NEONATAL JAUNDICE

MIHAI CRAIU MD PhD

Institute for Mother and Child Care
Alfred Rusescu

NEONATAL JAUNDICE
common neonatal problem most infants
present jaundice in the first days of life
NEONATAL JAUNDICE
most infants who present jaundice can be
treated with complete recovery
Neonatal jaundice can be a
significant problem 1
There are MULTIPLE reasons for this:
The 'blood-brain barrier' of the
neonate and, especially, of the
premature infant, fails to defend the
brain against high levels of un-
conjugated bilirubin, particularly in the
context of sepsis and acidosis;
Neonatal jaundice can be a
significant problem 2
The normal liver mechanisms that detoxify
bilirubin (the enzyme glucuronyl-transferase
conjugates bilirubin with glucuronic acid) are
underdeveloped, even in the term infant.
The enzyme responsible for glucuronidation of
bilirubin is called uridine diphospho-glucuronyl-
transferase , or UGT1A1
Levels in the newborn are just 1% of adult levels



Neonatal jaundice can be a
significant problem 3

In addition, liver uptake of bilirubin
from circulating albumin (where it is
tightly bound) is low in the newborn due
to low liver levels of ligandin;
Neonatal jaundice can be a
significant problem 4
There is degradation of the HEM
component of haemoglobin to form
bilirubin, so that even normal infants
are presenting hyperbilirubinaemia.
On a per kilogram basis, bilirubin
production in the neonate is more than
twice that in the adult!
Neonatal jaundice can be a
significant problem 5
There is enterohepatic recirculation of
bilirubin. Conjugated bilirubin may be de-
conjugated in the small bowel, and then re-
absorbed if not degraded by intestinal micro-
organisms.
The enzyme responsible for deconjugation is
beta-glucuronidase, which is found not only in
several intestinal bacteria (e.g. E. coli,
Clostridium), but also in the brush border of
the small intestine.
Neonatal jaundice can be a
significant problem 6
Even a moderate insult can tip a neonate
over the edge into severe unconjugated
hyperbilirubinaemia, with poor feeding,
decreased production of urine and stool,
and a vicious cycle of worsening jaundice.
The end result may be kernicterus , a
condition where bilirubin causes toxic
destruction of nerve cells in the basal
ganglia.
NEONATAL JAUNDICE

Neonatal hyperbilirubinaemia is usually
unconjugated.
Consequently, many normal infants have
a degree of "physiological jaundice ",
which often peaks on about the third
day after birth.
NEONATAL JAUNDICE
Physiological jaundice tends to reach
peak levels between
4 and 7 days in full term babies
7-10 days in the pre-term
It is not unusual for babies to still be
visually icteric at 2 weeks of age
especially if they are breast fed.
nu este anormal daca au icter fiziologic
la 2 sapt de viata daca sunt hraniti la
san!!
NEONATAL JAUNDICE
Term babies from the community with
prolonged jaundice at 14 days will go to
clinic.
In the preterm infant a prolonged
jaundice screen should be performed at
21 days of age.
NEONATAL JAUNDICE
About 5 to 10% of neonates may develop
bilirubin levels of more than 10mg%(170
micromoli/L.
Even at 37 weeks of gestation, infants
are four times more likely than a term
infant to have a serum bilirubin over
13mg%!
NEONATAL JAUNDICE
Risk factors include:
Gestational age under 37 weeks;
Birth weight below 2500g;
Jaundice in the first 24 hours;
Sepsis;
Resuscitation at birth;
Poor feeding, and loss of more than 10% of body weight after
birth ;
Hypoalbuminaemia;
Administration of drugs that might displace bilirubin from its
albumin binding sites (in the past, these included
sulfisoxazole, benzyl alcohol as an obsolete preservative in
normal saline, chloramphenicol, and streptomycin).

