Neonatal Jaundice 

Updated: Dec 27, 2017
Author: Thor WR Hansen, MD, PhD, MHA, FAAP; Chief Editor: Muhammad Aslam, MD 

Overview

Background

Jaundice is the most common condition that requires medical attention and hospital readmission in newborns.[89] The yellow coloration of the skin and sclera in newborns with jaundice is the result of accumulation of unconjugated bilirubin. In most infants, unconjugated hyperbilirubinemia reflects a normal transitional phenomenon. However, in some infants, serum bilirubin levels may rise excessively, which can be cause for concern because unconjugated bilirubin is neurotoxic and can cause death in newborns and lifelong neurologic sequelae in infants who survive (kernicterus).[89] For these reasons, the presence of neonatal jaundice frequently results in diagnostic evaluation.

Neonatal jaundice may have first been described in a Chinese textbook 1000 years ago. Medical theses, essays, and textbooks from the 18th and 19th centuries contain discussions about the causes and treatment of neonatal jaundice. Several of these texts also describe a lethal course in infants who probably had Rh isoimmunization. In 1875, Orth first described yellow staining of the brain, in a pattern later referred to by Schmorl as kernicterus.

Pathophysiology

Neonatal physiologic jaundice results from simultaneous occurrence of the following two phenomena[1] :

  • Bilirubin production is elevated because of increased breakdown of fetal erythrocytes. This is the result of the shortened lifespan of fetal erythrocytes and the higher erythrocyte mass in neonates.[2, 3]

  • Hepatic excretory capacity is low both because of low concentrations of the binding protein ligandin in the hepatocytes and because of low activity of glucuronyl transferase, the enzyme responsible for binding bilirubin to glucuronic acid, thus making bilirubin water soluble (conjugation).

Bilirubin is produced in the reticuloendothelial system as the end product of heme catabolism and is formed through oxidation-reduction reactions. Approximately 75% of bilirubin is derived from hemoglobin, but degradation of myoglobin, cytochromes, and catalase also contributes. In the first oxidation step, biliverdin is formed from heme through the action of heme oxygenase, the rate-limiting step in the process, releasing iron and carbon monoxide. The iron is conserved for reuse, whereas carbon monoxide is excreted through the lungs and can be measured in the patient's breath to quantify bilirubin production.

Next, water-soluble biliverdin is reduced to bilirubin, which, because of the intramolecular hydrogen bonds, is almost insoluble in water in its most common isomeric form (bilirubin IXα Z,Z). Because of its hydrophobic nature, unconjugated bilirubin is transported in the plasma tightly bound to albumin. Binding to other proteins and erythrocytes also occurs, but the physiologic role is probably limited. Binding of bilirubin to albumin increases postnatally with age and is reduced in infants who are ill.

The presence of endogenous and exogenous binding competitors, such as certain drugs, also decreases the binding affinity of albumin for bilirubin. A minute fraction of unconjugated bilirubin in serum is not bound to albumin. This free bilirubin is able to cross lipid-containing membranes, including the blood-brain barrier, leading to neurotoxicity. In fetal life, free bilirubin crosses the placenta, possibly by a carrier-mediated process,[4]  and excretion of bilirubin from the fetus occurs primarily through the maternal organism.

When it reaches the liver, bilirubin is transported into liver cells, where it binds to ligandin. Uptake of bilirubin into hepatocytes increases with increasing ligandin concentrations. Ligandin concentrations are low at birth but rapidly increase over the first few weeks of life. Ligandin concentrations may be increased by the administration of pharmacologic agents such as phenobarbital.

Bilirubin is bound to glucuronic acid (conjugated) in the hepatocyte endoplasmic reticulum in a reaction catalyzed by uridine diphosphoglucuronyltransferase (UDPGT). Monoconjugates are formed first and predominate in the newborn. Diconjugates appear to be formed at the cell membrane and may require the presence of the UDPGT tetramer.

Bilirubin conjugation is biologically critical because it transforms a water-insoluble bilirubin molecule into a water-soluble molecule. Water-solubility allows conjugated bilirubin to be excreted into bile. UDPGT activity is low at birth but increases to adult values by age 4-8 weeks. In addition, certain drugs (phenobarbital, dexamethasone, clofibrate) can be administered to increase UDPGT activity.

