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Neonatal jaundice
Current Paediatrics (1997) 7, 67-72 © 1997Pearson ProfessionalLtd
Mini-symposium: Neonatology
Neonatal jaundice
N. K. Ives
Jaundice is the most common clinical sign in neonatal medicine. Physiological jaundice, in the majority of term infants, merits neither investigation nor treatment. Vigilant appraisal of every jaundiced infant is, however, necessary in order to identify the small proportion of newborns with pathological jaundice or those at heightened risk of kernicterus. In the current era of early postnatal discharge from hospital, it is the paediatrician's task to identify those infants most likely to develop significant jaundice. Predictably, neonatal jaundice has become the most common reason for hospital readmission in the first week of life.
conjugated bilirubin entering the gut is hydrolysed by [3-glucuronidase to yield unconjugated bilirubin, which can readily re-enter the serum pool via the enterohepatic circulation.
P H Y S I O L O G I C A L JAUNDICE Under normal circumstances, the bilirubin level in cord blood at birth is in the region of 20-35 gmol/L. In most newborns, this increases postnatally as a result of immaturity of the mechanisms for liver uptake, transport and conjugation of bilirubin. Serum bilirubin peaks on the third to fourth day of life, attaining clinically detectable levels in approximately two-thirds of healthy term infants. 3 After this phase I peak, levels fall rapidly for 2-3 days and then more gradually, reaching normal adult values between 1 and 2 weeks of age (phase II). Phase II may be prolonged in the breast fed infant. Premature infants exhibit a higher peak serum bilirubin level, occurring on days 5 6, and a longer phase II, persisting for 2 4 weeks. Physiological jaundice may be exacerbated by the following:
BILIRUBIN B I O C H E M I S T R Y A N D METABOLISM
Bilirubin is formed as a result of the catabolism of haem in the reticuloendothelial system. ~ Why mammals should expend energy producing and excreting a potentially neurotoxic haem byproduct is not altogether clear. The need for products of fetal haem degradation to be lipophilic, and so able to cross the placenta, is considered important. Another plausible explanation stems from the discovery that bilirtlbin may have a significant antioxidant role to play in the newborn period? Bilirubin is transported in the blood, bound reversibly to albumin. Under normal circumstances the proportion of potentially toxic free bilirubin circulating in the jaundiced newborn is extremely low. Conjugation of bilirubin within the hepatocyte is catalysed by the enzyme, uridine diphosphoglucuronosyl transferase (UDPGT). A significant proportion of
• Polycythaemia Delayed cord clamping Materno-fetal transfusion Recipient of twin-twin transfusion • Extravasated blood Bruising (e.g. cephalhaematoma) Birth trauma Internal haemorrhage • Delayed passage of meconium • Swallowed blood • Hypocaloric feed intake • Dehydration • Breast feeding • Prematurity.
N. KevinIvesMD, ConsultantNeonatologistand Honorary Senior ClinicalLecturer,Neonatal Unit, Departmentof Paediatrics,John RadcliffeHospital, Oxford OX3 9DU, UK. Correspondence and requestsfor offprintsto NKI.
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Current Paediatrics
There has been a tendency to call physiological jaundice pathological if it is >2 SD above large population means (i.e. >220 gmol/L in term and >250 gmol/L in preterm infants). In the absence of a contributory disease process, the term 'exaggerated physiologicaljaundice' is a better description. Exaggerated physiological jaundice may, however, attain unconjugated bilirubin levels capable of transient and, on occasions, permanent neurological damage?
JAUNDICE IN THE HEALTHY BREAST FED INFANT Breast fed babies develop more marked and prolonged jaundice than those who are purely formula fed? Peak bilirubin levels in the breast fed infant may not occur until the fourth to sixth day of life, and up to one-third of breast fed babies remain clinically jaundiced beyond 2 weeks of age. In a few, this may persist for 2-3 months. The diagnosis of breast milk jaundice is made on exclusion of pathological causes. The association between breast feeding and heightened jaundice has recently been reviewed? The pathogenesis would appear to be multifactorial, involving some or all of the following: • Enhanced enterohepatic circulation Delayed passage of meconium ~-glucuronidase in breast milk Altered bacterial colonization of the gut • Impaired bilirubin metabolism Decreased caloric intake Inhibition of UDPGT by: metal ions, steroids, nucleotides and free fatty acids Infrequent and insufficient breast feeds may predispose to severe jaundice through poor caloric intake, excessive weight loss and slow clearance of meconium. An early initial breast feed and frequent subsequent feeds are advocated to lessen the peak bilirubin attained in the breast fed infant.
The imprecise relationship between total serum bilirubin levels and adverse neurological outcome has encouraged research seeking to identify more accurate markers of bilirubin toxicity. Assessment of free bilirubin levels, bilirubin binding capacity, brainstem auditory evoked responses and computer analysis of abnormality of the jaundiced infant's cry have been proposed. Such markers may prove of value in research environments, but are not universally available, or indeed feasible, in the acute clinical situation. More accessible is the bilirubin:albumin ratio, which provides an indirect guide to the free bilirubin level2 THE JAUNDICED INFANT: WHEN TO MEASURE THE SERUM BILIRUBIN Neonatal jaundice becomes clinically apparent when serum bilirubin levels reach 80--90 gmol/L. Newborns jaundiced within 24 h of birth and all preterms with detectable jaundice, regardless of their postnatal age, should have their serum bilirubin measured. Clinical judgement should be exercised in assessing the need to investigate an otherwise healthy term infant, with no known risk factors, who develops jaundice from day 2 onwards. In such an infant, the cephalocaudal progression of dermal jaundice8 can be used as a rough guide as to when to formally determine the serum bilirubin. If dermal jaundice has reached the hands and feet, the serum bilirubin level may be in excess of 300 gmol/L and should be measured. Transcutaneous bilirubinometry may have a role in screening otherwise healthy term and near-term newborns, provided a threshold is established, beyond which invasive assessment is mandatory. Carbon monoxide, being generated in equimolar quantities with bilirubin during haem catabolism, serves as a useful marker of bilirubin production. The accuracy of an automated end-tidal carbon monoxide analyser as an early warning device for significant haemolysis in newborns is currently being assessed. 9 IDENTIFYING PATHOLOGICAL JAUNDICE
BILIRUBIN ENCEPHALOPATHY
The word kernicterus originated as a description of yellow nuclear staining of the brain, but has become synonymous with the acute and chronic neurological sequelae of what is more correctly called bilirubin encephalopathy. The clinical manifestations of bilirubin encephalopathy arise from the susceptibility to damage of the basal ganglia, brainstem auditory pathways and oculomotor nuclei. Bilirubin's toxicity would appear to be that of a generalized cellular poison. Studies point to the importance of coexisting risk factors, such as acidosis, hypoxia, hypercapnia and blood-brain barrier disruption. 6
The more common causes of pathological hyperbilirubinaemia are listed in Boxes 1 and 2. Clinical features that suggest a pathological cause of jaundice and prompt further investigation are as follows: • Jaundice appearing in the first 24 h of life • Jaundice in a sick neonate • Total serum bilirubin level >250 gmol/L on day 2; >300 gmol/L thereafter • Rapidly rising serum bilirubin > 100 gmol/L/24 h • Prolonged jaundice > 14 days in term infants; >21 days in preterm infants • Conjugated serum bilirubin >25 gmol/L • Acholuric stools and dark urine.
