Current Issues in Neonatal CareNeonatal jaundice: aetiology, diagnosisand treatmentA significant proportion of term and preterm infantsdevelop neonatal jaundice. Jaundice in an otherwisehealthy term infant is the most common reason forreadmission to hospital. Jaundice is caused by anincrease in serum bilirubin levels, largely as a result ofbreakdown of red blood cells. Bilirubin is conveyed inthe blood as ‘unconjugated’ bilirubin, largely bound toalbumin. The liver converts bilirubin into a conjugatedform which is excreted in the bile. Very high levels ofunconjugated bilirubin are neurotoxic. Phototherapyis a simple and effective way to reduce the bilirubinlevel. Most term babies have ‘physiological’ jaundicewhich responds to a short period of phototherapy,and requires no other treatment. A few babies haverapidly rising bilirubin levels which place them at riskof kernicterus. Current management of jaundice inthe UK is guided by the NICE guideline. Any infant withhigh serum bilirubin or a rapidly rising bilirubin levelneeds to be treated urgently to avoid neurotoxicity.High levels of conjugated bilirubin in a term baby canindicate biliary atresia, and babies with persistingjaundice must have their level of conjugated bilirubinmeasured. Preterm infants on long-term parenteralnutrition may develop conjugated jaundice whichgenerally improves with the introduction of enteralfeed and weaning of intravenous nutrition.Keywords: Neonatal jaundice, kernicterus, conjugatedjaundice, phototherapy, exchange transfusionDr Subhabrata MitraConsultant Neonatologist, Neonatal Unit, ElizabethGarrett Anderson Wing, University College LondonHospital, London NW1 2BUDr Janet RennieConsultant Neonatologist, Neonatal Unit, ElizabethGarrett Anderson Wing, University College LondonHospital, LondonCorrespondence to: Dr Subhabrata [email protected] Neonatal jaundice is one of the most commonclinical signs in newborn infants. Jaundicepresent as yellow discolouration of the skinand sclera in infants, indicating a raised serumbilirubin level leading to accumulation of bilirubinin the tissues, including the skin and mucousmembranes. Jaundice is thought to be visible atbilirubin levels of around 90 mmol/litre in babieswith pale skin tones. The detection of jaundice ismore difficult in babies with dark skin tones, but thesclerae are always white and inspection of the eyesis a crucial part of visual assessment of jaundice.Around 60% of term and 80% of preterm infantsdevelop jaundice in the first week of life and 10% ofbreastfed infants remain jaundiced up to 1 monthof age. Jaundice was the most common reason foradmission from home to neonatal units in Englandfor term infants (Battersby et al, 2017).Most infants who become jaundiced developjaundice in the first week of life, and in the majorityof cases it is mild and harmless. Breast-fed infants aremore prone to develop physiological jaundice in thefirst week of life. The key challenge is to differentiatethe rare baby with significant jaundice which mightlead to bilirubin encephalopathy and kernicterusfrom the majority of babies in whom jaundice will beharmless. It is also essential to identify infants withconjugated hyperbilirubinaemia who have biliaryatresia as early as possible to improve outcome. Theoutcome for babies with biliary atresia whose surgeryis performed at less that 6 weeks of age is muchbetter than in those whose surgery is delayed by latediagnosis.The current national guideline in UK from theNational Institute for Health and Care Excellence(NICE) (2016) recommends a review of all infantswith risk factors for neonatal jaundice within the first48 hours of life and assessment of serum bilirubinlevel in any infant with clinical jaundice. The riskfactors are outlined in Table 1.Bilirubin metabolismIn newborn infants, bilirubin is mostly producedfrom the breakdown of red blood cells. Haemoglobin, 2017 MA Healthcare LtdAbstract

2017 MA Healthcare LtdCurrent Issues in Neonatal Carereleased from broken-down red blood cells, undergoesa two-stage catabolism within the reticuloendothelialsystem to produce bilirubin. This unconjugated (orindirect) bilirubin is transported in the circulationbound with serum albumin. Unconjugated bilirubincombines with glucuronic acid in the smoothendoplasmic reticulum inside the liver to producewater-soluble mono- or di-glucuronides of bilirubin,commonly referred as conjugated (or direct) bilirubin.Conjugated bilirubin is a component of bile andenters the gut via the biliary system. Although aproportion of conjugated bilirubin can be hydrolysedby beta-glucuronidase to unconjugated bilirubin inthe small