Indian Pediatrics 2002; 39: 30-42  

Unconjugated Hyperbilirubinemia in Newborns: Current Perspective

Ramesh Agarwal and A.K. Deorari

From the Neonatal Division, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110 029, India.

Correspondence to: Dr. Ashok K. Deorari, Additional Professor, All India Institute of Medical Scien- ces, New Delhi 110 029, India.

E-mail: [email protected]

Jaundice in newborn is quite common affecting nearly 70% of term and 80% of preterm neonates during first week of life. Luckily, majority of times this is a physio-logical event resulting from increased bilirubin load due to breakdown of red blood corpuscles (RBC); defective uptake, conjuga-tion and excretion by immature liver; and increased entero-hepatic circulation. Neo-natal hyperbilirubinemia also known as pathological jaundice results from increased production and limited elimination of bilirubin during the initial days of newborn period. This occurs in nearly 5 to 25% of neonates(1-3). The common causes include sepsis, G6PD deficiency, prematurity, blood group incompatibilities and majority being idiopathic. Other less common causes include polycythemia, extravasation and oxytocin infusion during labor(1,2). Immature new-born brain is susceptible to toxicity from unconjugated bilirubin resulting in "Kernicterus" or "bilirubin induced brain damage" (BIND).

Bilirubin is derived from the breakdown of the heme proteins that are present in hemoglobin, myoglobin and certain heme containing enzymes. Three fourth of the bilirubin comes from hemoglobin catabolism. One gram of hemoglobin results in the production of 34 mg of bilirubin. A normal term newborn produces about 6-10 mg/kg/day of bilirubin that is nearly 2 to 3 times as compared to adults.

Bilirubin is bound for transport in the blood. This bound bilirubin does not enter the central nervous system and is nontoxic. Upon reaching the liver, only bilirubin enters the liver cell and gets bound to ligandin, which helps to transport it to the site of conjugation. Conjugation occurs with glucuronic acid to produce mono and diglucuronides that are water-soluble. The conjugated bilirubin is transported with the bile to the gut. The gut bacteria reducesa this to stercobilin, which is excreted with feces. In the sterile newborn gut, there is an enzyme called beta-glucuronidase, which converts bilirubin glucuronide into unconjugated bilirubin that is reabsorbed into the circulation. This is called entero-hepatic circulation and is particularly important in babies who are not fed by mouth from birth. With introduction of feeds, bacteria destroy this enzyme.

The bilirubin combines with albumin in molar concentration (one gram of albumin binds to 8.5 mg of bilirubin). This albumin bound bilirubin is transported to liver for conjugation and excretion. The albumin bound bilirubin is unable to cross intact blood brain barrier (BBB) but once bilirubin sites on albumin are saturated, free bilirubin, appears in serum. This free bilirubin can cross the BBB and produce bilirubin brain damage. In cases of existing insult to BBB, even albumin bound bilirubin can get access to central nervous system. Once in contact with neurons, further damage to neurons depends on availability of hydrogen ion. Bilirubin normally exists as a bi-anion and combines with hydrogen ion to form bilirubin acid (BH2), which precipitates on to neurons producing damage. Other theory states that bilirubin combines with one hydrogen ion and this molecule positions itself between lipid bi-layer of the membranes. This moiety has surfactant like property and changes mem-brane function of ion channels producing early manifestation of bilirubin encephalo-pathy(4). This step is reversible on inter-vention thus explaining the reversibility of early bilirubin encephalopathy. However, if acidosis persists then BH2 is formed resulting in permanent neuronal damage.

Clinical judgement is widely used and utilizes the principle that clinical jaundice first becomes obvious on the face followed by a downward progression as it increases in intensity. Assessment of jaundice should be done in natural light. The pulp of finger or thumb is pressed on the baby’s skin, preferably over a bony part, till it blanches. The underlying skin is noted for yellow color. Extent of jaundice thus detected gives a rough estimate of serum bilirubin (Table I). Once bilirubin levels are more than 15 mg/dl, it results in staining of soles and palms. Serum bilirubin estimation should be done by laboratory tests to document bilirubin levels for proper management of neonatal jaundice.

In recent years, lot of efforts have gone in to predict babies likely to develop neonatal hyperbilirubinemia. Reliable predictors can reduce hospital stay for normal babies resulting in early discharge and identifying at risk or high-risk neonates likely to develop pathological jaundice. These neonates would need close monitoring so that potential risk for bilirubin induced brain damage can be reduced amongst term healthy newborns discharged early from hospital.