Neonatal jaundice Box 1 Causes of unconjugated jaundice in the newborn
Haemolysis Isoimmunization Rhesus ABO Minor blood groups Other Spherocytosis G-6PD deficiency Pyruvate kinase deficiency Sepsis* Disseminated intravascular coagulation Polyeythaemia Small for dates Twin-twin transfusion Delayed cord clamping Materno-fetal transfusion Infant of diabetic mother Extravasated blood Bruising, e.g. cephalhaematoma Pulmonary haemorrhage Cerebral haemorrhage Intra-abdominal haemorrhage Increased enterohepatic circulation Pyloric stenosis Bowel obstruction Swallowed blood Endocrine/metabofic Hypothyroidism Hypopituitarism* Hypoadrenalism* Glucuronosyl transferase deficiency Galactosaemia* Tyrosinosis* Hypermethioninaemia* * Conjugated jaundice often coexists
Box 2 Causes of conjugated jaundice in the newborn
Intrauterine infections Toxoplasmosis Rubella Cytomegalovirus Herpes simplex Coxsackie and other viruses Syphilis Bacterial sepsis Severe haemolysis, e.g. erythroblastosis Prolonged parenteral nutrition Biliary atresia ~l-antitrypsin deficiency Cystic fibrosis Cryptogenic hepatitis Choledochal cyst Inspissated bile plug syndrome Galactosaemia Tyrosinosis Hypermethioninaemia
When assessing the maternal history and examining the jaundiced newborn, particular attention should be paid to the following key diagnostic points: • Maternal and infant blood group and rhesus status • Maternal red cell antibody status • History suggestive of congenital infection • Likelihood of G-6PD deficiency from parental ethnicity
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• Family history of red cell morphological abnormalities, galactosaemia or Crigler Najjar syndrome • History of birth asphyxia and trauma • Clinical signs of polycythaemia, anaemia, hydrops, purpura, cataracts or hepatosplenomegaly • Assessment of maturity and intrauterine growth • Risk factors for, and evidence of, infection • Documentation of syphilis and hepatitis serology • The mode and success of feeding • The infant's state of hydration and weight trend since birth. Appropriate early investigation aims to identify treatable disease states, such as isoimmunization, infection, hypothyroidism, biliary atresia and galactosaemia. Unless there are diagnostic pointers to the more rarely encountered causes of neonatal jaundice, stepwise investigation (Box 3) should aim to identify the more common aetiologies first. Early onset jaundice demands prompt attention to identify possible causes of haemolysis.
PROLONGED JAUNDICE Visibly detectable jaundice beyond 2 weeks of age in the term infant and 3 weeks in the preterm merits the description 'prolonged jaundice'. The majority of term infants presenting with prolonged jaundice exhibit an unconjugated hyperbilirubinaemia and will be breast feeding. Providing there are no features in the history or on clinical examination that suggest a pathological cause, the following screening investigations can be safely performed between 2 and 3 weeks of age: • • • • • •
Total and conjugated serum bilirubin Full blood count including reticulocytes Examination of blood film Thyroid function tests Urinalysis for reducing sugars (Clinitest) Urine culture.
Further tests will be indicated according to the outcome of this initial screen. A more direct approach to investigations is necessary in cases where a specific pathology, such as biliary atresia, is suspected. CONJUGATED JAUNDICE Definitions of conjugated hyperbilirubinaemia vary. A serum conjugated bilirubin level of >25 gmol/L is a commonly adopted cut-off. Pale acholuric stools and dark bile-stained urine are the clinical markers of established conjugated jaundice, but neither may be present in the first weeks of many hepatic disease states, including biliary atresia. Diagnosis of an associated clotting disorder and its correction are urgent
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Current Paediatrics
Box 3 Investigationof jaundicein the newborn Early onset jaundice
Bloodgroupand DCT Haematocritand FBC Bloodfilmand reticulocytecount Infectionscreenif indicated Serologyfor congenitalinfections Urine for CMVculture Stoolfor virology G-6PD screen Red cellenzymeassays Prolongedjaundice Total and conjugatedserumbilirubin Thyroidfunctiontests Urine culture Urine Clinitestfor reducingsubstances Liverfunctiontests cd-antitrypsinassayand phenotype CysticFibrosisDNA screen Immunoreactivetrypsin Plasmacortisollevel Serumaminoacidscreen
requirements in the infant with conjugated jaundice. Several conditions present with a mixture of raised unconjugated and conjugated bilirubin. Notable amongst these are the intrauterine infections, bacterial sepsis, galactosaemia, aminoacidaemias and congenital hypopituitarism. If an obstructive aetiology is suspected, liver ultrasound and HIDA scan will be indicated. Visualization of the gallbladder on ultrasound does not rule out biliary atresia. The importance of making an early diagnosis of biliary atresia and the patient's prompt referral to a centre specializing in the management of childhood liver disorders cannot be overstated.