gut, from where it is reabsorbed (theenterohepatic circulation), the majority is excretedwith the stool. Establishing gut motility and a normalpattern of stooling is an important component ofreducing the bilirubin load from the enterohepaticcirculation in the first few days, which is part of thereason why breastfeeding support is an essentialcomponent of the management of neonatal jaundice.An excellent new e-learning resource packageregarding physiology of bilirubin metabolism underNHS Health Education England will be availablefor health-care professionals rialManagement.aspx? materialId 15591&rl prj& prjid 15146).higher peak in serum bilirubin levels along with alonger duration of hyperbilirubinaemia compared toterm infants.Infants with bruising related to birth trauma,scalp haematoma (e.g. cephalhaematoma) and bornafter delayed cord clamping need to be carefullymonitored early on as they have an increased risk ofdeveloping jaundice.Glucose-6-phosphatase deficiency (G6PD) is animportant underlying cause of kernicterus, bothworldwide and in the UK. Male babies of Asianethnicity are particularly at risk but this condition isnot confined to this group.Normal pattern of neonatal jaundiceBilirubin encephalopathyMost newborn infants develop jaundice in the firstweek of life. In term infants, the serum bilirubin levelreaches a clinically detectable level by day 3 or 4. Thisgradually falls over the next few days before reachingthe normal childhood serum bilirubin level by the endof the second week of life. This is generally referredto as physiological jaundice. Although prolongedunconjugated jaundice was previously attributedmainly to ‘breast milk jaundice’, it is becoming clearthat many of these cases have an underlying geneticexplanation (Bhutani, 2012). Up to one-third ofexclusively breast-fed infants remain jaundiced at theend of 2 weeks and this group contributes to mostcommunity referrals to hospital for review at this age.A confident diagnosis of breast milk jaundice canonly be made after exclusion of other possible causesand parents need an explanation of the nature ofthe problem. Beta-glucuronidase is present in breastmilk and can cause increased levels of unconjugatedbilirubin that enters the enterohepatic circulationfrom the gut. Altered gut flora in breast-fed infantshas also been implicated in the reduction of theconversion of bilirubin glucuronides to urobilinoids.Jaundice in preterm infants is characterised by aSick and preterm infants are more vulnerable to theneurotoxic effect of raised bilirubin levels (Gartneret al, 1970). Pathophysiological mechanisms includecell membrane function disruption, loweringof action potential, disturbed energy metabolismand disturbance in neurotransmitter synthesis(Volpe, 2008; Brites et al, 2009). The depositionof bilirubin in the brain, noted during autopsy ofinfants who had died as a result of acute bilirubintoxicity, was described as ‘kernicterus’. Involvementof the brainstem, hippocampus, cerebellum, globuspallidus and subthalamic nuclei has been described.This anatomical predisposition might be related toincreased metabolic activity and regional cerebralblood flow.Hypoxia, acidosis, hypercarbia, sepsis, seizuresand disturbances to the blood–brain barrier areco-existing risk factors for acute bilirubintoxicity (Wennberg et al, 2006). Medications thatinterfere with bilirubin albumin binding or inhibitp-glycoprotein are implicated in increasing the risk ofacute bilirubin encephalopathy (Watchko et al, 2002).More apoptosis was noted in less well-differentiatedastrocytes and neurons (Brites et al, 2009) indicating Table 1. Factors related to higher susceptibility ofnewborn infants for development of physiologicaljaundiceHigh haemoglobin concentration in newborn infantsImmaturity of hepatic uptake, transport and conjugationsystemShorter lifespan for neonatal red blood cells comparedto those of adultsIncreased level of beta-glucuronidase in the gut,releasing more unconjugated bilirubin to enter theenterohepatic circulation15

