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Current Paediatrics (2005) 15, 85 91

www.elsevier.com/locate/cupe

Investigation of prolonged neonatal jaundice

Nandiran Ratnavela, N. Kevin Ivesb,
a

Neonatal Transport Service, 1st Floor, Old Home, Royal London Hospital, Whitechapel Road, London E1 1BB, UK b Neonatal Unit, Womens Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK

KEYWORDS
Newborn; Neonatal; Hyperbilirubinaemia; Prolonged jaundice; Breast-milk jaundice; Conjugated bilirubin; Biliary atresia; Screening

Summary How to assess the infant with prolonged jaundice is a common clinical concern for health visitors, general practitioners and paediatricians. Over the past decade in the UK there have been attempts to co-ordinate a national screening programme for extra-hepatic biliary atresia. A reliable methodology would appear to be elusive. Currently, a variety of approaches to screening the baby with prolonged jaundice are being adopted. Most jaundice beyond 2 weeks of age in the term infant is associated with breastfeeding and, as such, is benign. Rarely, however, prolonged jaundice is the marker for a range of haematological, hepatobiliary, metabolic, endocrine, infectious and genetic disorders that are associated with signicant morbidity. Thorough clinical assessment is warranted in all cases of prolonged jaundice, but the threshold and range of investigation remain debatable. A reliable diagnosis of breast-milk jaundice can only be made on exclusion of pathological causes. A diagnosis of conjugated hyperbilirubinaemia prompts urgent further investigation. In all cases of neonatal hepatitis syndrome blood coagulation must be assessed if presentation with catastrophic haemorrhage is to be avoided. This article describes breast-milk jaundice and covers several of the more common pathologies that may present with prolonged jaundice. A clinical approach to investigation is provided based on current evidence. & 2005 Elsevier Ltd. All rights reserved.

Practice points

    

 

Jaundice beyond 2 weeks in the breast-fed infant is common The commonest cause of prolonged jaundice is breast-milk-related and benign
author. Tel.: +44 1865 221 358; fax:

Corresponding

+44 1865 228 985. E-mail address: kevin.ives@orh.nhs.uk (N.K. Ives). 0957-5839/$ - see front matter & 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.cupe.2004.12.014

A condent diagnosis of breast-milk jaundice follows exclusion of pathology History and clinical evaluation help to guide investigation of prolonged jaundice Screening must aim to detect biliary atresia in a surgically favourable phase Several causes of prolonged jaundice require urgent dietary or endocrine manipulation The formula-fed baby with prolonged jaundice is likely to have a pathological cause

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86 N. Ratnavel, N. K. Ives

Remember the risk of catastrophic haemorrhage in many cases of conjugated jaundice

Bilirubin metabolism
Bilirubin is a product of the breakdown of haemcontaining proteins and comes largely from haemoglobin released by red cells, but with a contribution from myoglobin and cytochromes. Haem is oxidised in a two-stage catabolism to biliverdin and iron within the reticuloendothelial system and biliverdin is subsequently reduced to bilirubin. Bilirubin is lipid soluble and only becomes sufciently water soluble to enter the bile following hepatic conjugation with glucuronic acid, in a reaction catalysed by the enzyme uridine diphosphoglucuronosyl transferase. Conjugated bilirubin passes into the bile and the intestine to be hydrolysed by bacteria and converted to urobilinogen, which itself is oxidised to stercobilin. It is stercobilin that gives stool its colour. In the absence of bilirubin entering the gut, the stool takes on a pale clay colour (acholic stool). In the newborn, a signicant proportion of conjugated bilirubin is hydrolysed by b-glucuronidase in the small gut to yield unconjugated bilirubin, which re-enters the circulating pool via the entero-hepatic circulation. b-glucuronidase in breast milk is thought to contribute to some cases of prolonged jaundice in this manner.

blood sample for a split bilirubin assay from babies reported in the community to have prolonged jaundice. In this case, an abnormal conjugated bilirubin level prompts further testing. Another approach has been to develop a mechanism for referral of jaundiced babies back from the community for assessment on the ward or attendance at a prolonged jaundice clinic run by a neonatal nurse practitioner, or junior paediatrician. We favour the prolonged jaundice clinic approach until such a time that community observation alone can be proven to be safe. Critics of this approach may argue that it screens for a wider range of pathologies than was originally envisaged by the yellow peril biliary atresia awareness campaigns and unless implemented well with an educational component it has the potential to raise parental anxiety.