CLINICAL MANAGEMENT OF T H E JAUNDICED INFANT The different modes of treatment of unconjugated jaundice are shown below: • Phototherapy • Exchange transfusion • Pharmacological agents Competitive inhibition of haem oxygenase, e.g. metalloporphyrins Liver enzyme induction, e.g. phenobarbitone Suppression of isoimmune haemolysis, e.g. intravenous immunoglobulin Inhibition of the enterohepatic circulation, e.g. agar and cholestyramine. Phototherapy
Phototherapy detoxifies bilirubin and facilitates its excretion from the body via routes other than conjugation in the liver. The biochemical basis of phototherapy has been well reviewed?° Phototherapy is safe and convenient and reduces the need for exchange
transfusion. However, phototherapy's ease of use has encouraged its overuse. Many newborns are 'placed under the lights' unnecessarily or treated for too long. The vogue for 'prophylactic' phototherapy from birth in very low birth weight infants has been shown to neither reduce the peak nor shorten the duration of their jaundice. Phototherapy would only appear to be effective as bilirubin enters the skin at serum levels >80 gmol/L. The recently developed fibreoptic systems for delivering phototherapy via a body pad or wrap have made its application more versatile. These devices are likely to gain greater acceptance in the context of healthy term infants nursed without eye pads and alongside their mothers. Trials have shown fibreoptic phototherapy to be as effective as conventional phototherapy in preterm infants, but less so in term infants. 11 The dose of phototherapy administered is conventionally expressed in terms of spectral irradiance (gW/cm2/nm). Before the mechanism of phototherapy was better understood, it was thought that saturation of dose-response occurred within the blue light range at a spectral irradiance of 4 gW/cm2/nm. This is true of the configurational isomer bilirubin-Z,E. However, it is now known that production of the more important structural photoisomer, lumirubin, has a dose-response relationship that does not attain saturation until a spectral irradiance of 25-30 gW/cm2/nm is achieved?° Exchange transfusion
Exchange transfusion will remain necessary for infants who fail to respond to adequate phototherapy or who present late with bilirubin levels in excess of exchange values. In the latter case, the baby should be placed under 'double phototherapy', pending the availability of blood for the exchange. Attention should be paid to correcting disturbances of hydration or acid-base balance, and to the treatment of any underlying infection. Pharmacological agents
Competitive inhibition of haem oxygenase by synthetic metalloporphyrins has been the most promising recent therapeutic development. The therapeutic potential of tin, zinc and chromium metalloporphyrins and their possible side-effects are discussed in a recent review.9 These agents are likely to find a role in the preventive treatment of certain populations at high risk of significant pathological jaundice or where conventional management with phototherapy and exchange transfusion is less readily available. Their more widespread use in neonatal jaundice will depend on their safety record. Another preventive therapy that may be of benefit to newborns presenting with severe rhesus or ABO isoimmunization is early administration of high dose
Neonatal jaundice intravenous ~-globulin. This treatment has been shown to inhibit haemolysis and significantly reduce the need for exchange transfusion in Rh incompatibility.~2 Phenobarbitone has been given antenatally in the context of rhesus disease to accelerate fetal maturation of liver conjugation. New inducers of UDPGT, lacking the sedative effects of phenobarbitone and designed for postnatal use, are currently under investigation. Attempts to limit the enterohepatic circulation of bilirubin with agents such as agar and cholestyramine, or by hastening the passage of meconium, have not provided clinically useful results. Guidelines for the use of phototherapy and exchange transfusion
The optimal use of phototherapy The efficacy of phototherapy can most readily be improved by attention to the dose of light used, and the proportion of the newborn's surface area of skin to which it is applied. Increasing the dose of phototherapy is achieved by operating the light source at the minimum recommended safe distance from the infant. Care must be taken to avoid over-heating. In order to maximize the area of skin exposed to treatment, more than one phototherapy unit can be used. Double phototherapy is most conveniently achieved by nursing the baby on a fibreoptic phototherapy pad whilst applying one or more conventional phototherapy units from above. There continues to be much debate as to which is the optimal wavelength of light to use. Pure blue light is poorly tolerated by staff and can mask cyanosis in a sick infant. Combinations of broad-spectrum white and blue light have proved more acceptable. There are theoretical reasons why green light phototherapy would be the most effective choice. Compared with blue light, green preferentially favours formation of lumirubin, the main excretory photoisomer, and its longer wavelength enhances skin penetration. ~° Comparative trials of these various colour combinations are difficult to interpret because the appliances are rarely matched for spectral irradiance. The fact that it takes up to 3 h for bilirubin to return to the skin following removal of photoisomers has prompted intermittent phototherapy regimes based on 1 in 4 h exposure to lights. It should be recognized that claims that such regimes have been shown to be
Table 1 Guidelines for treatment of preterms with phototherapy
and exchange transfusion Gestational age (weeks)
Serum bilirubin concentration (gmol/L) Phototherapy Exchange transfusion Sick* Well
36 32 28 24
250 150 100 80
300 250 200 150
Age(h)
25-48 49 72 >72
350 300 250 200
*Rh disease, perinatal asphyxia, hypoxia, acidosis, hypercapnia.
equally effective as continuous phototherapy are based on experience with mild to moderate physiological jaundice. Jaundice that has reached a level within 50 gmol/L of the exchange threshold should be treated with continuous phototherapy.
Treatment thresholds Newborns with haemolysis and those born prematurely would appear to be at heightened risk of bilirubin neurotoxicity.1 It is prudent to maintain our respect for a total bilirubin level of 340 gmol/L (20 mg/dL) in the term infant with haemolysis, and to use sliding scales prompting earlier intervention on the basis of gestational age (Table 1). Having grown up with this interventionalist approach, few recently trained paediatricians will have witnessed the acute effects of bilirubin toxicity.
Haemolytic disease of the newborn (HDN). Previous guidelines for early exchange transfusion in HDN based on cord blood values no longer apply, as most severely affected infants will have received in utero transfusion. The haematocrit and a Kleihauer estimation of the proportion of circulating fetal red cells are more relevant. Many such infants, adequately treated in utero, respond to intensive phototherapy followed by top-up transfusion. If, despite double phototherapy, the serum bilirubin continues to rise by more than l0 gmol/L/h, exchange transfusion is to be anticipated. Preterm infants. Phototherapy should be commenced and investigations initiated in all preterm infants who become clinically jaundiced within the first 24 h of life. From the second day onwards, phototherapy and exchange transfusion should be considered if the serum bilirubin has reached the values shown in Table 1.
