NEONATAL JAUNDICE Introduction

occurs in approximately 60% of newborns (unimportant in most) a few will become deeply jaundiced requiring investigation and treatment if inadequately managed, may result in o death o survival 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 closed jaundice may not be visible in the neonate's skin until the bilirubin concentration exceeds 70 - 100 micromol/L increasing total serum bilirubin levels are accompanied by the cephalocaudal progression of jaundice, predictably from the face to the trunk and extremities, and finally to the palms and soles. However, visual estimation of the degree of jaundice may be inaccurate, particularly in darkly pigmented newborns total serum bilirubin level should be used to determine management decisions in cases of predominantly unconjugated hyperbilirubinaemia serum albumin level does not need to be measured in addition to the bilirubin to determine management serum bilirubin from a capillary sample is assumed to be the same as that from a venous sample sunlight exposure is no longer recommended as treatment of jaundice

Risk factors for developing severe hyperbilirubinaemia

Major risk factors

jaundice within the first 48 hours blood group incompatibility previous sibling requiring phototherapy for haemolytic disease cephalhaematoma or significant bruising weight loss greater than 10% of birth weight; may be associated with ineffective breastfeeding family history of red cell enzyme defects

Minor risk factors

jaundice occurring before discharge previous sibling requiring phototherapy macrosomic infant of a diabetic mother

Causes
Physiological Jaundice
Develops because of increased production decreased uptake and binding by liver cells decreased conjugation (most important) decreased excretion increased 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 pathological usually due to haemolysis, with excessive production of bilirubin babies can be born jaundiced with o very severe haemolysis o hepatitis (unusual)

causes of haemolysis (decreasing order of probability) o ABO incompatibility o Rh immunisation o sepsis rarer causes o other blood group incompatibilities o red cell enzyme defects e.g. G6PD deficiency o red 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-utero transfusions 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 the baby's red cells), and elution test to detect anti-A or anti-B antibodies on baby's red cells (more sensitive than the direct Coombs test) full blood examination, looking for evidence of haemolysis, unusually-shaped red cells, or evidence of infection CRP 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, various causes 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, CNS haemorrhage, swallowed blood) polycythaemia (increased RBC mass) infection - a more likely cause during this time increased enterohepatic circulation (e.g. gut obstruction)

Infection If the baby has other signs of infection, as well as excessive jaundice, acute bacterial infection must be excluded (particularly urinary tract infection). Infections acquired early in pregnancy may cause neonatal hepatitis, but other clinical signs are obvious and a substantial 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-fed infants is higher than in those who are formula-fed. What it is in breast milk that causes excessive jaundice is not known, but unsaturated fatty acids or a lipase, which inhibits glucuronyl transferase, have been suspected. Because most babies are initially breast-fed, inadequate fluid and calorie intake

resulting in haemoconcentration are contributors to jaundice; unfortunately a specific diagnosis is not possible (breast-feeding jaundice). Increasing the frequency of feeds decreases the likelihood of significant hyperbilirubinaemia. (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 intake haemolysis 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 suggest hypothyroidism, further investigation is mandatory because appropriate early treatment may prevent profound developmental delay. Haemolysis When jaundice suddenly reappears after the infant has gone home, severe haemolysis is the usual cause, particularly in infants with G6PD deficiency who are exposed to mothballs (naphthalene). G6PD deficiency occurs most often in Mediterranean, Asian and 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 requires extensive investigation.Conjugated hyperbilirubinaemia is always abnormal. Hepatitis Can be caused by infection (toxoplasmosis, rubella, cytomegalovirus, hepatitis, or syphilis), or by metabolic disorders (e.g., galactosaemia). Biliary Atresia A very rare disorder in which the bile ducts are absent, causing an obstructive jaundice which is fatal in most cases. These babies usually have pale (clay coloured) stools and dark urine.

Prevention
Primary prevention
early and frequent breastfeeding (8-12 times per day for the first few days)

Secondary prevention
if a mother has not had prenatal blood grouping a Coombs' test, blood type, and an Rh (D) type should be done on the infant's (cord) blood risk assessment before discharge and adequate follow-up

All infants should be routinely monitored for jaundice at least 12 hourly

Assessment prior to discharge of the risk of developing hyperbilirubinaemia isespecially important in infants discharged before 72 hours of age

Monitoring of jaundice
Visual Inspection
There is a normal progression of the depth of jaundice from head to toe as the level of bilirubin rises. Kramer's rule describes the approximate serum bilirubin level with the level of skin discolouration: Lower body Zone SBR (mol/L) Head & neck 100 Chest 150 & thighs 200 below knees 250 Arms & legs Hands& feet >250

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

Transcutaneous bilirubinometers
Transcutaneous bilirubinometers are increasingly available. They are most accurate at the lower levels of hyperbilirubinaemia and therefore helpful in screening and avoiding blood tests. Transcutaneous bilirubin estimations should only be done by persons trained in use of these monitors. they may be useful for assessing infants who are jaundiced and more than 24 hours of age without risk factors for developing severe hyperbilirubinemia. If a transcutaneous bilirubinometer is used and the level is approaching the threshold for phototherapy, a formal serum bilirubin should always be performed.