NEONATAL JAUNDICE
For sick babies check:
direct bilirubin (if > 20% of the total
bilirubin !)
CBC, reticulocytes, film
Group, DCT
G
6
PD
TSH, T
4



NEONATAL JAUNDICE
Hyperbilirubinaemia is more common in
infants born at altitude! [Am J Dis Child
1984 Feb; 138(2): 157-61].
Most authorities seem to agree that a
bilirubin above 17mg% is definitely not
'physiological', although this is clearly
an arbitrary cutoff.
NEONATAL JAUNDICE
Some population groups appear
predisposed to neonatal jaundice, for a
variety of reasons, including a mutation
in UDP glucuronsyl transferase (Asians),
and a high incidence of glucose 6-
phosphate dehydrogenase deficiency
(Greeks, ...).
NEONATAL JAUNDICE
Conjugated hyperbilirubinaemia in the neonate (above
about 2mg%) is rare and worrisome
It suggests that there is obstruction to biliary
outflow, for example due to biliary atresia.
Uncommon enzyme deficiencies (e.g. Alpha-1
antitrypsin deficiency ) and other metabolic
abnormalities, sepsis, and parenteral nutrition may
also cause high levels of conjugated bilirubin in the
neonate

INFECTIA ,NUTRITIA PARENTERALA SI DEF DE
ANTITRIPSINA ...

CONJUGATED BILIRUBIN
as in other age groups, it is produced by
impaired excretion of bilirubin;
beyond scope of this lecture
Follow the list below to identify mechanism.
NEONATAL JAUNDICE
There are numerous reasons why infants
might develop severe unconjugated
hyperbilirubinaemia.
Formerly, before the problem of Rhesus
(Rh) incompatibility was recognised and
addressed, this was a relatively common
cause of major foetal morbidity and
mortality.
NEONATAL JAUNDICE
Mothers would become immunised to
the Rh antigen when small amounts of
foetal (Rh positive) blood leaked into
the Rh-ve maternal circulation, and with
the next pregnancy, the mother would
produce Immunoglobulin G, which
crossed the placenta to cause massive
haemolysis in the foetus.
NEONATAL JAUNDICE
If the baby survived it would often be
severely anaemic,
grossly jaundiced,
critically ill,
with frequent neurological consequences.
Now administration of anti-D should be
performed whenever there is a suspicion of
leakage of Rh
+
foetal cells into the circulation
of the Rh
-
mother,
The anti-D destroys the Rh
+
cells before
maternal sensitization takes place.
NEONATAL JAUNDICE
Perhaps the commonest is ABO
incompatibility - some Group O mothers
will produce IgG antibodies to the A or
B blood group antigens (commonly A),
and these may cause a picture similar to
Rh incompatiblity, but often milder.

NEONATAL JAUNDICE
Any other cause of increased breakdown of red blood
cells can produce a similar picture.
Such causes include:
Glucose 6-phosphate dehydrogenase deficiency ("G6PD",
male infants 'only') - in those with ethnic origins in Greece,
Turkey, Nigeria, Sardinia, and Sephardic Jews from
Kurdistan, Iraq, Iran and Syria.
Uncommon hereditary enzyme deficiencies other than G6PD
deficiency;
Other red cell abnormalities such as hereditary
spherocytosis;
Polycythaemia;
Bleeding into tissues, including cephalhaematomas related to
application of a ventouse (vacuum extraction);

NEONATAL JAUNDICE
Some infants may have markedly impaired liver
conjugation of bilirubin.
This occurs in:
Hypothyroidism (which should anyway be picked up with
routine neonatal screening for the disorder);
Congenital deficiency of bilirubin conjugation: Crigler-Najjar
syndrome types I and II. Patients with type I have absent
UGT1A1, with marked hyperbilirubinaemia and kernicterus;
those with type II have a partial deficiency and rarely
develop neurotoxicity.
Galactosaemia (This and uncommon metabolic disorders such
as tyrosinaemia and hypermethioninaemia frequently
manifest as conjugated hyperbilirubinaemia, but there may
be initial unconjugated hyperbilirubinaemia in galactosaemia);


NEONATAL JAUNDICE
In other disorders, the hyperbilirubinaemia is poorly
understood, or multifactorial.
Conditions include
Neonatal sepsis;
Maternal diabetes ("The infant of the diabetic mother");
Maternal oxytocin therapy;
Dehydration;
Fasting (with increased enterohepatic recirculation of
bilirubin);
Breast-milk jaundice ('maternal milk jaundice');
The combination of Gilbert's syndrome (mutations of
UGT1A1 that usually only manifest in adolescence) and
glucose-6-phosphate dehydrogenase deficiency.