Bhutani et al.(5) created percentile charts for serum bilirubin at different postnatal ages for direct Coomb’s negative healthy term and near-term newborn infants. The investigator concluded that by doing serum bilirubin at an early age (for example at 24-36 h), subsequent hyperbilirubinemia in a newborn can be predicted by plotting the value on the normogram. If the total serum bilirubin (TSB) value at this age is falling in high risk zone (above 95th percentile) or in intermediate risk zone (40th to 95th percentile zone) then chances of subsequent hyperbilirubinemia are 39.5% and 6.4%, respectively than when it is falling in low risk zone (less than 40th percentile), when there is no measurable risk at all.

In another study(6) of about 500 term healthy newborns, it was observed that a serum bilirubin ³6 mg/dl on the first day of life had a 90% sensitivity of predicting a subsequent TSB ³17 mg/dl between 2nd and 5th day of life. At this critical serum bilirubin value, the negative predictive value was 97.9%. No cases with TSB of <6 mg/dl in first 24 hours required a subsequent phototherapy treatment. In an Indian study(7), a cut off of 3.99 mg/dl at 18-24 h was found to have sensitivity and specificity of 67% each for prediction of subsequent hyperbilirubinemia. If confirmed in other studies, these results suggest that there is a group of infants, who atleast as far as hyperbilirubinemia is concerned, may not require an early follow up. Predischarge TSB levels may also alert the pediatrician to those infants who, because their TSB levels fall in high risk zone, require much more careful surveillance and follow up.

The catabolism of hemoglobin results in equimolar formation of CO and bilirubin. End-tidal carbon monoxide corrected for room air is an indicator of hemolysis and bilirubin production. An elevated end-tidal CO identifies neonates who are high producer of bilirubin, even before the onset of hyper-bilirubinemia, and can aid the pediatrician in rapid identification of neonates at risk for hyperbilirubinemia or hemolytic disease(8).

A number of studies(9,10) have demons-trated the possibility of prediction of serum bilirubin in neonates by analysis of the spectral reflectance from the skin. However, the accuracy of these techniques has been complicated by the variability introduced by skin pigmentation and the dermal maturity; hence the results of studies in white infants may not be applicable to heterogeneous Indian population. A handled Transcutaneous bilirubinometer (Bili CheckTM) has been designed to correct for these interfering factors; being based on recent studies on light scattering charactristics of the human skin. The overall correlation between BiliCheck measurements and serum bilirubin estimation by HPLC is linear (r = 0.91). The measure-ments were independent of gestation, race and ethnicity(11). However, a recent study by our group(12) revealed that transcutaneous bilirubin estimation may be useful screening tool, but it cannot substitute for total serum bilirubin estimation parti-cularly for babies with serum bilirubin >13 mg/dl.

Raised cord blood bilirubin in ABO or non-ABO situation indicates ongoing in-utero hemolysis. These babies are more likely to develop hyperbilirubinemia. A cord bilirubin level >2.5 mg/dl predicts development of pathological jaundice (defined as bilirubin >13 mg/dl) with sensitivity of 71% and specificity of 96%(13).

Healthy term newborn means a baby born at equal to or more than 37 week of gestation, not having any hemolysis or medical illness. American Academy of Pediatrics (AAP) has laid down the guidelines for management of jaundice in these babies(14) (Table II). It was believed that bilirubin induced brain damage (BIND) is unlikely to occur in these babies and therapeutic intervention carries more risk than uncertain risk of hyperbilirubinemia in this population. Recently concern has been expressed over AAP practice parameter:

(i) There have been reports(15) of Kernicterus occurring in otherwise healthy term newborns, with no identifiable risk factors. The infants reported were commonly breastfed and frequently discharged from hospital very soon after birth.

(ii) It relies solely on visual assessment of jaundice that has its own limitation and variations are known to occur especially when not done in proper condition(16). Moreover, once the jaundice involves entire body then it is difficult to quantify bilirubin levels.

(iii) The time interval specified in parameter is too long. A total serum bilirubin (TSB) of 8 at 24.1 h and 47.9 h are to be treated in the same way as both values are occurring on day two. However, in the first situation, TSB is above 95th percentile thus has high risk of subsequent hyperbilirubinemia and needs close follow up while in later situation it is in low risk zone and probably requires no further action. In summary, it can be stated that AAP practice parameter is somewhat liberal but as of now till better guidelines are available, the present one can be used for management of hyperbilirubinemia in healthy term babies.

