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Jaundice in the first two weeks of life

IntroductionPhysiological JaundicePathological JaundiceTreatment of JaundicePhototherapyExchange TransfusionTables

Introduction

occurs in approximately 60% of newborns (unimportant in most)a few will become deeply jaundiced requiring investigation and treatmentif inadequately managed, may result in

deathsurvival with severe brain damage

early detection of jaundice (appears in the sclera with SBR of 35-40 micromol/L)may be difficult in newborns because eyelids often swollen and usually closedjaundice may not be visible in the neonate's skin until the bilirubin concentrationexceeds 70 - 100 micromol/Lincreasing total serum bilirubin levels are accompanied by the cephalocaudalprogression of jaundice, predictably from the face to the trunk and extremities,and finally to the palms and soles. However, visual estimation of the degree ofjaundice may be inaccurate, particularly in darkly pigmented newbornstotal serum bilirubin level should be used to determine management decisions incases of predominantly unconjugated hyperbilirubinaemiaserum albumin level does not need to be measured in addition to the bilirubin todetermine managementserum bilirubin from a capillary sample is assumed to be the same as that from avenous samplesunlight exposure is no longer recommended as treatment of jaundice

Kramer’s rule

There is a normal progression of the depth of jaundice from head to toe as the level ofbilirubin rises. Kramer described the approximate serum bilirubin level with the level ofskin discolouration:

Visual inspection of the infant, including Kramer’s rule, can only be used as a guide tothe level of jaundice. There is a wide inter-observer error in the clinical estimation of thedepth of jaundice which should therefore not be substituted for a formal bilirubinmeasurement in equivocal cases

The bilirubin range associated with each zone is

Zone 1 2 3 4 5

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Definition Head andneck

Uppertrunk

Lower trunkand thighs

Arms andlower legs

Palms andsoles

SBR (micromol/L) 100 150 200 250 >250

Risk factors for developing severe hyperbilirubinaemia

Major risk factors include

jaundice within the first 48 hoursblood group incompatibilityprevious sibling requiring phototherapy for haemolytic diseasecephalhaematoma or significant bruisingweight loss greater than 10% of birth weight; may be associated with ineffectivebreast-feedingfamily history of red cell enzyme defects

Minor risk factors include

jaundice occurring before dischargeprevious sibling requiring phototherapymacrosomic infant of a diabetic mother

Causes

physiologicalpathological

Physiological Jaundice

Develops because of

increased productiondecreased uptake and binding by liver cellsdecreased conjugation (most important)decreased excretionincreased enterohepatic circulation of bilirubin

As the name implies, physiological jaundice is common and harmless

Pathological Jaundice

Best considered in relation to time from birth.

(1) "Too Early" (< 48 hours of age)

always pathologicalusually due to haemolysis, with excessive production of bilirubinbabies can be born jaundiced with

very severe haemolysishepatitis (unusual)

causes of haemolysis (decreasing order of probability)



ABO incompatibilityRh immunisationsepsis

rarer causesother blood group incompatibilitiesred cell enzyme defects e.g. G6PD deficiencyred cell membrane defects, e.g., hereditary spherocytosis

If there is substantial elevation of conjugated bilirubin (>15% of the total),consider hepatitis (see later). This may also occur in Rh babies who have had in-uterotransfusions and even in some that haven't.

Investigation of early pathological jaundice

total and conjugated serum bilirubin concentration (SBR)maternal blood group and antibody titres (if Rh negative)baby's blood group, direct antiglobulin (Coombs) test (detects antibodies on thebaby's red cells), and elution test to detect anti-A or anti-B antibodies on baby'sred cells (more sensitive than the direct Coombs test)full blood examination, looking for evidence of haemolysis, unusually-shaped redcells, or evidence of infectionCRP to assist with diagnosis of infection

(2) "Too High" (24 hours - 10 days of age)

If the serum bilirubin concentration exceeds 200-250 micromol/L, over this time, variouscauses include

mild dehydration/insufficient milk supply (breast-feeding jaundice)haemolysis - continuing causes as discussed under "too early"breakdown of extravasated blood (e.g. cephalhaematoma, bruising, CNShaemorrhage, swallowed blood)polycythaemia (increased RBC mass)infection - a more likely cause during this timeincreased enterohepatic circulation (e.g. gut obstruction)

Infection

If the baby has other signs of infection, as well as excessive jaundice, acute bacterialinfection must be excluded (particularly urinary tract infection). Infections acquired earlyin pregnancy may cause neonatal hepatitis, but other clinical signs are obvious and asubstantial fraction of the jaundice is conjugated (>15%).