NEONATAL JAUNDICE
Breast milk may cause jaundice.
The mechanism may be related to inhibition of
UGT1A1 by a substance in breast milk.
This 'something' may increase neonatal levels
of free fatty acids, which inhibit UGT1A1.
Fatty acids themselves accumulate in stored
milk and this may explain why such milk tends
to raise bilirubin levels even more. Breast milk
may also increase bilirubin absorption from
the intestine - human breast milk is said to
have substantial beta-glucuronidase activity.


NEONATAL JAUNDICE
Several factors may combine to produce
breast-milk jaundice - a recent report
implicates underlying mutations in UGT1A1 as
a predisposing factor [Pediatrics 2000
Nov;106(5):E59]
Some infant formulae may lessen jaundice!
L-aspartic acid in casein hydrolysate infant
formulae may inhibit beta glucuronidase in the
intestine and thus decrease enterohepatic
recirculation of bilirubin [Pediatr Res 2001
Oct;50(4):460-6].

NEONATAL JAUNDICE
Clearly, it is not just sufficient to treat neonatal
hyperbilirubinaemia - the cause should be found.
Often, a thorough history from the mother and
examination of the infant will reveal a likely cause.
ABO incompatibility in a previous infant is likely to be
followed by jaundice of a similar degree in subsequent ABO
incompatible neonates.
If jaundice due to ABO incompatibility is anticipated, it is
extremely useful to have a sample of cord blood available, so
that infant blood group can be determined, and a Coombs'
test performed if the infant is A, B or AB.
NEONATAL JAUNDICE
Apart from determining infant levels of
conjugated and unconjugated bilirubin, it
may be appropriate to do:
a full blood count (CBC)
a blood smear for red cell morphology,
other tests, depending on ethnicity and
clinical suspicion of red cell haemolytic
disorders.
NEONATAL JAUNDICE
Check the serum albumin levels, as they
regard low values as a risk factor for more
severe consequences of hyperbilirubinaemia.
Albumin can poduce equimolar- binding of
unconjugated bilirubin.
If the albumin level is 30g/dl, then 25mg/dl
of bilirubin is the maximum binding capacity.
NEONATAL JAUNDICE

In children with ABO incompatibility, a
negative Coombs' test does not exclude
haemolysis, as this test is infrequently
positive.
A positive result may suggest more severe
haemolysis.

KRAMERS RULE
Clinical assessment of
the degree of jaundice is
often poorly correlated
with serum levels,
however it is well
recognised that as the
severity increases, so
yellow pigmentation
spreads from the face to
the trunk and eventually
the extremities.
NEONATAL JAUNDICE
If there is staining of the feet, a serum
bilirubin is most advisable.
Transcutaneous bilirubinometry has
been used to screen for infants with
significant hyperbilirubinaemia.
End-tidal carbon monoxide levels have
been described as a measure of bilirubin
production, although this test is not yet
widely available.
NIVLE DE CO AU FOST TESTATE!!
BHUTANI NOMOGRAM
NEONATAL JAUNDICE
Generally, premature infants are at greater
risk of kernicterus, and the tendency is to
start treatment of hyperbilirubinaemia at
lower levels of bilirubin.
Infants with haemolysis are at greater risk
of kernicterus than infants with similar
levels of bilirubin, without haemolysis.
NEONATAL JAUNDICE
Bilirubin levels are commonly expressed
in the old "milligrams percent" (mg/dl),
as paediatricians are familiar with such
levels.
The conversion factor is seventeen - for
example, a level of 20mg% is the same
as 340mol/litre.
In healthy term infants, bilirubin levels
be kept under 20mg%.