Since a significant proportion of deliveries are still occurring at home, Rh isoimmuniza-tion is an important public health problem in India(1-3). These babies can present as hydrops at birth if sensitization has been severe enough or as rapidly rising or seriously elevated TSB. Progressive anemia and hepato-splenomegaly are usually present. Peripheral smear shows evidence of hemo-lysis in form of aniso-poikilocytosis, elevated normoblasts and fragmented red cells. The babies are usually Coomb’s positive and reticulocyte count is elevated.

Management of an immune hydrops is a real challenge. Effective management requires team approach of obstetricians and neonatologists beginning from early gesta-tion. Detailed discussion of management of immune hydrops is beyond the scope of present communication. Babies, who are not hydropic, should have TSB and PCV measurement of cord blood in addition to ABO typing and Coomb’s test. In event of severe anemia (PCV <30), partial exchange blood transfusion using 50 ml/kg of packed red blood cells should be carried out for rapid correction of anemia. Double volume exchange blood transfusion is performed if other criteria are met. TSB should be monitored closely every 8-12 hourly and babies should be managed aggressively using intensive phototherapy(17) (Table III).

High dose intravenous immunoglobulin (IVIG) when given early in course of disease can modify the course of illness. When given in dose of 0.5-1 g/kg as single dose, it reduces hemolysis significantly and minimizes the need for exchange transfusion and duration of phototherapy(18,19). Developing countries like ours, where Rh iso-immunization still exists, provide an ideal scenario for conducting a randomized controlled study to show efficacy and safety of IVIG therapy in Rh iso-immunized neonates.

With decrease in incidence of Rh hemolytic disease, ABO incompatibility has become an important cause of hemolytic jaundice in newborn(1-3). In ‘O’ blood group mother isohaemagglutins (Anti A and Anti B) of IgG type cross the placenta and destroy the A or B type red blood cells of the fetus. These isohaemagglutins are of IgG class and differ from the usual isohaemagglutins of IgM class (unable to cross the placenta) normally present in the blood (Anti A in blood group B and Anti B in blood group A). Hemolysis is observed to be more pronounced in infants with blood group ‘A’ than ‘B’. In ABO incompatibility, the hemolysis is usually less severe as compared to Rh incompatibility and present most times after 24 hours of age. Pre-sence of setting does not mean incompati-bility, hence evidence of hemolysis should be carefully looked for by examining the peri-pheral smear and performing reticulocyte count. Direct Coomb’s test is usually nega-tive(13). The suggested management of ABO incompatibility is summarised in Table IV.

Minor blood group incompatibilities, G-6-PD deficiency, hereditary spherocytosis, autoimmune hemolytic anemia are other causes of hemolytic jaundice. Out of these, G-6-PD deficiency deserves special mention. G-6-PD deficiency is a common condition in India, the incidence varying 5-20% among different ethnic groups (1,2,20). It is more common in Tribes and Parsis. Jaundice can present anytime during neonatal period either spontaneously or following exposure to oxidative stress. The patho-physiologic basis for excessive jaundice in infants with G-6-PD deficiency has not been established. Increased erythrocyte breakdown and reduced glucuronidation of bilirubin caused by defective G-6-PD activity in the hepato-cyte may have a role in the pathogenesis(21). It can be severe enough to require exchange blood transfusion(1,2). All infants developing hyperbilirubinemia should have screening for G-6-PD deficiency for counseling of the family regarding avoidance of harmful drugs in later life.

Table IV__Management of ABO Incompatibility

Use correspondingly low level for preterm babies.

5. Preterm Babies

Bilirubin levels for intervention have been reported earlier in babies with standard risk and high risk(22). High risk infants are those having birth weight of less than 1500 g, hypothermia, asphyxia, acidosis, hypo-albuminemia, sepsis, meningitis or being administered drugs having potential to displace bilirubin from albumin. In high risk infants cut off for intervention are lower. As a broad guideline exchange blood transfusion was recommended for babies having bilirubin level of 1% of bodyweight in grams, i.e., for a baby with birth wieght 1700 g bilirubin level for exchange is 17 mg/dl.