Breast-milk Jaundice

From as early as the third day of life, the serum bilirubin concentration of breast-fedinfants is higher than in those who are formula-fed. What it is in breast milk that causesexcessive jaundice is not known, but unsaturated fatty acids or a lipase, which inhibitsglucuronyl transferase, have been suspected. Because most babies are initially breast-fed, inadequate fluid and calorie intake resulting in haemoconcentration are contributorsto jaundice; unfortunately a specific diagnosis is not possible (breast-feeding jaundice).Increasing the frequency of feeds decreases the likelihood of significanthyperbilirubinaemia.

(3) "Too Long" (> 10 days of age, especially > 2 weeks)

The major clue to diagnosis is whether the elevated bilirubin is mostly unconjugated(>85%) or whether the conjugated fraction is substantially increased (>15% of the total).



Causes of persistent unconjugated hyperbilirubinaemia

breast milk jaundice (diagnosis of exclusion, cessation not necessary)continued poor milk intakehaemolysis infection (especially urinary tract infection)hypothyroidism

Hypothyroidism

Persistent jaundice may be the earliest sign of hypothyroidism in the infant. Fortunately,all babies are routinely screened for this disease. However, if other signs suggesthypothyroidism, further investigation is mandatory because appropriate early treatmentmay prevent profound developmental delay.

Haemolysis

When jaundice suddenly reappears after the infant has gone home, severe haemolysisis the usual cause, particularly in infants with G6PD deficiency who are exposed tomothballs (naphthalene). G6PD deficiency occurs most often in Mediterranean, Asianand African ethnic groups, and is more severe in males (being X-linked).

Causes of Persistent Conjugated Hyperbilirubinaemia

A simple test of urine for bile will suggest substantial elevation of conjugated bilirubin.This is rare, and the infant either has hepatitis or biliary atresia and therefore requiresextensive investigation.Conjugated hyperbilirubinaemia is always abnormal.

Hepatitis

Can be caused by infection (toxoplasmosis, rubella, cytomegalovirus, hepatitis, orsyphilis), or by metabolic disorders (e.g., galactosaemia).

Biliary Atresia

A very rare disorder in which the bile ducts are absent, causing an obstructive jaundicewhich is fatal in most cases. These babies usually have pale (clay coloured) stools anddark urine.

Treatment of jaundice

Unconjugated bilirubin can be toxic to the brain, and can cause the disease calledkernicterus; this is characterised by the death of brain cells and yellow staining,particularly in the grey matter of the brain. Kernicterus refers to the permanent clinicalsequelae of bilirubin toxicity (see below). The signs of acute bilirubin encephalopathyinclude

lethargypoor feedingtemperature instabilityhypotonia arching of the head, neck and back (opisthotonos)spasticity seizures

Death may follow. In those who survive, all will have permanent brain damage, includingathetoid cerebral palsy, deafness, and mental retardation.



The risk of developing kernicterus increases with

increasing unconjugated bilirubin - concentrations greater than 340 micromol/Lare considered unsafedecreasing gestation - preterm infants may be at risk at lower concentrations ofbilirubin, 300 micromol/L or lessasphyxia, acidosis, hypoxia, hypothermia, meningitis, sepsis, and decreasedalbumin binding (serum albumin concentration too low, or binding interfered withby drugs)

Many describe a transient change in infant behaviour, even in the bilirubin level doewsnot reach the level for an exchange transfusion. This correlates with a measurabletransient alteration in brainstem evoked potentials.

Available therapies

treatment of the cause (e.g. infection, hypothyroidism)adequate hydration (via gut, may reduce enterohepatic circulation of bilirubin)phototherapy exchange transfusion

Phototherapy

Exposure of jaundiced skin to light photo-isomerises the bilirubin molecule into forms,which can be excreted directly into the bile, without having to be conjugated.

The effectiveness of phototherapy increases with

blue lightintensity of the light (can be checked with a light intensity metre)the greater the amount of skin exposedthe closer the lights to the baby

The major drawback with phototherapy is that its effect is slow (despite a rapid onset ofaction); phototherapy alone is rarely effective with severe haemolytic causes of jaundicewhere the bilirubin concentration can rise rapidly (and continue to rise despiteaggressive phototherapy).