Table 2 Management of jaundice in the healthy term newborn: American Academy of Pediatrics Guidelines.
Reproduced by kind permission of
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P e d i a t r i c s ~6
Consider phototherapy
Total serum bilirubin level (gmol/L) Phototherapy Exchange if intensive phototherapy fails*
Exchange and intensive phototherapy
> 170 >260 _>290
>260 _>310 _>340
>430 _>510 _>510
>340 >430 _>430
*Failure of intensive phototherapy to reduce serum bilirubin by 17-34 gmol/L within 4-6 h.
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On current evidence, calls to greatly relax such an approach to jaundice in the preterm population should be resisted, m4
Healthy term infants. The fact that healthy term infants would appear to tolerate higher levels of bilirubin than their haemolysing or sick contemporaries has prompted calls for a more relaxed approach to the management of their jaundice from day 2 or 3 onwards? ,15 Over the past decade, most paediatricians caring for healthy jaundiced newborns in the U K have been willing participants in a cautious relaxation of the threshold for phototherapy from 250 gmol/L to 300-350 gmol/L, and for exchange transfusion from 340 gmol/L to 400-450 gmol/L. In the USA, the call for a 'kinder, gentler approach' to the jaundiced term infant ~5has been incorporated in a 'practice parameter' issued by a subcommittee of the American Academy o f Pediatrics, as summarized in Table 2.16 These guidelines should not be interpreted as a carte blanche for allowing term infants to attain serum bilirubin levels of 500 gmol/L. Evidence supporting the safety of such practice is very sparse beyond bilirubin levels of 425 gmol/L. 15 Ideally, significant changes in management of the well-jaundiced infant should be matched with prospective follow-up studies of neurodevelopmental outcome and audiometry screening. Extension of the current clinical practice of performing formal audiology tests on all infants undergoing exchange transfusion for hyperbilirubinaemia to any term infant with a peak serum bilirubin in excess of 400 gmol/L may help in this respect. Major complications o f jaundice in this group of infants are, however, extremely rare, and perhaps more likely to surface through medical litigation than medical research.
SUMMARY Until such time as safe preventative pharmacological therapies evolve, jaundice will remain the most common clinical sign in the newborn. Advances in the antenatal management of rhesus disease, the effectiveness of phototherapy in preterms, and a gentler approach to the jaundiced term infant have made the need for exchange transfusion a rarity. This does not, however, mean that we can all relax. The yellow peril still exists! The current trend towards earlier postnatal discharge has meant that most babies develop their jaundice at home. It is, therefore, the responsibility of hospital midwives and paediatricians to identify newborns at heightened risk of significant jaundice, and for health professionals in the community to be alert to features suggestive of pathology. G o o d communication between community midwives, health visitors, general practitioners
and the paediatric unit is essential, with an established system for referring babies back to hospital for assessment.
Key points • First day jaundice is pathological until proven otherwise • Every jaundiced baby should be assessed for predisposing risk factors • Phototherapy should not be started without initiating investigations • The diagnosis of breast milk jaundice is made in exclusion • Prolonged jaundice demands enquiry as to the baby's stool and urine colour • Jaundice still present at 3 weeks must be investigated • Conjugated jaundice should be evaluated promptly to identify surgically correctable causes.
REFERENCES 1. Maisels M J. Jaundice. In: AveryG B, Fletcher M A, MacDonald M G, eds. Neonatology:pathophysiologyand management of the newborn, 4th edn. Philadelphia: Lippincott, 1994:630-725. 2. McDonaghA F. Is bilirnbin good for you?Clin Perinatol 1990; 17: 359-369. 3. Maisels M J, Gifford K L. Normal serum bilirubin levels in the newborn and the effect of breast feeding. Pediatrics 1986; 78: 837-843. 4. MaiselsM J. NewmanT B. Kernicterus occurs in otherwise healthy, breast-fed term newborns. Pediatrics 1995;96: 730-733. 5. Gourley (3 R. Pathophysiologyof breast milkjaundice. In: Polin R A, Fox W W, eds. Fetal and neonatal physiology. Philadelphia: Saunders, 1992:1173-1179. 6. VolpeJ J. Neurologyof the newborn, 3rd edn. Philadelphia: Saunders, 1995:490-515. 7-. AhlforsC E. Criteria for exchangetransfusion in jaundiced newborns. Pediatrics 1994;93: 488494. 8. Kramer L I. Advancementof dermal icterus in the jaundiced newborn. Am J Dis Child 1969; 118:454458. 9. Yao T C, StevensonD K. Advancesin the diagnosis and treatment of neonatal hyperbilirubinaemia. Clin Perinatol 1995; 22: 741-758. 10. EnneverJ E Phototherapy for neonataljaundice. In: Polin R A, Fox W W, eds. Fetal and neonatal physiology. Philadelphia: Saunders, 1992:1165-1173. 11. Tan K L. Comparisonof the efficacyof fiberopticand conventional phototherapy for neonatal hyperbilirubinaemia. J Pediatr 1994; 125:607-612. 12. Rubo J, Albrecht K, Lasch Pet al. High dose intravenous immune globulintherapy for hyperbilirubinaemia caused by Rh haemolyticdisease. J Pediatr 1992; 121:93-97. 13. WatchkoJ F, Oski F A. Kernicterus in preterm newborns: past, present, and future. Pediatrics 1992;90:707-715. 14. IvesN K. Kernicterus in preterm infants: lest we forget (to turn on the lights). Pediatrics 1992;90: 757-759. 15. NewmanT B, Maisels M J. Evaluation of jaundice in the term newborn: a kinder, gentler approach. Pediatrics 1992;89" 809-818. 16. Provisionalcommittee for quality improvementand subcommittee on hyperbilirubinaemia. Practice parameter: management of hyperbilirubinaemia in the healthy term newborn. Pediatrics 1994;94: 558-565.