Need to treat guides

Prediction of likelihood of requirement of treatment can be assisted by using likelihood calculators - available on line at http://bilitool.org established nomograms o graphs produced by Bhutani predicting risk of subsequent significant jaundice in mature infants included in American Academy of Pediatrics clinical practice guidelines o tables indicating need for treatment included below

Treatment of jaundice
Unconjugated bilirubin can be toxic to the brain, and can cause the disease called kernicterus; 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 clinical sequelae of bilirubin toxicity (see below). The signs of acute bilirubin encephalopathy include lethargy poor feeding temperature instability hypotonia arching of the head, neck and back (opisthotonos) spasticity seizures

Death may follow. In those who survive, all will have permanent brain damage, including athetoid cerebral palsy, deafness, and mental retardation. The risk of developing kernicterus increases with increasing unconjugated bilirubin - concentrations greater than 340 micromol/L are considered unsafe decreasing gestation - preterm infants may be at risk at lower concentrations of bilirubin, 300 micromol/L or less asphyxia, acidosis, hypoxia, hypothermia, meningitis, sepsis, and decreased albumin binding (serum albumin concentration too low, or binding interfered with by drugs)

Many describe a transient change in infant behaviour, even in the bilirubin level doews not reach the level for an exchange transfusion. This correlates with a measurable transient 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) o if breast fed the baby should be put to the breast between 8-12 times per day for the first several days o if supplementation of breast feeding is required this should be with expressed breast milk or formula not water o if oral intake is inadequate give intravenous fluids phototherapy exchange transfusion IV immunoglobulin (0.5-1 g/kg over 2 hours) may be given to infants with isoimmune haemolytic disease and rising bilirubin despite intensive phototherapy or bilirubin within 30-50 mcromol of 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 light (460 - 490 nm) intensity of the light ( > 30W/cm-2/nm-1, can be checked with a light intensity metre) the greater the amount of skin exposed (circumferential exposure maximises the exposed area and thus increases clinical effectiveness, may require combined use of more than one device) the closer the lights to the baby (limited by risk of overheating the infant)

The major drawback with phototherapy is that its effect is slow (despite a rapid onset of action); phototherapy alone is rarely effective with severe haemolytic causes of jaundice where the bilirubin concentration can rise rapidly (and continue to rise despite aggressive phototherapy). In breast fed infants who require phototherapy, if possible, breastfeeding should continue. There is no evidence to support the administration of additional fluids to jaundiced infants.

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 60-70 micromol/L below the exchange value (see Tables).

All infants receiving phototherapy must have a serum bilirubin level measured as well as basic investigations to exclude the common causes of unconjugated hyperbilirubinemia. The bilirubin level should be checked 4-6 hours after starting phototherapy. Commencement of phototherapy is not an indication for transfer of infant from the postnatal ward to the special care nursery. Transfer to the special care nursery may be required in order to provide intensive phototherapy because of the clinical condition of the infant o requirement for specialised observation o care requirements o intravenous fluids

'Biliblankets' may have a role in the following situations outpatient management allows infant to stay in an open cot in infants receiving intensive phototherapy to provide therapy to the area of the body that is facing away from the overhead phototherapy unit

Monitoring
While recieving phototherapy infants require ongoing monitoring including adequacy of hydration and nutrition temperature clinical improvement in jaundice potential signs of bilirubin encephalopathy

Complications
overheating water loss diarrhoea ileus (preterm infants) rash (no specific treatment required) retinal damage (theoretical) parental anxiety/separation 'bronzing ' of infants with conjugated hyperbilirubinemia

Ceasing phototherapy
Visual estimations of the bilirubin level or estimation by trancutaneous monitor in infants undergoing phototherapy are not reliable.