Breast-milk jaundice
Breastfed babies develop more marked and prolonged jaundice than those who are purely formulafed. Up to one-third of breastfed babies remain clinically jaundiced beyond 2 weeks of age and they represent the clear majority of infants presenting for a prolonged jaundice screen. Several hypotheses have been put forward to explain the association between breastfeeding and heightened jaundice. There appears to be an early and a late phase to such jaundice and a valiant attempt to distinguish these phases as breastfeeding jaundice and breast-milk jaundice has been made.2 Causes are likely to be multifactorial with overlap between the two phases. Lower-calorie intake and slower passage of meconium during the rst week in the breast-fed infant are implicated in the early phase. In some cases, the term lack-of-breast-milk jaundice may be more applicable. The second phase is considered to be related to enhanced enterohepatic circulation of bilirubin. The presence in breast milk of b-glucuronidase, which unconjugates bilirubin in the infant gut, thus enabling it to re-enter the circulation, is thought to be contributory. Altered bacterial colonisation of the gut in the breastfed baby with a resultant decrease in the conversion of bilirubin glucuronides to urobilinoids may also play a role. Inhibition of hepatic conjugation has been postulated, but most of the mechanisms advanced have been disproved.3 There has been recent interest shown in the potential confounding inuence of Gilberts syndrome in prolonged jaundice,4 just as it has been implicated in severe hyperbilirubinaemia and

Prolonged jaundice
Prolonged jaundice can be dened as visibly detectable hyperbilirubinaemia beyond 2 weeks of age in a term infant and 3 weeks in a preterm. The majority of term infants presenting with prolonged jaundice have unconjugated hyperbilirubinaemia and will be breastfeeding. Providing there are no features in the history or on clinical examination that suggest a pathological cause (in particular, the urine and stool colour are normal and the baby is thriving), screening can be safely deferred until 3 weeks of age. The form that this screening takes varies widely in different UK settings. There are those1 who suggest that there should be evaluation of community screening of stool colour and infant heath on day 28. The threshold for further investigation being a high suspicion of neonatal hepatitis syndrome. Others have developed an approach whereby a community nurse obtains a

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Investigation of prolonged neonatal jaundice kernicterus in combination with dual pathology, such as glucose-6-phosphate dehydrogenase deciency (G6PD).5 A reliable diagnosis of breast-milk jaundice can only be made on exclusion of pathological causes.5 A sensible quest for a potentially harmful underlying cause of prolonged jaundice should be undertaken. Once the probable diagnosis of breast-milk jaundice is made, parents should be advised that, although it is likely to peak at 23 weeks, resolution of the jaundice might take as long as 23 months. They should be told to report back if the nature of the jaundice changes (more marked, pale stools, dark urine), there is failure to thrive or the jaundice persists beyond 23 months. Although the interruption of breast-milk feeds and supplementation with formula for 2448 h may be associated with a marked decline in serum bilirubin and lower rebound on re-introduction, the practice is rarely justied. It should be reserved for cases where the total serum bilirubin is approaching 400 mmol/L and other pathologies have been excluded. Also to be discouraged is the vogue for supplementing jaundiced breastfed infants with water, regardless of their state of hydration. Such practice does not hasten bilirubin excretion.5
Table 1 1. 2. Causes of prolonged jaundice. Breast milk jaundice Haemolysis Coombs positive Rhesus incompatibility Anti-Kell, anti-Duffy ABO incompatibility Coombs negative Red cell membrane defects e.g. sphero/ elliptocytosis Red cell enzyme defects e.g. G6PD, pyruvate kinase deciency Haemoglobinopathy Sepsis Disseminated intravascular coagulation Increased enterohepatic circulation Pyloric stenosis Intestinal obstruction Functional ileus Decreased conjugation (unconjugated) CriglerNajjar syndrome Gilberts disease Hypothyroidism Prematurity Decreased excretion (conjugated) Obstruction Biliary atresia Choledochal cyst Spontaneous bile duct perforation Hepatoblastoma, haemangioma, neuroblastoma Infection Septicaemia, UTI TORCH infections, syphilis Hepatitis, Varicella zoster, HIV and other viral7 Inherited/metabolic/endocrine a1-antitrypsin deciency Alagilles syndrome Cystic brosis Galactosaemia, fructosaemia Glycogen storage diseases Tyrosinosis Hypermethioninaemia Hypopituitarism/hypoadrenalism Mytochondrial cytopathies PFIC syndromes Chromosomal disorders Turners syndrome Trisomy 13, 18, 21 Toxic/drugs Fetal alcohol syndrome Chloral hydrate, rifampicin, erythromycin Ideopathic neonatal hepatitis