Infants who have Gilbert syndrome or who are compound heterozygotes for the Gilbert promoter and structural mutations of the UDPGT1A1 coding region are at an increased risk of significant hyperbilirubinemia. Interactions between the Gilbert genotype and hemolytic anemias such as glucose-6-phosphatase dehydrogenase (G-6-PD) deficiency, hereditary spherocytosis, or ABO hemolytic disease also appear to increase the risk of severe neonatal jaundice.

Further, the observation of jaundice in some infants with hypertrophic pyloric stenosis may also be related to a Gilbert-type variant. Genetic polymorphism for the organic anion transporter protein OATP-2 correlates with a 3-fold increased risk for developing marked neonatal jaundice. Combination of the OATP-2 gene polymorphism with a variant UDPGT1A1 gene further increases this risk to 22-fold.[5] Studies also suggest that polymorphisms in the gene for glutathione-S-transferase (ligandin) may contribute to higher levels of total serum bilirubin.

Thus, some interindividual variations in the course and severity of neonatal jaundice may be explained genetically.[6]  As the impact of these genetic variants is more fully understood, development of a genetic test panel for risk of severe and/or prolonged neonatal jaundice may become feasible.[7]

Once excreted into bile and transferred to the intestines, bilirubin is eventually reduced to colorless tetrapyrroles by microbes in the colon. However, some deconjugation occurs in the proximal small intestine through the action of B-glucuronidases located in the brush border. This unconjugated bilirubin can be reabsorbed into the circulation, increasing the total plasma bilirubin pool. This cycle of uptake, conjugation, excretion, deconjugation, and reabsorption is termed 'enterohepatic circulation'. The process may be extensive in the neonate, partly because nutrient intake is limited in the first days of life, prolonging the intestinal transit time.

In mother-infant dyads who are experiencing difficulties with the establishment of breast feeding, inadequate fluid and nutrient intake often leads to significant postnatal weight loss in the infant. Such infants have an increased risk of developing jaundice through increased enterohepatic circulation, as described above. This phenomenon is often referred to as breastfeeding jaundice and is different from the breast milk jaundice described below.

Certain factors present in the breast milk of some mothers may also contribute to increased enterohepatic circulation of bilirubin (breast milk jaundice). β-glucuronidase may play a role by uncoupling bilirubin from its binding to glucuronic acid, thus making it available for reabsorption. Data suggest that the risk of breast milk jaundice is significantly increased in infants who have genetic polymorphisms in the coding sequences of the UDPGT1A1[8] or OATP2 genes. Although the mechanism that causes this phenomenon is not yet agreed on, evidence suggests that supplementation with certain breast milk substitutes may reduce the degree of breast milk jaundice (see Other therapies).

Neonatal jaundice, although a normal transitional phenomenon in most infants, can occasionally become more pronounced. Blood group incompatibilities (eg, Rh, ABO) may increase bilirubin production through increased hemolysis. Historically, Rh isoimmunization was an important cause of severe jaundice, often resulting in the development of kernicterus. Although this condition has become relatively rare in industrialized countries following the use of Rh prophylaxis in Rh-negative women, Rh isoimmunization remains common in low- and middle-income countries (LMICs).

Nonimmune hemolytic disorders (spherocytosis, G-6-PD deficiency) may also cause increased jaundice, and increased hemolysis appears to have been present in some of the infants reported to have developed kernicterus in the United States in the past 15-20 years. The possible interaction between such conditions and genetic variants of the Gilbert and UDPGT1A1 genes, as well as genetic variants of several other proteins and enzymes involved in bilirubin metabolism, is discussed above. More recently, 3 novel mutations in genes encoding either alpha or beta spectrin (SPTA1 or SPTB) were found in 3 unrelated neonates with nonimmune hemolytic jaundice.[87]

These discoveries also highlight the challenges involved in the common use of the terms physiologic jaundice and pathologic jaundice. Although physiologic jaundice is a helpful concept from a didactic perspective, applying it to an actual neonate with jaundice is more difficult.