Infants can tolerate higher SBR once sepsis, haemolysis excluded in well term baby

Cease phototherapy when more than 50micromol/L below the phototherapy range (generally less than 240micromol/L)

Rechecking the bilirubin level after cessation is not usually required unless increased risk of significant rebound haemolytic disease gestation less than 37 weeks cessation of phototherapy at less than 72 hours of age

Discharge from hospital need not be delayed to observe rebound of bilirubin

Exchange Transfusion
Indications
consider in infants with Rh disease who have not received blood transfusions in utero o cord blood haemoglobin < 100 g/L o or cord bilirubin > 80 micromol/L o or baby visibly jaundiced within 12 hours of birth

These infants are at high risk of needing an exchange transfusion and preparations should be made (lines inserted, blood ordered) whilst a formal serum bilirubin level is urgently ordered. The effects of intrauterine transfusions are unpredictable, but haemolysis is usually less severe because more of the baby's blood is Rh negative donor blood. well term infants o bilirubin >340 micromol/L o and likely to exceed that concentration for any length of time o and due to haemolysis (for non-haemolytic jaundice, see the Tables) In preterm or sick infants, lower concentrations of bilirubin may warrant exchange transfusion Infants manifesting the signs of intermediate to advanced stages of acute bilirubun encephalopathy even if the bilirubin level is failing Since exchange transfusions are rarely performed today, especially outside level III centres, it is advisable that any baby who requires an exchange transfusion be transferred to a level-III centre. Risks of exchange transfusion (although uncommon) include o Apnoea o Bradycardia o Cyanosis o Vasospasm o Air embolism o Infection o Thrombosis o Necrotising enterocolitis o (rarely) death

Thse risks are higher in sick, preterm infants.

After an exchange transfusion subsequent monitoring of the haemoglobin is necessary because 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 weeks gestation
These are based on the American Academy of Pediatrics Guidelines (published in Pediatrics 114:297-316, July 2004) Infants at medium risk (38 or more Infants at higher risk Infants at lower risk (38 weeks plus risk factors or 35 (35 - 376 weeks plus risk factors or more weeks and well) 6 37 weeks and well) SBR (micormol/L) SBR (micromol/L) Birth 12 hrs 24hrs 48hrs 72hrs 96hrs 5 days 6 plus days Notes Use total serum bilirubin (TSB) (do not subtract direct reacting or conjugated bilirubun) Risk factors include isoimmune haemolytis disease, G6PD deficiency, asphyxia, significant lethargy, temperature instability, sepsis, acidosis or albumin <3.0 g/L</span/> For well infants 35- 376 weeks can adjust TSB levels for intervention around the medium risk section. It is an option to intervene at lower TSB levels for infants closer to 35 wekks and at higher TSB levesl for those closer to 376 weeks 70 100 135 185 230 250 255 255 SBR (micromol/L) 85 110 160 220 260 295 305 305 100 150 195 255 295 340 360 360

Age

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

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

Age (hrs)

Infants at higher risk Infants at medium

Infants ay lower risk

(35-37+6 weeks + risk risk (>= 38 weeks + factors) risk factors or 3537+6 weeks and well
SBR (micromol/L) Birth 12 hours 24 hours 48 hours 72 hours 96 hours 5 days 6 days 7 days Notes 200 230 255 290 315 320 320 320 320 SBR (micromol/L) 235 255 280 320 360 380 380 380 380

(>= 38 weeks and well)

SBR (micromol/L) 270 295 320 375 405 425 425 425 425

the levels in the first 24 hours are less certain due to a wide range of clinical circumstances and a range of responses to phototherapy immediate exchange transfusion is recommended in infants showing signs of acute bilirubin encephalopathy or if TSB is >= 85 micromol/L above these levels risk factors include isoimmune haemolytic disease, G6PD deficiency, asphyxia, significant lethargy, temperature instability, sepsis and acidosis use 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 for exchange based on actual gestational age during birth hospitalisation exchange is recommended if the TSB rises to these levels despite intensive phototherapy for readmitted infants if the TSB level is above the exchange level, repeat TSB measurements every 2-3 hours and consider exchange if TSB remains above the levels indicatedafter intensive phototherapy for 6 hours

3. Guidelines for the use of phototherapy in low birthweight infants based on birth weight
Note: In small for gestational age (SGA) infants use gestation rather than birth weight

Age (hrs)
<24</p/> 24-48 hours 49-72hours >72 hours

Wt <1500g</strong/> SBR (micromol/L) >70 >85 >120 >140

Wt 1500-2000g
SBR (micromol/L) >70 >120 >155 >170

Wt >2000g
SBR (micromol/L) >85 >140 >200 >240

Notes lower bilirubin concentrations should be used for infants who are sick. These include sepsis, acidosis, hypoalbuminaemia, haemolytic disease use total serum bilirubin levels (do not subtract direct acting or conjugated bilirubin levels from total) levels for exchange transfusion assume that bilirubin continues to rise or remains at these levels despite intensive phototherapy

4. Guidelines for the use of exchange transfusion in low birthweight infants based on age
Note: In small for gestational age (SGA) infants use gestation rather than birth weight Age Wt<1500g</strong/> SBR (micromol/L) >170-255 >170-255 >170-255 >255 Wt 1550-2000g SBR (micromol/L) >255 >255 >270 >290 Wt >2000g SBR (micromol/L) >270-310 >270-310 >290-320 >310-340

Hours
<24</p/> 24-48 49-72 >72 Notes

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