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Investigation of prolonged jaundice

A list of some of the causes of prolonged neonatal jaundice is provided in Table 1. This list appears dauntingly long, but it should be remembered that many of these conditions are extremely rare. It would be unrealistic to commence screening investigations to exclude all listed causes. Indeed, this list is not as comprehensive as that supplied by tertiary paediatric hepatologists,6,7 who should be consulted if a diagnosis is proving elusive. Clinical evaluation with a full history and examination will either provide the diagnosis in a case of prolonged jaundice, or focus the direction of investigations beyond the initial screening tests. Examples of these clinical leads for causes of prolonged jaundice are provided in Table 2. A greater index of suspicion should be observed in assessing an exclusively formula-fed infant with prolonged jaundice and in cases of parental consanguinity. Where there is a high unconjugated but normal conjugated bilirubinaemia, the haematological causes should be pursued and Type II CriglerNajjar syndrome borne in mind. The presence of severe anaemia prompts the urgent consideration of an appropriate batch of investigations to be performed prior to blood transfusion. The conjugated

G6PD, glucose-6-phosphate dehydrogenase deciency; UTI, urinary tract infection; TORCH, Toxoplasmosis, Rubella, Cytomegalovirus and Herpes; HIV, human immunodeciency virus; PFIC, progressive familial intrahepatic cholestasis.

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Table 2 Prolonged jaundice: diagnostic clues from the history and examination. Breastmilk jaundice Healthy, breast-fed baby No family history No clinical signs suggestive of pathology Haemolysis Family history of haemolytic disease Had there been early onset jaundice (o24 h)? Pallor, hepatosplenomegaly Ethnic background (G6PD deciency) Galactosaemia Vomiting Lethargy Poor feeding Hepatosplenomegaly Coliform sepsis Cystic brosis Family history Echogenic bowel on antenatal scan Delayed passage of meconium Intestinal obstruction Pyloric stenosis Hypothyroidism Lethargy Hoarse cry Poor temperature control Macroglossia Dry skin Congenital infection Maternal febrile illness in pregnancy IUGR Purpuric rash, thrombocytopaenia Hepatosplenomegaly Inherited/metabolic Family history Hepatomegaly Congenital dysmorphic syndromes Septo-optic dysplasia, hypoglycaemia, hypopituitarism (micropenis in male) Alagilles syndrome Drug related Maternal and neonatal drug history Chromosomal Phenotypic features of Turners syndrome, trisomies 13, 18, 21 Obstructive jaundice Pale stools (43 consecutive acholic stools) Dark urine
G6PD, glucose-6-phosphate dehydrogenase deciency; IUGR, intrauterine growth retardation.

N. Ratnavel, N. K. Ives

Conjugated hyperbilirubinaemia
Denitions of conjugated hyperbilirubinaemia vary. Serum conjugated bilirubin levels of above 20, 25 or 30 mmol/L are commonly adopted cut-offs. We use 25 mmol/L. Adopting percentage values of the total serum bilirubin as an upper limit of normal for conjugated jaundice may be falsely reassuring in cases of high total values. Several conditions present with a mixture of raised unconjugated and conjugated bilirubin. Notable among these are the intrauterine infections, bacterial sepsis, galactosaemia, aminoacidaemias and congenital hypopituitarism. Neonatal hepatitis syndrome is the collective name given to a varied group of disorders that result in a combination of conjugated hyperbilirubinaemia, decreased or absent bile ow, dark urine and pale acholic stools. Neonatal hepatitis syndrome occurs in one in 25003000 live births.8 Investigation of such patients may be directed by family history or specic clinical ndings, but is likely to depend on a stepwise approach to the differential diagnosis with particular emphasis being placed on early diagnosis of biliary atresia.8 In as many as one-third of cases no specic cause is identied, thus leaving a group collectively known as idiopathic neonatal hepatitis. This is a diagnosis that carries a favourable prognosis with all but 10% showing full recovery within the rst year of life. Some of this group are acquiring diagnostic labels, as causes are being discovered.7 Coincident with investigation of the cause of neonatal hepatitis syndrome, it is mandatory to assess any liver-related clotting disorder and to treat any co-existing coagulopathy. Failure to respond to parenteral vitamin K would be an ominous reection on liver function.