Consider the following metaphor: Think of total serum bilirubin in neonatal jaundice as a mountain covered by a glacier. If a measurement of the height of the mountain is taken when standing on the summit, the amount of rock and the amount of ice that comprise this measurement is unclear. The same is true for many total serum bilirubin values obtained in neonatal jaundice. An underpinning of physiologic processes and pathological process (eg, Rhesus incompatibility) may clearly contribute to the measurement. However, how much of the measured total value comes from each of these components is unclear. Also, because genetic variants in bilirubin metabolism are only exceptionally pursued in the diagnostic work-up of infants with jaundice, their possible contribution to the measured total serum bilirubin is usually unknown.

Etiology

Physiologic jaundice is caused by a combination of increased bilirubin production secondary to accelerated destruction of erythrocytes, decreased excretory capacity secondary to low levels of ligandin in hepatocytes, and low activity of the bilirubin-conjugating enzyme uridine diphosphoglucuronyltransferase (UDPGT).

Pathologic neonatal jaundice occurs when additional factors accompany the basic mechanisms described above. Examples include immune or nonimmune hemolytic anemia, polycythemia, and the presence of bruising or other extravasation of blood.

Decreased clearance of bilirubin may play a role in breast feeding jaundice, breast milk jaundice, and in several metabolic and endocrine disorders.

Risk factors include the following:

  • Race: Incidence is higher in East Asians and American Indians and is lower in Africans/African Americans.

  • Geography: Incidence is higher in populations living at high altitudes. Greeks living in Greece appear to have a higher incidence than those living outside of Greece.

  • Genetics and familial risk: Incidence is higher in infants with siblings who had significant neonatal jaundice and particularly in infants whose older siblings were treated for neonatal jaundice. Incidence is also higher in infants with mutations/polymorphisms in the genes that code for enzymes and proteins involved in bilirubin metabolism, and in infants with homozygous or heterozygous glucose-6-phosphatase dehydrogenase (G-6-PD) deficiency and other hereditary hemolytic anemias. Combinations of such genetic variants appear to exacerbate neonatal jaundice.[1, 5, 9, 10, 6]

  • Nutrition: Incidence is higher in infants who are breastfed or who receive inadequate nutrition. The mechanism for this phenomenon may not be fully understood. However, when inadequate feeding volume is involved, increased enterohepatic circulation of bilirubin probably contributes to prolonged jaundice. Recent data have shown that breast milk jaundice correlates with higher levels of epidermal growth factor, both in breast milk and in infants' serum.[11]  Data suggest that the difference between breastfed and formula-fed infants may be less pronounced with some modern formulas. However, formulas containing protein hydrolysates have been shown to promote bilirubin excretion.

  • Maternal factors: Infants of mothers with diabetes have higher incidence. Use of some drugs may increase the incidence, whereas others decrease the incidence. Some herbal remedies taken by the lactating mother may apparently exacerbate jaundice in the infant.

  • Birthweight and gestational age: Incidence is higher in premature infants and in infants with low birthweight.

  • Congenital infection

Epidemiology

United States data

An estimated 50% of term and 80% of preterm infants develop jaundice, typically 2-4 days afer birth.[3] Neonatal hyperbilirubinemia is extremely common because almost every newborn develops an unconjugated serum bilirubin level of more than 30 µmol/L (1.8 mg/dL) during the first week of life. Incidence figures are difficult to compare because authors of different studies do not use the same definitions for significant neonatal hyperbilirubinemia or jaundice. In addition, identification of infants to be tested depends on visual recognition of jaundice by health care providers, which varies widely and depends both on observer attention and on infant characteristics such as race and gestational age.[12]

With the above caveats, epidemiologic studies provide a frame of reference for estimated incidence. In 1986, Maisels and Gifford reported 6.1% of infants with serum bilirubin levels of more than 220 µmol/L (12.9 mg/dL).[13] In a 2003 study in the United States, 4.3% of 47,801 infants had total serum bilirubin levels in a range in which phototherapy was recommended by the 1994 American Academy of Pediatrics (AAP) guidelines, and 2.9% had values in a range in which the 1994 AAP guidelines suggest considering phototherapy.[14] In some LMICs, the incidence of severe neonatal jaundice may be as much as 100 times higher than in higher-income countries.[15]

International data

Incidence varies with ethnicity and geography. Incidence is higher in East Asians and American Indians and lower in Africans. Greeks living in Greece have a higher incidence than those of Greek descent living outside of Greece.