In breast fed infants who require phototherapy, if possible, breastfeeding shouldcontinue.

There is no evidence to support the administration of additional fluids to jaundicedinfants.

Indications

Phototherapy should only be used when the bilirubin is approaching a concentration,which would usually lead to an exchange transfusion. In practice, this is 60-70micromol/L below the exchange value (see Tables). All infants receiving phototherapymust have a serum bilirubin level measured as well as basic investigations to excludethe common causes of unconjugated hyperbilirubinemia. The bilirubin level should bechecked 4-6 hours after starting phototherapy.

Complications

overheatingwater lossdiarrhoea ileus (preterm infants)

rash (no specific treatment required)retinal damageparental anxiety/separation'bronzing ' of infants with conjugated hyperbilirubinemia

Ceasing phototherapy

generally when 'out of range'worthwhile checking SBR day after cessation as may reboundcan tolerate higher SBR once sepsis, haemolysis excluded in well term baby

Visual estimation of the bilirubin level in infants undergoing phototherapy are notreliable.

Exchange Transfusion

Indications

consider in infants with Rh disease who have not received blood transfusions inutero

cord blood haemoglobin < 100 g/Lor cord bilirubin > 80 micromol/Lor baby visibly jaundiced within 12 hours of birth

These infants are at high risk of needing an exchange transfusion and preparationsshould be made (lines inserted, blood ordered) whilst a formal serum bilirubin level isurgently ordered.

The effects of intrauterine transfusions are unpredictable, but haemolysis is usually lesssevere because more of the baby's blood is Rh negative donor blood.

well term infantsbilirubin >340 micromol/Land likely to exceed that concentration for any length of timeand due to haemolysis (for non-haemolytic jaundice, see the Tables)

In preterm or sick infants, lower concentrations of bilirubin may warrantexchange transfusionInfants manifesting the signs of intermediate to advanced stages of acutebilirubun encephalopathy even if the bilirubin level is failingSince exchange transfusions are rarely performed today, especially outsidelevel III centres, it is advisable that any baby who requires an exchangetransfusion be transferred to a level-III centre.Risks of exchange transfusion (although uncommon) include

ApnoeaBradycardiaCyanosisVasospasmAir embolismInfectionThrombosisNecrotising enterocolitis(raraley) death

Thse risks are higher in sick, preterm infants.

After an exchange transfusion subsequent monitoring of the haemoglobin is necessarybecause ongoing haemolysis may result in significant anaemia, and the baby may still

need a number of top-up simple blood transfusions.

Tables

1. Guidelines for phototherapy in hospitalised infants of 35 or more weeksgestation

These are based on the American Academy of Pediatrics Guidelines (published inPediatrics 114:297-316, July 2004)

Age Infants at higherrisk (35 - 376 weeksplus risk factors

Infants at medium risk (38 ormore weeks plus risk factors or35 - 376 weeks and well)

Infants at lowerrisk (38 or moreweeks and well)

SBR (micromol/L)

SBR (micromol/L) SBR (micormol/L)

Birth 70 85 100

12hrs 100 110 150

24hrs 135 160 195

48hrs 185 220 255

72hrs 230 260 295

96hrs 250 295 340

5days 255 305 360

6plusdays

255 305 360

Notes

Use total serum bilirubin (TSB) (do not subtract direct reacting or conjugatedbilirubun)Risk factors include isoimmune haemolytis disease, G6PD deficiency, asphyxia,significant lethargy, temperature instability, sepsis, acidosis or albumin <3.0g/LFor well infants 35- 376 weeks can adjust TSB levels for intervention around themedium risk section. It is an option to intervene at lower TSB levels for infantscloser to 35 wekks and at higher TSB levesl for those closer to 376 weeks



2. Guidelines for exchange transfusion in infants of 35 or more weeks’gestation

These are based on the American Academy of Pediatrics Guidelines (published inPediatrics 114:297-316, July 2004).