Mini-symposium: Neonatology
Neonatal jaundice
N. K. Ives
Jaundice is the most common clinical sign in neonatal medicine. Physiological jaundice, in the majority of term infants, merits neither investigation nor treatment. Vigilant appraisal of every jaundiced infant is, however, necessary in order to identify the small proportion of newborns with pathological jaundice or those at heightened risk of kernicterus. In the current era of early postnatal discharge from hospital, it is the paediatrician's task to identify those infants most likely to develop significant jaundice. Predictably, neonatal jaundice has become the most common reason for hospital readmission in the first week of life.
conjugated bilirubin entering the gut is hydrolysed by [3-glucuronidase to yield unconjugated bilirubin, which can readily re-enter the serum pool via the enterohepatic circulation.
P H Y S I O L O G I C A L JAUNDICE Under normal circumstances, the bilirubin level in cord blood at birth is in the region of 20-35 gmol/L. In most newborns, this increases postnatally as a result of immaturity of the mechanisms for liver uptake, transport and conjugation of bilirubin. Serum bilirubin peaks on the third to fourth day of life, attaining clinically detectable levels in approximately two-thirds of healthy term infants. 3 After this phase I peak, levels fall rapidly for 2-3 days and then more gradually, reaching normal adult values between 1 and 2 weeks of age (phase II). Phase II may be prolonged in the breast fed infant. Premature infants exhibit a higher peak serum bilirubin level, occurring on days 5 6, and a longer phase II, persisting for 2 4 weeks. Physiological jaundice may be exacerbated by the following:
BILIRUBIN B I O C H E M I S T R Y A N D METABOLISM
Bilirubin is formed as a result of the catabolism of haem in the reticuloendothelial system. ~ Why mammals should expend energy producing and excreting a potentially neurotoxic haem byproduct is not altogether clear. The need for products of fetal haem degradation to be lipophilic, and so able to cross the placenta, is considered important. Another plausible explanation stems from the discovery that bilirtlbin may have a significant antioxidant role to play in the newborn period? Bilirubin is transported in the blood, bound reversibly to albumin. Under normal circumstances the proportion of potentially toxic free bilirubin circulating in the jaundiced newborn is extremely low. Conjugation of bilirubin within the hepatocyte is catalysed by the enzyme, uridine diphosphoglucuronosyl transferase (UDPGT). A significant proportion of
• Polycythaemia Delayed cord clamping Materno-fetal transfusion Recipient of twin-twin transfusion • Extravasated blood Bruising (e.g. cephalhaematoma) Birth trauma Internal haemorrhage • Delayed passage of meconium • Swallowed blood • Hypocaloric feed intake • Dehydration • Breast feeding • Prematurity.
N. KevinIvesMD, ConsultantNeonatologistand Honorary Senior ClinicalLecturer,Neonatal Unit, Departmentof Paediatrics,John RadcliffeHospital, Oxford OX3 9DU, UK. Correspondence and requestsfor offprintsto NKI.
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Current Paediatrics
There has been a tendency to call physiological jaundice pathological if it is >2 SD above large population means (i.e. >220 gmol/L in term and >250 gmol/L in preterm infants). In the absence of a contributory disease process, the term 'exaggerated physiologicaljaundice' is a better description. Exaggerated physiological jaundice may, however, attain unconjugated bilirubin levels capable of transient and, on occasions, permanent neurological damage?
JAUNDICE IN THE HEALTHY BREAST FED INFANT Breast fed babies develop more marked and prolonged jaundice than those who are purely formula fed? Peak bilirubin levels in the breast fed infant may not occur until the fourth to sixth day of life, and up to one-third of breast fed babies remain clinically jaundiced beyond 2 weeks of age. In a few, this may persist for 2-3 months. The diagnosis of breast milk jaundice is made on exclusion of pathological causes. The association between breast feeding and heightened jaundice has recently been reviewed? The pathogenesis would appear to be multifactorial, involving some or all of the following: • Enhanced enterohepatic circulation Delayed passage of meconium ~-glucuronidase in breast milk Altered bacterial colonization of the gut • Impaired bilirubin metabolism Decreased caloric intake Inhibition of UDPGT by: metal ions, steroids, nucleotides and free fatty acids Infrequent and insufficient breast feeds may predispose to severe jaundice through poor caloric intake, excessive weight loss and slow clearance of meconium. An early initial breast feed and frequent subsequent feeds are advocated to lessen the peak bilirubin attained in the breast fed infant.
The imprecise relationship between total serum bilirubin levels and adverse neurological outcome has encouraged research seeking to identify more accurate markers of bilirubin toxicity. Assessment of free bilirubin levels, bilirubin binding capacity, brainstem auditory evoked responses and computer analysis of abnormality of the jaundiced infant's cry have been proposed. Such markers may prove of value in research environments, but are not universally available, or indeed feasible, in the acute clinical situation. More accessible is the bilirubin:albumin ratio, which provides an indirect guide to the free bilirubin level2 THE JAUNDICED INFANT: WHEN TO MEASURE THE SERUM BILIRUBIN Neonatal jaundice becomes clinically apparent when serum bilirubin levels reach 80--90 gmol/L. Newborns jaundiced within 24 h of birth and all preterms with detectable jaundice, regardless of their postnatal age, should have their serum bilirubin measured. Clinical judgement should be exercised in assessing the need to investigate an otherwise healthy term infant, with no known risk factors, who develops jaundice from day 2 onwards. In such an infant, the cephalocaudal progression of dermal jaundice8 can be used as a rough guide as to when to formally determine the serum bilirubin. If dermal jaundice has reached the hands and feet, the serum bilirubin level may be in excess of 300 gmol/L and should be measured. Transcutaneous bilirubinometry may have a role in screening otherwise healthy term and near-term newborns, provided a threshold is established, beyond which invasive assessment is mandatory. Carbon monoxide, being generated in equimolar quantities with bilirubin during haem catabolism, serves as a useful marker of bilirubin production. The accuracy of an automated end-tidal carbon monoxide analyser as an early warning device for significant haemolysis in newborns is currently being assessed. 9 IDENTIFYING PATHOLOGICAL JAUNDICE
BILIRUBIN ENCEPHALOPATHY
The word kernicterus originated as a description of yellow nuclear staining of the brain, but has become synonymous with the acute and chronic neurological sequelae of what is more correctly called bilirubin encephalopathy. The clinical manifestations of bilirubin encephalopathy arise from the susceptibility to damage of the basal ganglia, brainstem auditory pathways and oculomotor nuclei. Bilirubin's toxicity would appear to be that of a generalized cellular poison. Studies point to the importance of coexisting risk factors, such as acidosis, hypoxia, hypercapnia and blood-brain barrier disruption. 6
The more common causes of pathological hyperbilirubinaemia are listed in Boxes 1 and 2. Clinical features that suggest a pathological cause of jaundice and prompt further investigation are as follows: • Jaundice appearing in the first 24 h of life • Jaundice in a sick neonate • Total serum bilirubin level >250 gmol/L on day 2; >300 gmol/L thereafter • Rapidly rising serum bilirubin > 100 gmol/L/24 h • Prolonged jaundice > 14 days in term infants; >21 days in preterm infants • Conjugated serum bilirubin >25 gmol/L • Acholuric stools and dark urine.