NEONATAL JAUNDICE
AAP GUIDELINES
PHOTOTHERAPY
This 'normal' isomer is
sometimes called the
4Z-15Z, or 'ZZ' isomer.
The reactions that
occur with light include
cis-trans isomerisation
about the C 4 -C 5 and C
15 -C 16 double bonds
arrowed above, photo-
oxidation, and
occurrence of an intra-
molecular cyclisation (to
form lumirubin).
PHOTOTHERAPY 1
There are no clear, well-
validated recommendations as
to when phototherapy should
be started.
The American Academy of
Pediatrics have made
recommendations for term
otherwise healthy neonates
that suggest commencement
at levels varying from 15mg%
(levels at 25 to 48 hours), to
20mg% (72 hours or more)
but these have been criticised
as being too relaxed.
PHOTOTHERAPY 2
There are no well-founded recommendations
for neonates who are premature, or those
with haemolysis, although lower threshold
levels seem advisable.
Some have advised phototherapy at all levels
over 10mg% in well prems, or term but ill
neonates, and even more aggressive
management in ill premature babies, for
example at levels of just 5mg%.
PHOTOTHERAPY 3

In suspected ABO incompatibility
[maternal Group O] some perform a
serum bilirubin at 6 hours post-delivery,
and if this is >4.7 mg% (80 mol/l),
phototherapy is started.
KERNICTERUS 1
Pathologically the name 'kernicterus'
comes from the yellow staining seen in the
basal ganglia at post-mortem.
This may manifest as
lethargy, hypotonia and seizures (Phase 1),
followed by hypertonia, opisthotonos and
fever (Phase 2),
and then marked hypertonia (Phase 3, after
about a week).

KERNICTERUS 1bis
With severe haemolysis, kernicterus
occurred in
8% of babies with bilirubin 19-24mg%,
one third of those with bilirubins 25-29mg%,
in three quarters of those with levels of >30.
The long term sequelae are devastating -
delayed motor skills, abnormalities of tone
and reflexes, culminating in cerebral palsy
(especially athetoid CP), and frequent
deafness.
KERNICTERUS 2
There have been reports of
kernicterus in term infants
with hyperbilirubinaemia of
20mg%, and no other 'risk
factors' - such babies were
commonly discharged early on,
and breast-fed.
Such cases have raised
concern about the risks of
watchful management of
hyperbilirubinaemia
PHOTOTHERAPY 4
Modern phototherapy starts from a nurse who
noticed that babies nearer the windows of a
nursery in Essex were less jaundiced than those
further into the room.
The observant nurse who has saved many people
from the ravages of severe hyperbilirubinaemia
was Sr J. Ward (Vincent Harrison, in 2006
provided the name of the nurse ) and the
attending physician was RJ Cremer.
Phototherapy caught on rapidly after his initial
report (apart from in North America, where
delays were substantial).
PHOTOTHERAPY 5
Conventional phototherapy works . There is no
doubt that blue or green light of sufficient
intensity effectively causes
photoisomerisation of bilirubin to products
such as the water-soluble lumirubin, rapidly
excreted in bile (and urine).
There has been much argument about
refinements to the technique of
phototherapy, for example use of high
intensity monochromatic laser light to rapidly
bleach the skin of bilirubin. (An argon laser,
for example, produces light of the
appropriate wavelength).
PHOTOTHERAPY 6
Clearly, the effectiveness of
phototherapy depends not only on the
wavelength and intensity of the light,
but also on duration of therapy and area
of skin exposed to light.
The greater the bilirubin levels in skin,
the more effective phototherapy will
be.
PHOTOTHERAPY 7
Important points in
phototherapy are(1):
Give adequate
phototherapy to a large
skin surface for sufficient
time, turning the infant to
expose all skin areas;
If the light source has a
strong central focus,
position the infant in the
centre of the 'spotlight'.

PHOTOTHERAPY 8
Important points in
phototherapy are(2):
The lamps should not
be more than about
50cm from the
infant's skin.
Energy delivery can be
optimised by having
white reflective cloths
around the
phototherapy unit.

PHOTOTHERAPY 9
Important points in
phototherapy are(3):
Avoid dehydration -
frequent breast-feeding is
appropriate where possible,
otherwise give bottle
supplements (do NOT stop
breast-feeding);
Keep the eyes of the infant
shielded from the light at
all times;

PHOTOTHERAPY 10a
Other important points in phototherapy
are:
The infant's temperature must be
assiduously monitored, preferably using a
skin probe with a reflective backing;
Equipment must be regularly maintained
(fluorescent tubes deteriorate and will
eventually provide inadequate light
intensities; where ultraviolet filters are
used, these too can fail, resulting in burns).

