NEONATAL JAUNDICE

MIHAI CRAIU MD PhD Institute for Mother and Child Care Alfred Rusescu

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

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 unconjugated 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-glucuronyltransferase , 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 deconjugated in the small bowel, and then reabsorbed if not degraded by intestinal microorganisms. 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.

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%. 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 G6PD TSH, T4

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 6phosphate 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

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
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.

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.

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.

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, photooxidation, and occurrence of an intramolecular cyclisation (to form lumirubin).

PHOTOTHERAPY 1
There are no clear, wellvalidated 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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