Current Issues in Neonatal CareSerum bilirubin level 340 mmol/litre in a term infant( 37 weeks)Rapid rise in the serum bilirubin level ( 8.5 mmol/litre/hour)Clinical signs suggestive of bilirubin encephalopathythe importance of the developmental stage of thebrain in relation to bilirubin toxicity. A UK surveillancestudy has reported an occurrence of kernicterus in 1in 100 000 live births (Manning et al, 2007).Risk factors for developing kernicterus arepresented in Table 2.Previously described different stages of bilirubinencephalopathy (Connolly and Volpe, 1990) are nowrare in current clinical practice. Opisthotonus (Figure1) generally indicates neuronal toxicity. Magneticresonance imaging of the brain is the investigationof choice in suspected cases and presents acharacteristic picture in cases of kernicterus (FigureFigure 1. Typical opisthotonic posture in a baby with neonataljaundice and acute bilirubin encephalopathy.Figure 2. Characteristic changes in kernicterus. a and b.Hyperintense signal and symmetrical scarring in globus palliduson T2-weighted imaging on brain magnetic resonance imagingin kernicterus in two different cases and (c) macroscopicappearance of brain in kernicterus with characteristic yellowbilirubin staining.a16 bc2). High intensity areas in the posteromedial borderof the globus pallidus on T2-weighted imaging isthe most sensitive finding (Yokochi, 1995; Govaertet al, 2003). It is important to remember that longterm neurological impairment can be associatedwith normal magnetic resonance imaging after acutebilirubin encephalopathy (Katar et al, 2008). Longterm features include extrapyramidal disturbances,sensorineural hearing loss, auditory impairment andupward gaze palsies. The resultant cerebral palsynormally includes a degree of athetosis.It is difficult to correlate a specific serum bilirubinlevel to the onset of bilirubin neurotoxicity. Thereport from the Pilot USA Kernicterus Registrysuggested that a bilirubin level 598 mmol/litre canhave a profoundly deleterious effect (Bhutani andJohnson, 2009).Analysis of the NHS Resolution data regardingsettled kernicterus claims in England also found thatterm babies had bilirubin levels above 600 mmol/litre at presentation (J Rennie et al on behalf of theNHS Improvement Patient Safety Programme, 2017,unpublished data).Aetiology of neonatal jaundiceIn view of the current era of early postnatal dischargeand community support in the NHS, risk factors(Khoury et al, 1988; Newman et al, 2002; Kerenet al, 2005; Maisels et al, 2009) associated withdevelopment of significant jaundice need to bereviewed before discharge (Table 3). The NICE(2016) guideline recommends that a second clinicalexamination is conducted before 48 hours of age.A detailed family history and clinical examinationis extremely important in all infants with jaundice forunderstanding of the possible aetiopathophysiology.Appropriate investigations can identify treatableconditions early (e.g. isoimmunisation, infection,biliary atresia) and improve outcome.Early jaundiceClinical jaundice within the first 24 hours of life islikely to be pathological and commonly a result ofisoimmunisation (most commonly ABO or rhesusincompatibility) or other causes of significanthaemolysis. Blood group and rhesus status for bothmother and infant need to be reviewed along with adirect agglutination test (DAT). Anti-D prophylaxis inrhesus-negative mothers can cause a weakly positiveDAT result as a result of passive transfer of antibody.A positive DAT test does not always correlate withthe severity of jaundice (Bakkeheim et al, 2009).Reticulocyte count and blood film also carry a low 2017 MA Healthcare LtdTable 2. Risk factors associated with the developmentof kernicterus

Current Issues in Neonatal CareTable 3. Risk factors in babies more likely todevelop significant jaundiceGestational age 38 weeksHistory of previous sibling needingphototherapyExclusive breast feedingClinical jaundice visible within first 24 hours oflifesensitivity and specificity for diagnosis of haemolysisin newborn infants (Newman and Easterling, 1994).Review of maternal antenatal notes oftengives vital information about other blood groupincompatibilities (e.g. Kell group) or the presence ofother antibodies. Infection should always be excludedin sick newborns with early jaundice. Although G6PDdeficiency-related jaundice presents after 48 hours,it needs to be part of the investigations in infantswith relevant ethnicity (parents with Mediterranean,Asian or African origin). If haemolysis is ruled out,Crigler–Najjar syndrome should be considered.Although rare, it can develop a rapidly deterioratingnon-haemolytic unconjugated jaundice early in life.Infants with G6PD deficiency can also present withnon-haemolytic jaundice in the neonatal period. 2017 MA Healthcare LtdProlonged jaundicePersistent clinical jaundice in term infants at 2 weeksand in preterm infants at 3 weeks of age is termedprolonged jaundice. This is a common referral fromthe community and mostly presents as unconjugatedjaundice noted in breastfed infants. Feeding history,colour of stool and urine and clinical examinationcan mostly rule out pathological causes. Theinvestigations should be done stepwise de