PHOTOTHERAPY 10b
Other important points in
phototherapy are:
Monitor the serum bilirubin
levels and adjust therapy
accordingly;
Frequency of monitoring
must be individualised
according to the patient
Some paediatricians monitor
levels as frequently as
hourly, when initial values
are high.

PHOTOTHERAPY 11
There is a wide variety of
devices available for
phototherapy, but no
standardisation.
A recent paper by Dicken
et al [Physiol Meas 2000
Nov;21(4):493-503]
reviews the problem.
RISKS OF PHOTOTHERAPY
There may be potential for retinal damage if the
eyes are not shielded, and blue light potentially
may cause cellular damage (including damage to
DNA) [Acta Paediatr 1994 Jan;83(1):7-12].
Some units use 'cut-down' nappies, so male
gonads are shielded.
Dehydration is not a problem if hyperthermia is
avoided (transcutaneous temperature probe).
Stools may be more loose than normal.
DISCONTINUATION OF
PHOTOTHERAPY

There is variation about the level at
which phototherapy may be discontinued.
Most give values of about 4mg%.
There is no evidence that a "rebound
hyperbilirubinaemia" occurs after
discontinuation of phototherapy.
Watch the infant carefully, especially
where underlying haemolytic anemia is
present.
EXCHANGE TRANSFUSION
Exchange transfusion involves simultaneously
removing small volumes of patient blood, and
transfusing similar volumes of donor blood mixed with
plasma.
Ultimately, two whole blood volumes are replaced!
The procedure is effective, but substantial potential
complications in up to 12% include:
electrolyte disturbances;
portal vein thrombosis;
infection and even necrotising enterocolitis;
thrombocytopaenia;
subsequent graft-versus-host disease (should the blood not
always be leukodepleted?)

EXCHANGE TRANSFUSSION
There is no exact cutoff level above which exchange
transfusion is mandatory, as the risk factors and
general state of the infant have to be taken into
consideration. Generally it is performed if:
Bilirubin levels have responded poorly to
phototherapy. Urgent phototherapy can still be
attempted, even if levels are initially above threshold
levels for exchange transfusion, but then levels must:
Drop by 1 to 2mg% (20-35mol/l) within 4-6 hr of
immediately starting phototherapy (note that sometimes the
drop is far more impressive, eg. 5mg% or even 10mg% in 2hr,
such substantial drops being more likely, the higher the level
of bilirubin );
Continue to fall progressively thereafter;
EXCHANGE TRANSFUSSION
The bilirubin is above threshold levels.
Threshold levels are generally regarded as
being:
~24 to 25mg% in the term infant without risk
factors (400-430 mol/l);
20mg% in the term infant WITH risk factors;
Unclear in all other infants (See our discussion of
indications for phototherapy ).
An experienced paediatrician should weigh the
risks and benefits.
OTHER OPTIONS 1
Metalloporphyrins (such as tin
mesoporphyrin 6 mol/kg) are reported
to be extremely effective in preventing
hyperbilirubinaemia in healthy term
neonates (but are still somewhat
experimental, despite being described
years ago);
OTHER OPTIONS 2
Phenobarbital takes time to work, and is
not often used owing to the potential
for increased neurotoxicity;
A wide variety of intravenous
supplements have been given with
varying success, including:
albumin (to diminish toxicity),
immunoglobulins (to limit haemolysis);

OTHER OPTIONS 3
Activated charcoal to bind bilirubin in
the gastrointestinal tract (only tried so
far in rats);
Agar has been used orally in neonates,
with moderate success,
Cholestyramine failed in one study of
neonates;




OTHER OPTIONS 4
Use of blood filters containing fungal
bilirubin-oxidase is an interesting but
still experimental therapy (that works,
in rats)!
Also in rats, oral bilirubin-oxidase has
lowered hyperbilirubinaemia.
OTHER OPTIONS 5

Moderate alkalinization (to a pH not over
7.55) has been recommended as a means
of preventing bilirubin neurotoxicity.
Note that glycerine enemas to remove
meconium have no effect on bilirubin
levels

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