There is change in spectrum of bilirubin induced brain damage in preterm babies with virtual disappearance of kernicterus in modern neonatal units in West. New evi-dences suggest that low bilirubin kernicterus in seventies and eighties, which formed basis for these recommendation, was probably because of nature of supportive care and NICU practices such as use of sulfisoxozale and benzyl alcohol. Additionally, in neuro-developmental follow up studies, hyper-bilirubinemia has not emerged as a sole risk factor for poor neurological outcome(23). Recently, there has been a change in management practices of hyperbilirubinemia in preterm babies in form of initiating intervention at higher levels(24). Table V refers to weight based cut off for phototherapy and exchange transfusion. These are approximate guidelines. It has been recommended that each baby should be individualized for the intervention.

Bilirubin handling is related to maturity of hepatobiliary system and hence while deciding for intervention, the gestational age rather than weight should be taken into account.

Multiple studies over last two decades have found higher incidence of hyper-bilirubinemia in breastfed babies. In contrast, De Carvalho et al.(25) reported that fre-quency of feeding was crucial in genesis of neonatal hyperbilirubinemia. More aggres-sive breastfeeding resulted in less incidence of jaundice. These investigators also demonstrated that water or glucose-water supplementation in breastfed infants results in higher serum bilirubin concentrations than in unsupplemented breastfed infants(26). Yammauchi et al. reported that babies breastfeeding more frequently consumed more milk and have less weight loss(27). The degree of jaundice on day 6 of age correlated inversely with frequency of feeding in first 24 hours. In a recent study(28) the role of breastfeeding in jaundice occurring in first week demonstrated a statistically significant positive correlation between patients with a TSB>12.9 mg/dl and supplementary feeding. Breastfed infants did not have higher frequency of significant hyperbilirubinemia but a very small subpopulation had high bilirubin level. Weight loss was strongly associated with significant hyperbilirubi-nemia and it was more pronounced in infants with mixed feeding rather than in those on exclusive breastfeeding. A well-designed longitudinal study on pattern of physiological jaundice in optimally breastfed infant is still lacking. But it is felt that exaggeration of jaundice in breastfed babies is due to inadequate intake of milk and calories rather than any ingredient of breastmilk itself exaggerating jaundice. In optimally breastfed babies, pattern should not differ and exaggeration is probably related to unphysio-logical management of breastfeeding. So while managing these babies, frequent and exclusive breastfeeding should be under-taken.

Table V__ Management of Neonatal Hyperbili-rubinemia in Very Low Birth Weight Babies Based on Bilirubin Level (mg/dl)(24)

a. These are guidelines; each baby should be individualized.
b. As a rough guide, start phototherapy in a well VLBW baby if the bilirubin levels are about one per cent of birth weight and exchange blood transfusion at a value of above plus additional 5 g/dl. A sick VLBW baby requires intervention earlier.

No firm rules can be framed to define abnormal persistence of jaundice in a newborn. It is common to see newborns significantly jaundiced even at 2-3 weeks. A careful review of maternal and infant history and thorough clinical examination of the infant will guide proper management (Table VI). As per AAP practice parameter, these babies should be investigated after three weeks, provided that they are free from any illness, not having abnormal physical examination, dark urine or light stools(14). By far, the most common cause of prolonged jaundice is so called ‘breastmilk jaundice’ (BMJ). These babies can be managed effectively with continuation of breastfeeding and phototherapy even if TSB exceeds 20 mg/dl in a term baby. It is important that one does not stop breastfeeding routinely in these babies, which is of immense benefit for the infant(29). Stopping of breastfeeding, even for short duration, will result in anxiety and consequent suppression of lactation in the mother and many babies may not go on to exclusive breastfeeds again. In addition, this spreads a wrong message about the breast-feeding. Recently, guidelines have been laid down for management of babies with pro-longed conjugated hyperbilirubinemia (30).

Exchange transfusion (ET) is an effective method of lowering seriously elevated bili-rubin. Early exchange blood transfusion reverses the transient bilirubin brain damage(31). Abnormal auditory brainstem evoked response recording in case of neonatal hyperbilirubinemia which persisted even after therapy correlated well with neuro-development delay at 1 year of age(32). Fresh blood, preferably <72 hours old is used. For choice of blood refer to Table VII. The procedure is performed by passing a 5 or 6 F catheter in umbilical vein for a distance where free flow of blood is obtained. In addition to the risk of blood borne infection, ET carries a significant risk of morbidity from vascular accidents, cardiac complications and bio-chemical or hematological disturbances though mortality due to the procedure itself is very rare(1,3,33).