Biliary atresia
Biliary atresia has an incidence of 1:14,000 live births. Successful outcome from a Kasai portoenterostomy is favoured if surgery is performed before eight weeks of age.8 The baby with biliary atresia is likely to be appropriately grown at birth and may continue growing normally in the rst months of life. It is a common misconception that all babies with biliary atresia show early failure to thrive. The passage of normally pigmented stool can occur in up to 30% of cases in the rst weeks of life and does not rule out an evolving diagnosis with progression to acholic stool and hepatomegaly.8 This time course is in keeping with the recognised pattern of a progressive obliteration of

hyperbilirubinaemias are pathological until proven otherwise and particular attention should be directed towards treatable causes and any associated coagulopathy.

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Investigation of prolonged neonatal jaundice extra-hepatic ducts. Radiology may be helpful, but liver biopsy is usually necessary to help provide a diagnosis. Abdominal ultrasound, preferably after a between-feed fast, may reveal absence of the gallbladder, but the presence of a gallbladder, albeit small in many cases of biliary atresia, does not rule out the diagnosis. Ultrasound is, however, more useful in the diagnosis of choledochal cyst. Radioisotope hepatobiliary excretion studies using an immino-diacetic acid derivative often raise diagnostic expectations, but they are more useful in conrming bile duct patency in equivocal cases than they are in making a diagnosis. Severe intrahepatic cholestasis of various aetiologies will give a non-excretory picture mimicking biliary atresia. Pretreatment with phenobarbitone (5 mg/kg/day for three days) will improve the chance of achieving a successful excretory study, as will repeated imaging for up to 24 h postinjection. It cannot be stressed too strongly that communication with a specialist paediatric hepatology service and timely referral are essential if optimal diagnostic and surgical management of biliary atresia is to be achieved.7,9 Experienced interpretation of a percutaneous liver biopsy performed in such centres will conrm the diagnosis of biliary atresia in the majority of cases. In some instances, endoscopic retrograde cholangiopancreatography is a necessary step in diagnosis. 89 prolonged parenteral nutrition, had intermittent enteral feeds, recurrent sepsis and, in many cases, abdominal surgery with gut resection. The nutritional and medical supportive management of such patients is important, with close attention to coagulation disorders.6 How long one holds off from a search for dual pathology with a prolonged jaundice screen is for individual practice. We would suggest further investigation if a progressive deterioration in liver function is seen and if there are clues to an additional disease process. A high level of suspicion of infection and, in particular, line sepsis, should be adopted with prompt treatment. Discussion with a paediatric hepatologist will be helpful with respect to the timing of denitive investigation for biliary atresia in the ex-preterm population. There is often a preference for allowing a baby to reach term equivalent post-conceptual age or a target weight.

Community assessment of prolonged jaundice

A pilot community screening programme in Shefeld in the mid 1990s1 aimed to assess whether stool and urine colour charts used by parents and primary health care staff could be of assistance in identifying cases of signicant prolonged jaundice in well breast-fed term babies. Of 3661 babies recruited, 127 were found to be clinically jaundiced by their health visitor on day 28 and, of these, all but two were breast-fed. The presence of prolonged jaundice in bottle-fed infants was considered sufcient grounds to merit immediate referral. All babies with prolonged jaundice had blood taken for split bilirubin (total and conjugated) and liver function tests (LFTs). None of this group had abnormal stool or urine colour and none were found to have liver disease. Ten babies had a conjugated bilirubin level greater than 20 mmol/L, but none greater than 26 mmol/L. The LFTs, gammaglutamyl transferase (GGT) and alanine aminotransferase (ALT), gave results above the reference range used in approximately one-fth of cases. Four non-jaundiced infants passed pale stools on three or less occasions. Observation of urine colour proved too difcult to be reliably assessed. The authors of the study1 concluded that jaundiced breastfed babies who are well are unlikely to have serious disease and that elevated LFTs are compatible with a diagnosis of breast-milkrelated jaundice. Of these comments, the former cannot be sustained from such a small group and

Alpha-1-antitrypsin deciency
Assessment of alpha-1-antitrypsin levels and phenotyping will reveal cases of abnormal protease inhibitors (Pi). The PiZZ, Pinulnul and PiZnul variants are associated with liver disease in infancy and pulmonary emphysema in later life. Any vitamin-K-responsive coagulopathy should be sought and treated in cases with ongoing hepatic derangement. The prognosis is variable.6,7 Severe forms of alpha-1-antitrypsin deciency are difcult to distinguish from biliary atresia and since the protease level may be falsely elevated into the normal range in the context of hepatitis or infection, the phenotype should always be determined.7

Cholestatic jaundice and prolonged parenteral nutrition

Hospital-based paediatricians are more commonly presented with the cholestatic jaundice picture seen in prematurely born infants who have received