Neonatal jaundice Box 1 Causes of unconjugated jaundice in the newborn
Haemolysis Isoimmunization Rhesus ABO Minor blood groups Other Spherocytosis G-6PD deficiency Pyruvate kinase deficiency Sepsis* Disseminated intravascular coagulation Polyeythaemia Small for dates Twin-twin transfusion Delayed cord clamping Materno-fetal transfusion Infant of diabetic mother Extravasated blood Bruising, e.g. cephalhaematoma Pulmonary haemorrhage Cerebral haemorrhage Intra-abdominal haemorrhage Increased enterohepatic circulation Pyloric stenosis Bowel obstruction Swallowed blood Endocrine/metabofic Hypothyroidism Hypopituitarism* Hypoadrenalism* Glucuronosyl transferase deficiency Galactosaemia* Tyrosinosis* Hypermethioninaemia* * Conjugated jaundice often coexists
Box 2 Causes of conjugated jaundice in the newborn
Intrauterine infections Toxoplasmosis Rubella Cytomegalovirus Herpes simplex Coxsackie and other viruses Syphilis Bacterial sepsis Severe haemolysis, e.g. erythroblastosis Prolonged parenteral nutrition Biliary atresia ~l-antitrypsin deficiency Cystic fibrosis Cryptogenic hepatitis Choledochal cyst Inspissated bile plug syndrome Galactosaemia Tyrosinosis Hypermethioninaemia
When assessing the maternal history and examining the jaundiced newborn, particular attention should be paid to the following key diagnostic points: • Maternal and infant blood group and rhesus status • Maternal red cell antibody status • History suggestive of congenital infection • Likelihood of G-6PD deficiency from parental ethnicity
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• Family history of red cell morphological abnormalities, galactosaemia or Crigler Najjar syndrome • History of birth asphyxia and trauma • Clinical signs of polycythaemia, anaemia, hydrops, purpura, cataracts or hepatosplenomegaly • Assessment of maturity and intrauterine growth • Risk factors for, and evidence of, infection • Documentation of syphilis and hepatitis serology • The mode and success of feeding • The infant's state of hydration and weight trend since birth. Appropriate early investigation aims to identify treatable disease states, such as isoimmunization, infection, hypothyroidism, biliary atresia and galactosaemia. Unless there are diagnostic pointers to the more rarely encountered causes of neonatal jaundice, stepwise investigation (Box 3) should aim to identify the more common aetiologies first. Early onset jaundice demands prompt attention to identify possible causes of haemolysis.
PROLONGED JAUNDICE Visibly detectable jaundice beyond 2 weeks of age in the term infant and 3 weeks in the preterm merits the description 'prolonged jaundice'. The majority of term infants presenting with prolonged jaundice exhibit an unconjugated hyperbilirubinaemia and will be breast feeding. Providing there are no features in the history or on clinical examination that suggest a pathological cause, the following screening investigations can be safely performed between 2 and 3 weeks of age: • • • • • •
Total and conjugated serum bilirubin Full blood count including reticulocytes Examination of blood film Thyroid function tests Urinalysis for reducing sugars (Clinitest) Urine culture.
Further tests will be indicated according to the outcome of this initial screen. A more direct approach to investigations is necessary in cases where a specific pathology, such as biliary atresia, is suspected. CONJUGATED JAUNDICE Definitions of conjugated hyperbilirubinaemia vary. A serum conjugated bilirubin level of >25 gmol/L is a commonly adopted cut-off. Pale acholuric stools and dark bile-stained urine are the clinical markers of established conjugated jaundice, but neither may be present in the first weeks of many hepatic disease states, including biliary atresia. Diagnosis of an associated clotting disorder and its correction are urgent
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Current Paediatrics
Box 3 Investigationof jaundicein the newborn Early onset jaundice
Bloodgroupand DCT Haematocritand FBC Bloodfilmand reticulocytecount Infectionscreenif indicated Serologyfor congenitalinfections Urine for CMVculture Stoolfor virology G-6PD screen Red cellenzymeassays Prolongedjaundice Total and conjugatedserumbilirubin Thyroidfunctiontests Urine culture Urine Clinitestfor reducingsubstances Liverfunctiontests cd-antitrypsinassayand phenotype CysticFibrosisDNA screen Immunoreactivetrypsin Plasmacortisollevel Serumaminoacidscreen
requirements in the infant with conjugated jaundice. Several conditions present with a mixture of raised unconjugated and conjugated bilirubin. Notable amongst these are the intrauterine infections, bacterial sepsis, galactosaemia, aminoacidaemias and congenital hypopituitarism. If an obstructive aetiology is suspected, liver ultrasound and HIDA scan will be indicated. Visualization of the gallbladder on ultrasound does not rule out biliary atresia. The importance of making an early diagnosis of biliary atresia and the patient's prompt referral to a centre specializing in the management of childhood liver disorders cannot be overstated.