Table VI__Prolonged Jaundice

Phototherapy has been found to be effective in treating hyperbilirubinemia in hemolytic as well as in non-hemolytic settings. It has dramatically reduced the need for exchange transfusion. The decline in TSB is dependent upon dose of irradiance, area of skin exposed and initial TSB level. Unconjugated bilirubin in skin gets converted into water-soluble photoproducts on exposure to light of a particular wavelength (425-475 mm). These photoproducts are water soluble, nontoxic and excreted in intestine and urine. For phototherapy to be effective, bilirubin needs to be present in skin so there is no role for prophylactic phototherapy(24).

(a) Configuration isomerization: Here the Z-isomers of bilirubin are converted into E-isomers. The reaction is instantaneous upon exposure to light but reversible as bilirubin reaches into the bile duct. After exposure of 8-12 hours of phototherapy, this constitutes about 25% of TSB, which is nontoxic. Since this is excreted slowly from body so this is not a major mecha-nism for decrease in TSB.

(b) Structural isomerization: This is an irreversible reaction where the bilirubin is converted into lumirubin. The reaction is directly proportional to dose of photo-therapy. This product forms 2-6% of TSB which is rapidly excreted from body and is mainly responsible for phototherapy induced decline in TSB.

(c) Photo oxidation: This is a minor reaction, where photoproducts are excreted in urine.

Table VII__ Choice of Blood for Exchange Blood Transfusion

The most effective lights for are those with high-energy output near the maximum adsorption peak of bilirubin (450-460 nm). Special blue lamps with a peak output at 425-475 nm are the most efficient and these do not emit harmful ultraviolet rays. Blue green light may interfere with the monitoring of cyanosis. In addition, blue light causes nausea, giddiness and headache to the staff working in NICU. Green light causes erythema and subsequent tanning of skin. A combination of alternating two blue and two white tubelights (20 w each) are sufficient to provide adequate irradiance of 4 to 8 microwatt/cm2/nm. To increase the irradiance to 10-12 microwatt/cm2/nm a combination of four blue and two white tubes have to be used. The irradiance should be measured by fluxmeter(34).

Cool daylight lamps (fluorescent tubelights 6 to 8, 20 W each) with a principal peak at 550 to 600 nm and a range of 380 to 700 nm are most commonly used in phototherapy units in our country. These units provide 4-6 microwatt/cm2/nm, when the fluorescent tubes are new. With usage the irradiance is bound to be much lower than required for therapeutic purposes. These units are effective in the treatment of non-hemolytic jaundice in term and preterm neonates. Occasionally these are not effective especially in cases of severe or rapidly increasing neonatal jaundice. Remember the lamps should be changed every 3 months or earlier if irradiance is being monitored. Putting a blue plastic/perspex or glass sheet in front of white lamps will not increase irradiance of unit in bluegreen range, but rather decrease it. In an attempt to deliver intensified phtotherapy; Carvalho et al. designed a unit using seven daylight fluorescent tubes placed immediately under the floor of a transparent Plexiglas crib(35). The unit delivered an irradiance of 19 µw/cm2/nm and was as efficacious as a unit containing special blue fluorescent tube in treatment of non-hemolytic hyperbilirubi-nemia in term babies.

Halogen white light (150 W, 21 V) having significant output in blue spectrum is useful for infants under radiant warmers. Aperture size (3-20 inch) and unit to mattress distance can be controlled. Inner reflecting surface lining of halogen bulb absorbs majority of infrared (IR) rays (a fan continuously cools it) and a UV filter in front of bulb blocks harmful UV rays from reaching the baby. Indigenous halogen bulb phototherapy units may lack UV filter and thus may not be safe for use(34). The recent fiber-optic light system delivers light from a high-intensity lamp to a fiber-optic pad or blanket. The illumination is transmitted from a halogen lamp source to a bundle of fiber-optic fibers contained in a pad on which the infant can lie. These systems have obvious advantages of not requiring eye patching, does not warm the baby; the equipment is less bulky than conventional phototherapy equipment and babies can be held and nursed while they receive photo-therapy. Available studies(36) have shown that the fiber-optic system is as effective as conventional phototherapy systems in term and preterm babies. Double surface photo-therapy is more effective than the single surface because the average irradiance of the former is greater(37). Double surface photo-therapy can be provided either by double surface special blue lights or by conventional blue light and undersurface fiber-optic photo-therapy. This is a convenient way of deliver-ing double phototherapy when it is necessary to reduce the bilirubin level as rapidly as possible.

