Jaundice in the first two weeks of life
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
- death
- 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
Kramer’s rule
There is a normal progression of the depth of jaundice from head to toe as the level of bilirubin rises. Kramer described the approximate serum bilirubin level with the level of skin discolouration:
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
The bilirubin range associated with each zone is
|
Zone |
1 |
2 |
3 |
4 |
5 |
|
Definition |
Head and neck |
Upper trunk |
Lower trunk and thighs |
Arms and lower legs |
Palms and soles |
|
SBR (micromol/L) |
100 |
150 |
200 |
250 |
>250 |
Risk factors for developing severe hyperbilirubinaemia
Major risk factors include
-
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 breast-feeding
-
family history of red cell enzyme defects
Minor risk factors include
-
jaundice occurring before discharge
-
previous sibling requiring phototherapy
-
macrosomic infant of a diabetic mother
Causes
- physiological
- pathological
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
- very severe haemolysis
- hepatitis (unusual)
- causes of haemolysis (decreasing order of probability)
- ABO incompatibility
- Rh immunisation
- sepsis
- rarer causes
- other blood group incompatibilities
- red cell enzyme defects e.g. G6PD deficiency
- 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.
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)
- 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 light
- intensity of the light (can be checked with a light intensity metre)
- the greater the amount of skin exposed
- the closer the lights to the baby
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.
Complications
- overheating
- water loss
- diarrhoea
- ileus (preterm infants)
- rash (no specific treatment required)
- retinal damage
- parental anxiety/separation
- 'bronzing ' of infants with conjugated hyperbilirubinemia
Ceasing phototherapy
- generally when 'out of range'
- worthwhile checking SBR day after cessation as may rebound
- can tolerate higher SBR once sepsis, haemolysis excluded in well term baby
Visual estimation of the bilirubin level in infants undergoing phototherapy are not reliable.
Exchange Transfusion
Indications
- consider in infants with Rh disease who have not received blood transfusions in utero
- cord blood haemoglobin < 100 g/L
- or cord bilirubin > 80 micromol/L
- 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
- bilirubin >340 micromol/L
- and likely to exceed that concentration for any length of time
- 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
-
Apnoea
-
Bradycardia
-
Cyanosis
-
Vasospasm
-
Air embolism
-
Infection
-
Thrombosis
-
Necrotising enterocolitis
-
(raraley) 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)
| Age | Infants at higher risk (35 - 376 weeks plus risk factors | Infants at medium risk (38 or more weeks plus risk factors or 35 - 376 weeks and well) | Infants at lower risk (38 or more weeks and well) |
|
SBR (micromol/L) |
SBR (micromol/L) |
SBR (micormol/L) |
|
|
Birth |
70 |
85 |
100 |
|
12 hrs |
100 |
110 |
150 |
|
24hrs |
135 |
160 |
195 |
|
48hrs |
185 |
220 |
255 |
|
72hrs |
230 |
260 |
295 |
|
96hrs |
250 |
295 |
340 |
|
5 days |
255 |
305 |
360 |
|
6 plus days |
255 |
305 |
360 |
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
2. Guidelines for exchange transfusion in infants of 35 or more weeks’ gestation
These are based on the American
|
Age (hrs) |
Infants at higher risk (35-37+6 weeks + risk factors) |
Infants at medium risk (>= 38 weeks + risk factors or 35-37+6 weeks and well |
Infants ay lower risk (>= 38 weeks and well) |
|
|
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 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 indicated after 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) |
Wt <1500g</strong/> |
Wt 1500-2000g |
Wt >2000g |
|
|
SBR (micromol/L) |
SBR (micromol/L) |
SBR (micromol/L) |
|
<24</p/> |
>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. 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/> |
Wt 1550-2000g |
Wt >2000g |
|
Hours |
SBR (micromol/L) |
SBR (micromol/L) |
SBR (micromol/L) |
|
<24</p/> |
>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 with water 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) blood
-
if there is unlikely to be appropriate surveillance, risk assessment before discharge and adequate follow-up, if the mother is blood group O it is recommended 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 hyperbilirubinaemia especially in infants discharged before 72 hours of age for full list see AAP Guideline
Other issues
-
transcutaneous bilirubinometers are increasingly available they are most accurate at the lower levels of hyperbilirubinaemia and therefore helpful in screening and avoiding blood tests
-
if a transcutaneous bilirubinometer is used and the level is approaching the threshold for phototherapy, a formal serum bilirubin should always be performed
-
‘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 side that is facing away from the overhead phototherapy unit
-
References
-
-
Maisels MJ, Watchko JF. Treatment of jaundice in low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2003;88:F459-63
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