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90 the latter may reect the inaccuracy of the reference ranges for the LFTs being used. If an upper limit of normal of 25 mmol/L had been adopted for conjugated bilirubin, and GGT and ALT had not been included as part of the rst-phase investigations for prolonged jaundice, there would have been just one false positive value in this cohort. Performing additional LFTs and, in particular, liver enzymes, with the initial screen has the tendency to throw up borderline or raised values, which, in the absence of a conjugated hyperbilirubinaemia, become the focus of unnecessary further investigation. Looking at split serum bilirubin screening alone for biliary atresia and other causes of signicant neonatal liver disease has been suggested and a feasibility study conducted.10 However, this approach remains to be progressed. N. Ratnavel, N. K. Ives with the following being performed at 3 weeks of age:

    

total and conjugated serum bilirubin haematocrit urine culture stool inspection for bile pigmentation G6PD level in black, Asian and Mediterranean infants

It could be argued that these selective screening tests could be streamlined further. The key investigations in an infant in whom clinical anaemia is not suspected are

 

serum bilirubin, total and conjugated urine test-strip for protein, red cells, nitrites and leucocyte esterase

What should constitute an initial prolonged jaundice screen?

A prospective study at Kings College Hospital, London over a 17-month period looked at the referral pattern for prolonged jaundice and the yield of diagnoses from their screening programme.11 The existing protocol was that all infants jaundiced at 14 days of age should be referred for assessment. They recorded 154 referrals for prolonged jaundice from a live birth population of 7139. In a community with a breastfeeding rate of 65% at age ten days, this 2% referral rate reects signicant under-reporting of prolonged jaundice. Of the cases referred, nine (6%) had associated pathology. This would appear to be a surprisingly high yield from screening and suggests a degree of selection on grounds of clinical suspicion in several of the cases. One infant had a conjugated hyperbilirubinaemia due to giant cell hepatitis. G6PD deciency was detected in three cases and urinary tract infection in two cases. Failure to regain birthweight by day 16 was implicated in one case. The remaining two cases (hepatoblastoma and trisomy 9p) were serendipitous ndings on clinical examination at hospital assessment. The authors stressed that clinical examination by a paediatrician or experienced nurse practitioner is an important component of the screening process. They also took the view that in the absence of a raised conjugated bilirubin, other LFTs were unhelpful due to the wide range of normal values during the neonatal period.11 Following the study, their investigations were streamlined in keeping with their local population,

If anaemia is suspected on clinical grounds a full blood count, lm and Group and Coombs can be added to the initial screen. If the jaundice is more than mild at this stage it may be prudent to add a G6PD screen in black, Asian and Mediterranean babies. If the community heel prick screen for hypothyroidism has not been performed, thyroid function tests should be performed. Abnormal urinalysis will prompt a formal urine culture. If the jaundice is pronounced, bilirubinometer estimation should be obtained before the baby returns home, or a same day laboratory value guaranteed. The traditional practice of testing the urine for reducing sugars at this stage is probably unnecessary. Cases of galactosaemia will be discovered as part of the work-up for a conjugated hyperbilirubinaemia. Once the differentiation between conjugated, unconjugated and mixed hyperbilirubinaemia has been made, the decision as to which batch of further investigations should be performed may be aided by consideration of clues elicited from the history and the physical examination (Table 2). Otherwise, it is a case of a progression through the tests associated with the conditions that form the differential diagnosis (see Table 1 and references6,7). Treatable and more common causes should be sought rst. Greater urgency and a more direct approach to specic investigations are necessary in cases where a specic pathology, such as biliary atresia, is suspected. In all cases of conjugated hyperbilirubinaemia clotting studies are mandatory.

References
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Investigation of prolonged neonatal jaundice
prolonged jaundice in infancy. Acta Paediatr 1999;88: 96974. Gartner LM. Breastfeeding and jaundice. J Perinatol 2001;21(Suppl. 1):S259. Gourley GR. Breastfeeding, neonatal jaundice and kernicterus. Semin Neonatol 2002;7:13541. Monaghan G, McLellan A, McGeehan A, et al. Gilberts syndrome is a contributory factor in the prolonged unconjugated hyperbilirubinaemia of the newborn. J Pediatr 1999;134:4416. Ives NK. Neonatal jaundice. In: Rennie JM, Roberton NRC, editors. Textbook of neonatology. 3rd ed. London: Churchill Livingstone; 1999. p. 71532 (4th ed., in press). McKiernan PJ. The infant with prolonged jaundice: investigation and management. Curr Paediatr 2001;11:839.

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