Incidence is higher in populations living at high altitudes. In 1984, Moore et al reported 32.7% of infants with serum bilirubin levels of more than 205 µmol/L (12 mg/dL) at 3100 m of altitude.[16]

A study from Turkey reported significant jaundice in 10.5% of term infants and in 25.3% of near-term infants.[17] Significant jaundice was defined according to gestational and postnatal age and leveled off at 14 mg/dL (240 µmol/L) at 4 days in preterm infants and 17 mg/dL (290 µmol/L) in the term infants. Severe neonatal jaundice is 100-fold more frequent in Nigeria than in industrialized countries.[15] In Denmark, 24 in 100.000 infants met exchange transfusion criteria, while 9 in 100.000 developed acute bilirubin encephalopathy.[18]

Studies seem to suggest that some of the ethnic variability in the incidence and severity of neonatal jaundice may be related to differences in the distribution of the genetic variants in bilirubin metabolism discussed above.[1, 5]

Race-related demographics

The incidence of neonatal jaundice is increased in infants of East Asian, American Indian, and Greek descent, although the latter appears to apply only to infants born in Greece and thus may be environmental rather than ethnic in origin. African infants are affected less often than non-African infants. For this reason, significant jaundice in an African infant merits a closer evaluation of possible causes, including G-6-PD deficiency. In 1985, Linn et al reported on a series in which 49% of East Asian, 20% of white, and 12% of black infants had serum bilirubin levels of more than 170 µmol/L (10 mg/dL).[19]

The possible impact of genetic polymorphisms on ethnic variation in incidence and severity should be recognized. Thus, in a study of Taiwanese infants, Huang et al reported that neonates who carry the 211 and 388 variants in the UGT1A1 and OATP2 genes and who are breastfed are at particularly high risk for severe hyperbilirubinemia.[1]

Sex- and age-related demographics

Risk of developing significant neonatal jaundice is higher in male infants. This does not appear to be related to bilirubin production rates, which are similar to those in female infants.

The risk of significant neonatal jaundice is inversely proportional to gestational age.

Prognosis

Prognosis is excellent if the patient receives treatment according to accepted guidelines.

Brain damage due to kernicterus remains a true risk, and the apparent increased incidence of kernicterus in recent years may be due to the misconception that jaundice in the healthy full-term infant is not dangerous and can be disregarded.

Mortality/morbidity

Kernicterus is a complication of neonatal jaundice.

The incidence of kernicterus in North America and Europe ranges from 0.4-2.7 cases per 100,000 births.[20]  Death from physiologic neonatal jaundice per se should not occur. Death from kernicterus may occur, particularly in countries with less developed medical care systems. In one small study from rural Nigeria, 31% of infants with clinical jaundice tested had G-6-PD deficiency, and 36% of the infants with G-6-PD deficiency died with presumed kernicterus compared with only 3% of the infants with a normal G-6-PD screening test result.[21]

Please see the Medscape Drugs & Diseases article Kernicterus for more information.

Patient Education

Parents should be educated about neonatal jaundice and receive written information prior to discharge from the birth hospital. The parent information leaflet should preferably be available in several languages.

A novel 2-color icterometer (Bilistrip) appears to have the potential to facilitate early maternal detection of clinically significant jaundice and help them in decision making to seek medical treatment. In a study that trained mothers in a maternity hospital to use the icterometer on the blanched skin of their infant's nose to determine absence (light yellow) or presence (dark yellow) of significant jaundice, there was a 95.8% sensitivity and 95.8% negative predictive value for detecting infants requiring phototherapy.[82]  Of the 2,492 mother-infant pairs in the study, 347 (13.9%) selected dark yellow; the 2-color icterometer missed only 1 of the 24 neonates who required phototherapy.