A new high intensity gallium nitric blue light emitting diode phototherapy has been tested recently and found to be effective in lowering bilirubin by providing much higher irradiance for intensive phototherapy(38).

It is a mistake to assume that just because a phototherapy unit is emitting fluorescent light when it is switched on; it is necessarily providing treatment for the jaundiced baby. In an audit of phtotherapy units in twenty-four centers providing neonatal care in different parts of country, it was found that only 31% (18/50) units provided an acceptable level of irradiance(39). So it is imperative that one must periodically check irradiance of photo-therapy units used for treating pathological jaundice. Phototherapy used for treating pathological jaundice is like giving a drug. One is not justified in using substandard light sources for treatment of neonatal jaundice. Sunlight is relatively ineffective because of low blue content of light. Besides, hyper-pyrexia and skin burns can occur in prolonged sunlight exposure.

Phototherapy is in use since last 50 years and has shown excellent track of safety. Recently, the effect of phototherapy on cerebral blood flow velocity (CBFV) has been reported. Phototherapy increased mean CBFV in all preterm infants, which returned to pre-therapy values after discontinuation of phototherapy only in non-ventilated babies(4). Even in term babies, phototherapy increased CBFV, which returned to pre-therapy level upon discontinuation of phototherapy(41). Phototherapy has been shown to affect short-term behavior of the term infant, which has been attributed to maternal separation(42). So one should encourage mother to breast-feed and interact with her baby regularly. In addition, phototherapy influences cytokine production by peripheral mononuclear blood cells(43). Phototherapy also has photoxidative effects on intravenous lipids, proteins and drugs like amphotericin B.

Phenobarbitone has long been in use for prevention of jaundice. It induces glucuronyl transferase enzyme thus improves conjuga-tion as well as uptake and excretion of bilirubin by liver cells. Though its use has not become standard of care as of now, there are increasing evidence that phenobarbitone can be a useful preventive measure, especially in preterms(44), hemolytic setting and in event of extravasated blood. If used in doses of 5-10 mg/kg/day, it can have beneficial effect without significant adverse effects.

Hyperbilirubinemia in both Rh and ABO sensitized infants results from destruction of neonatal red cells coated by transplacentally acquired antibodies that causes red cell destruction mediated by Fc receptor bearing cells within the reticuloendothelial system. Recent studies have demonstrated that high dose intravenous immunoglobulin therapy is effective in modifying the hyperbilirubinemia in most cases of Coomb’s positive hemolytic anemia(18,19). It has been proposed that immunoglobulin blocks Fc receptors thereby inhibiting hemolysis and reducing formation of bilirubin. Intravenous immunoglobulin is given in dose of 500-1000 mg/kg as slow infusion over 2 hours. The infant should be carefully monitored for possible adverse effects with particular attention to heart rate and blood pressure.

Metalloporphyrins are competitive inhibi-tor of heme oxygenase, a rate-limiting enzyme in heme catabolism thus reducing the bilirubin production. Clinical trials have demonstrated that tin mesoporphyrins (SnMP) suppresses bilirubin production. The drug has been found to be devoid of major adverse effect, the only being transient cuta-neous rash. SnMP at a single dose of 6 µmol/kg proved more effective than phototherapy in a group of term and near term infants without hemolytic disease(45). Recently a similar study on term breastfed infants without hemolytic disease also showed the ability of SnMP to abolish the need for phototherapy(46). Till date, SnMP remains experimental but it appears to hold a promise for future.

In conclusion, management of unconju-gated hyperbilirubinemia in newborns has undergone changes based on emerging evidences. New approaches for prevention of bilirubin brain damage are on the horizon, but phototherapy and exchange blood transfusion are still the most commonly used effective modalities for lowering serum bilirubin levels. Early prediction of ‘at risk’ neonate for development of significant jaundice is gaining attention and interest of pediatricians. This issue is especially relevant in context of early hospital discharge policy in the developing countries where there is scarcity of resources.

Contributors: AKD provided the framework and overall concept of the article. He will act as the guarantor of the paper. RA collected the data and drafted the manuscript, which was edited by AKD.

Funding: None.

Competing interests: None stated.

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