CLINICAL MANAGEMENT OF T H E JAUNDICED INFANT The different modes of treatment of unconjugated jaundice are shown below: • Phototherapy • Exchange transfusion • Pharmacological agents Competitive inhibition of haem oxygenase, e.g. metalloporphyrins Liver enzyme induction, e.g. phenobarbitone Suppression of isoimmune haemolysis, e.g. intravenous immunoglobulin Inhibition of the enterohepatic circulation, e.g. agar and cholestyramine. Phototherapy
Phototherapy detoxifies bilirubin and facilitates its excretion from the body via routes other than conjugation in the liver. The biochemical basis of phototherapy has been well reviewed?° Phototherapy is safe and convenient and reduces the need for exchange
transfusion. However, phototherapy's ease of use has encouraged its overuse. Many newborns are 'placed under the lights' unnecessarily or treated for too long. The vogue for 'prophylactic' phototherapy from birth in very low birth weight infants has been shown to neither reduce the peak nor shorten the duration of their jaundice. Phototherapy would only appear to be effective as bilirubin enters the skin at serum levels >80 gmol/L. The recently developed fibreoptic systems for delivering phototherapy via a body pad or wrap have made its application more versatile. These devices are likely to gain greater acceptance in the context of healthy term infants nursed without eye pads and alongside their mothers. Trials have shown fibreoptic phototherapy to be as effective as conventional phototherapy in preterm infants, but less so in term infants. 11 The dose of phototherapy administered is conventionally expressed in terms of spectral irradiance (gW/cm2/nm). Before the mechanism of phototherapy was better understood, it was thought that saturation of dose-response occurred within the blue light range at a spectral irradiance of 4 gW/cm2/nm. This is true of the configurational isomer bilirubin-Z,E. However, it is now known that production of the more important structural photoisomer, lumirubin, has a dose-response relationship that does not attain saturation until a spectral irradiance of 25-30 gW/cm2/nm is achieved?° Exchange transfusion
Exchange transfusion will remain necessary for infants who fail to respond to adequate phototherapy or who present late with bilirubin levels in excess of exchange values. In the latter case, the baby should be placed under 'double phototherapy', pending the availability of blood for the exchange. Attention should be paid to correcting disturbances of hydration or acid-base balance, and to the treatment of any underlying infection. Pharmacological agents
Competitive inhibition of haem oxygenase by synthetic metalloporphyrins has been the most promising recent therapeutic development. The therapeutic potential of tin, zinc and chromium metalloporphyrins and their possible side-effects are discussed in a recent review.9 These agents are likely to find a role in the preventive treatment of certain populations at high risk of significant pathological jaundice or where conventional management with phototherapy and exchange transfusion is less readily available. Their more widespread use in neonatal jaundice will depend on their safety record. Another preventive therapy that may be of benefit to newborns presenting with severe rhesus or ABO isoimmunization is early administration of high dose
Neonatal jaundice intravenous ~-globulin. This treatment has been shown to inhibit haemolysis and significantly reduce the need for exchange transfusion in Rh incompatibility.~2 Phenobarbitone has been given antenatally in the context of rhesus disease to accelerate fetal maturation of liver conjugation. New inducers of UDPGT, lacking the sedative effects of phenobarbitone and designed for postnatal use, are currently under investigation. Attempts to limit the enterohepatic circulation of bilirubin with agents such as agar and cholestyramine, or by hastening the passage of meconium, have not provided clinically useful results. Guidelines for the use of phototherapy and exchange transfusion
The optimal use of phototherapy The efficacy of phototherapy can most readily be improved by attention to the dose of light used, and the proportion of the newborn's surface area of skin to which it is applied. Increasing the dose of phototherapy is achieved by operating the light source at the minimum recommended safe distance from the infant. Care must be taken to avoid over-heating. In order to maximize the area of skin exposed to treatment, more than one phototherapy unit can be used. Double phototherapy is most conveniently achieved by nursing the baby on a fibreoptic phototherapy pad whilst applying one or more conventional phototherapy units from above. There continues to be much debate as to which is the optimal wavelength of light to use. Pure blue light is poorly tolerated by staff and can mask cyanosis in a sick infant. Combinations of broad-spectrum white and blue light have proved more acceptable. There are theoretical reasons why green light phototherapy would be the most effective choice. Compared with blue light, green preferentially favours formation of lumirubin, the main excretory photoisomer, and its longer wavelength enhances skin penetration. ~° Comparative trials of these various colour combinations are difficult to interpret because the appliances are rarely matched for spectral irradiance. The fact that it takes up to 3 h for bilirubin to return to the skin following removal of photoisomers has prompted intermittent phototherapy regimes based on 1 in 4 h exposure to lights. It should be recognized that claims that such regimes have been shown to be
Table 1 Guidelines for treatment of preterms with phototherapy
and exchange transfusion Gestational age (weeks)
Serum bilirubin concentration (gmol/L) Phototherapy Exchange transfusion Sick* Well
36 32 28 24
250 150 100 80
300 250 200 150
Age(h)
25-48 49 72 >72
350 300 250 200
*Rh disease, perinatal asphyxia, hypoxia, acidosis, hypercapnia.
equally effective as continuous phototherapy are based on experience with mild to moderate physiological jaundice. Jaundice that has reached a level within 50 gmol/L of the exchange threshold should be treated with continuous phototherapy.
Treatment thresholds Newborns with haemolysis and those born prematurely would appear to be at heightened risk of bilirubin neurotoxicity.1 It is prudent to maintain our respect for a total bilirubin level of 340 gmol/L (20 mg/dL) in the term infant with haemolysis, and to use sliding scales prompting earlier intervention on the basis of gestational age (Table 1). Having grown up with this interventionalist approach, few recently trained paediatricians will have witnessed the acute effects of bilirubin toxicity.
Haemolytic disease of the newborn (HDN). Previous guidelines for early exchange transfusion in HDN based on cord blood values no longer apply, as most severely affected infants will have received in utero transfusion. The haematocrit and a Kleihauer estimation of the proportion of circulating fetal red cells are more relevant. Many such infants, adequately treated in utero, respond to intensive phototherapy followed by top-up transfusion. If, despite double phototherapy, the serum bilirubin continues to rise by more than l0 gmol/L/h, exchange transfusion is to be anticipated. Preterm infants. Phototherapy should be commenced and investigations initiated in all preterm infants who become clinically jaundiced within the first 24 h of life. From the second day onwards, phototherapy and exchange transfusion should be considered if the serum bilirubin has reached the values shown in Table 1.
