full-term neonate. Pediatrics 1984;73:520-5.

13. Schneider AP II. Breast milk jaundice in the new-born. A real entity. JAMA 1986;255:3270-4.

14. Poland RL. Breast-milk jaundice. J Pediatr 1981;99:86-8.

15. Brodersen R, Herman LS. Intestinal reabsorption ofunconjugated bilirubin. Lancet 1963;1:1242.

16. Kramer LI. Advancement of dermal icterus in thejaundiced newborn. Am J Dis Child 1969;118:454-8.

17. Knudsen A, Ebbesen F. Cephalocaudal progressionof jaundice in newborns admitted to neonatalintensive care units. Biol Neonate 1997;71:357-61.

18. Moyer VA, Ahn C, Sneed S. Accuracy of clinicaljudgment in neonatal jaundice. Arch Pediatr Ado-

lesc Med 2000;154:391-4.19. Hsai DY, Allen FH, Gellis SS, Diamond LK. Erythro-blastosis fetalis. VIII. Studies of serum bilirubin in rela-tion to kernicterus. N Engl J Med 1952;247:668-71.

20. Gartner LM, Herrarias CT, Sebring RH. Practice pat-terns in neonatal hyperbilirubinemia. Pediatrics1998;101(1 pt 1):25-31.

21. Newman TB, Maisels MJ. Does hyperbilirubinemiadamage the brain of healthy full-term infants? ClinPerinatol 1990;17:331-58.

22. Bhutani VK, Johnson L, Sivieri EM. Predictive abilityof a predischarge hour-specific serum bilirubin forsubsequent significant hyperbilirubinemia inhealthy term and near-term newborns. Pediatrics1999;103:6-14.

23. Maisels MJ. Why use homeopathic doses of pho-

totherapy? Pediatrics 1996;98(2 pt 1):283-7.24. Yetman RJ, Parks DK, Huseby V, Mistry K, Garcia J.Rebound bilirubin levels in infants receiving pho-totherapy. J Pediatr 1998;133:705-7.

25. Lazar L, Litwin A, Merlob P. Phototherapy forneonatal nonhemolytic hyperbilirubinemia. ClinPediatr [Phila] 1993;32:264-7.

26. Jackson JC. Adverse events associated withexchange transfusion in healthy and ill newborns.Pediatrics 1997;99:E7.

27. Brown AK, Kim MH, Wu YK, Bryla DA. Efficacy ofphototherapy in prevention and management ofneonatal hyperbilirubinemia. Pediatrics 1985;75(2pt 2):393-400.


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Hyperbilirubinemia of Newborn

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