Age (hrs) Infants at higher risk(35-37+6 weeks +risk factors)

Infants at mediumrisk (>= 38 weeks +risk factors or 35-37+6 weeks and well

Infants ay lower risk(>= 38 weeks andwell)

SBR (micromol/L) SBR (micromol/L) SBR (micromol/L)

Birth 200 235 270

12 hours 230 255 295

24 hours 255 280 320

48 hours 290 320 375

72 hours 315 360 405

96 hours 320 380 425

5 days 320 380 425

6 days 320 380 425

7 days 320 380 425

Notes

the levels in the first 24 hours are less certain due to a wide range of clinicalcircumstances and a range of responses to phototherapyimmediate exchange transfusion is recommended in infants showing signs ofacute bilirubin encephalopathy or if TSB is >= 85 micromol/L above these levelsrisk factors include isoimmune haemolytic disease, G6PD deficiency, asphyxia,significant lethargy, temperature instability, sepsis and acidosisuse total serum bilirubin (do not subtract direct acting or conjugated bilirubin)if infant is well and 35-37+6 weeks (median risk) can individualise TSB levels forexchange based on actual gestational ageduring birth hospitalisation exchange is recommended if the TSB rises tothese levels despite intensive phototherapyfor readmitted infants if the TSB level is above the exchange level, repeat TSBmeasurements every 2-3 hours and consider exchange if TSB remains above thelevels indicated after intensive phototherapy for 6 hours

3. Guidelines for the use of phototherapy in low birthweight infants basedon birth weight

Note: In small for gestational age (SGA) infants use gestation rather than birth weight

Age (hrs) Wt <1500g Wt 1500-2000g Wt >2000g

SBR (micromol/L) SBR (micromol/L) SBR (micromol/L)

<24 >70 >70 >85

24-48 hours >85 >120 >140

49-72hours >120 >155 >200

>72 hours >140 >170 >240

Notes

lower bilirubin concentrations should be used for infants who are sick. Theseinclude sepsis, acidosis, hypoalbuminaemia, haemolytic diseaseuse total serum bilirubin levels (do not subtract direct acting or conjugatedbilirubin levels from total)levels for exchange transfusion assume that bilirubin continues to rise or remainsat these levels despite intensive phototherapy

4. Guidelines for the use of exchange transfusion in low birthweight infantsbased on age

Note: In small for gestational age (SGA) infants use gestation rather than birth weight

Age Wt<1500g Wt 1550-2000g Wt >2000g

Hours SBR (micromol/L) SBR (micromol/L) SBR (micromol/L)

<24 >170-255 >255 >270-310

24-48 >170-255 >255 >270-310

49-72 >170-255 >270 >290-320

>72 >255 >290 >310-340

Notes

sick infants include those with Rhesus disease, perinatal asphyxia, hypoxia,acidosis or hypercapnia



Prevention of Hyperbilirubinaemia

Primary prevention includes

early and frequent breastfeeding (8-12 times per day for the first few days)avoidance of routine supplementation of non-dehydrated breastfed infants withwater or dextrose water

Secondary prevention includes

if a mother has not had prenatal blood grouping or is Rh-negative, a Coombs’test, blood type, and an Rh (D) type should be done on the infant’s (cord) bloodif there is unlikely to be appropriate surveillance, risk assessment beforedischarge and adequate follow-up, if the mother is blood group O it isrecommended that the infant’s blood type and Coombs’ test be checked

? All infants should be routinely monitored for jaundice

? Assessment prior to discharge of the risk of developing hyperbilirubinaemiaespecially in infants discharged before 72 hours of age for full list see AAP Guideline

Other issues

transcutaneous bilirubinometers are increasingly available they are mostaccurate at the lower levels of hyperbilirubinaemia and therefore helpful inscreening and avoiding blood testsif a transcutaneous bilirubinometer is used and the level is approaching thethreshold for phototherapy, a formal serum bilirubin should always be performed‘Biliblankets’ may have a role in the following situations

outpatient managementallows infant to stay in an open cotin infants receiving intensive phototherapy to provide therapy to the sidethat is facing away from the overhead phototherapy unit

References

American Academy of Pediatrics. Clinical Practice Guideline. Subcommittee onHyperbilirubinaemia: Management of hyperbilirubinaemia in the newborn infant35 or more weeks of gestation. Pediatrics 2004;114:297-316 Maisels MJ, Watchko JF. Treatment of jaundice in low birthweight infants. ArchDis Child Fetal Neonatal Ed 2003;88:F459-63

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