Table 2 Management of jaundice in the healthy term newborn: American Academy of Pediatrics Guidelines.
Reproduced by kind permission of
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P e d i a t r i c s ~6
Consider phototherapy
Total serum bilirubin level (gmol/L) Phototherapy Exchange if intensive phototherapy fails*
Exchange and intensive phototherapy
> 170 >260 _>290
>260 _>310 _>340
>430 _>510 _>510
>340 >430 _>430
*Failure of intensive phototherapy to reduce serum bilirubin by 17-34 gmol/L within 4-6 h.
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Current Paediatrics
On current evidence, calls to greatly relax such an approach to jaundice in the preterm population should be resisted, m4
Healthy term infants. The fact that healthy term infants would appear to tolerate higher levels of bilirubin than their haemolysing or sick contemporaries has prompted calls for a more relaxed approach to the management of their jaundice from day 2 or 3 onwards? ,15 Over the past decade, most paediatricians caring for healthy jaundiced newborns in the U K have been willing participants in a cautious relaxation of the threshold for phototherapy from 250 gmol/L to 300-350 gmol/L, and for exchange transfusion from 340 gmol/L to 400-450 gmol/L. In the USA, the call for a 'kinder, gentler approach' to the jaundiced term infant ~5has been incorporated in a 'practice parameter' issued by a subcommittee of the American Academy o f Pediatrics, as summarized in Table 2.16 These guidelines should not be interpreted as a carte blanche for allowing term infants to attain serum bilirubin levels of 500 gmol/L. Evidence supporting the safety of such practice is very sparse beyond bilirubin levels of 425 gmol/L. 15 Ideally, significant changes in management of the well-jaundiced infant should be matched with prospective follow-up studies of neurodevelopmental outcome and audiometry screening. Extension of the current clinical practice of performing formal audiology tests on all infants undergoing exchange transfusion for hyperbilirubinaemia to any term infant with a peak serum bilirubin in excess of 400 gmol/L may help in this respect. Major complications o f jaundice in this group of infants are, however, extremely rare, and perhaps more likely to surface through medical litigation than medical research.
SUMMARY Until such time as safe preventative pharmacological therapies evolve, jaundice will remain the most common clinical sign in the newborn. Advances in the antenatal management of rhesus disease, the effectiveness of phototherapy in preterms, and a gentler approach to the jaundiced term infant have made the need for exchange transfusion a rarity. This does not, however, mean that we can all relax. The yellow peril still exists! The current trend towards earlier postnatal discharge has meant that most babies develop their jaundice at home. It is, therefore, the responsibility of hospital midwives and paediatricians to identify newborns at heightened risk of significant jaundice, and for health professionals in the community to be alert to features suggestive of pathology. G o o d communication between community midwives, health visitors, general practitioners
and the paediatric unit is essential, with an established system for referring babies back to hospital for assessment.
Key points • First day jaundice is pathological until proven otherwise • Every jaundiced baby should be assessed for predisposing risk factors • Phototherapy should not be started without initiating investigations • The diagnosis of breast milk jaundice is made in exclusion • Prolonged jaundice demands enquiry as to the baby's stool and urine colour • Jaundice still present at 3 weeks must be investigated • Conjugated jaundice should be evaluated promptly to identify surgically correctable causes.
REFERENCES 1. Maisels M J. Jaundice. In: AveryG B, Fletcher M A, MacDonald M G, eds. Neonatology:pathophysiologyand management of the newborn, 4th edn. Philadelphia: Lippincott, 1994:630-725. 2. McDonaghA F. Is bilirnbin good for you?Clin Perinatol 1990; 17: 359-369. 3. Maisels M J, Gifford K L. Normal serum bilirubin levels in the newborn and the effect of breast feeding. Pediatrics 1986; 78: 837-843. 4. MaiselsM J. NewmanT B. Kernicterus occurs in otherwise healthy, breast-fed term newborns. Pediatrics 1995;96: 730-733. 5. Gourley (3 R. Pathophysiologyof breast milkjaundice. In: Polin R A, Fox W W, eds. Fetal and neonatal physiology. Philadelphia: Saunders, 1992:1173-1179. 6. VolpeJ J. Neurologyof the newborn, 3rd edn. Philadelphia: Saunders, 1995:490-515. 7-. AhlforsC E. Criteria for exchangetransfusion in jaundiced newborns. Pediatrics 1994;93: 488494. 8. Kramer L I. Advancementof dermal icterus in the jaundiced newborn. Am J Dis Child 1969; 118:454458. 9. Yao T C, StevensonD K. Advancesin the diagnosis and treatment of neonatal hyperbilirubinaemia. Clin Perinatol 1995; 22: 741-758. 10. EnneverJ E Phototherapy for neonataljaundice. In: Polin R A, Fox W W, eds. Fetal and neonatal physiology. Philadelphia: Saunders, 1992:1165-1173. 11. Tan K L. Comparisonof the efficacyof fiberopticand conventional phototherapy for neonatal hyperbilirubinaemia. J Pediatr 1994; 125:607-612. 12. Rubo J, Albrecht K, Lasch Pet al. High dose intravenous immune globulintherapy for hyperbilirubinaemia caused by Rh haemolyticdisease. J Pediatr 1992; 121:93-97. 13. WatchkoJ F, Oski F A. Kernicterus in preterm newborns: past, present, and future. Pediatrics 1992;90:707-715. 14. IvesN K. Kernicterus in preterm infants: lest we forget (to turn on the lights). Pediatrics 1992;90: 757-759. 15. NewmanT B, Maisels M J. Evaluation of jaundice in the term newborn: a kinder, gentler approach. Pediatrics 1992;89" 809-818. 16. Provisionalcommittee for quality improvementand subcommittee on hyperbilirubinaemia. Practice parameter: management of hyperbilirubinaemia in the healthy term newborn. Pediatrics 1994;94: 558-565.