A smartphone application (BiliCam) has also been developed to assess neonatal jaundice.[81] It shows promise for effectively screening newborns in a diverse sample of newborns (age < 7 days), including black, Hispanic, and Asian infants. In a study comprising 530 newborns whose estimated bilirubin levels were calculated and compared with total serum bilirubin levels, the use of 2 decision rules resulted in the application providing accurate estimates of total serum bilirubin levels.[81]

 

Presentation

History

Presentation and duration of neonatal jaundice

Note the following:

  • Typically, neonatal jaundice presents on the second or third day of life.

  • Jaundice that is visible during the first 24 hours of life is likely to be nonphysiologic; further evaluation is suggested.

  • Infants who present with jaundice after 3-4 days of life may also require closer scrutiny and monitoring.

  • In infants with severe jaundice or jaundice that continues beyond the first 1-2 weeks of life, the results of the newborn metabolic screen should be checked for galactosemia and congenital hypothyroidism, further family history should be explored (see below), the infant's weight curve should be evaluated, the mother's impressions as far as adequacy of breastfeeding should be elicited, and the stool color should be assessed.

Family history

Obtain the following information:

  • Previous sibling with jaundice in the neonatal period, particularly if the jaundice required treatment

  • Other family members with jaundice or known family history of Gilbert syndrome

  • Anemia, splenectomy, or bile stones in family members or known heredity for hemolytic disorders

  • Liver disease in family members

History of pregnancy and delivery

Ascertain the following information:

  • Maternal illness suggestive of viral or other infection

  • Maternal drug intake, including the use of herbal remedies

  • Delayed cord clamping

  • Birth trauma with bruising and/or fractures.

Postnatal history

Obtain details of the following:

  • Loss of stool color

  • Breastfeeding

  • Use of drugs and herbal remedies in the lactating mother

  • Greater than average weight loss

  • Symptoms or signs of hypothyroidism

  • Symptoms or signs of metabolic disease (eg, galactosemia)

  • Exposure to total parental nutrition

Physical Examination

Neonatal jaundice first becomes visible in the face and forehead. Identification is aided by pressure on the skin, since blanching reveals the underlying color. Jaundice then gradually becomes visible on the trunk and extremities. This cephalocaudal progression is well described, even in 19th-century medical texts. Jaundice disappears in the opposite direction. The explanation for this phenomenon is not well understood, but both changes in bilirubin-albumin binding related to pH and differences in skin temperature and blood flow have been proposed.[22, 23]  This phenomenon is claimed to be clinically useful because, independent of other factors, visible jaundice in the lower extremities strongly suggests the need to check the bilirubin level, either in the serum or noninvasively via transcutaneous bilirubinometry.

Recent work in the author’s group (Tølløfsrud et al, unpublished data) was not able to confirm this so-called cephalocaudal progression of jaundice. Thus, when dermal jaundice was measured noninvasively on the forehead, sternum, and symphysis, no cephalocaudal trend was evident.

In most infants, yellow color is the only finding on physical examination. More intense jaundice may be associated with drowsiness. Brainstem auditory-evoked potentials performed at this time may reveal prolongation of latencies, decreased amplitudes, or both.

Overt neurologic findings, such as changes in muscle tone, seizures, or altered cry characteristics, in a significantly jaundiced infant are danger signs and require immediate attention to prevent kernicterus. In the presence of such symptoms or signs, effective phototherapy should commence immediately without waiting for the laboratory test results (see Laboratory Studies). The potential need for exchange transfusion should not preclude the immediate initiation of phototherapy.[24, 25]

Hepatosplenomegaly, petechiae, and microcephaly may be associated with hemolytic anemia, sepsis, and congenital infections and should trigger a diagnostic evaluation directed towards these diagnoses. Neonatal jaundice may be exacerbated in these situations.

 

DDx

Diagnostic Considerations

Important considerations

Clinicians should recognize the potential of significant jaundice to cause brain damage, even in the healthy full-term neonate.

Assess whether a "healthy full-term neonate" is both healthy and was really delivered at term.

Clinicians should personally examine an infant reported by parents or other caregivers to be significantly jaundiced.

Consider risk factors for significant jaundice when an infant is prepared for early discharge from the birth hospital, and factor such risks, if present, into the plan for follow-up of the baby.

Other conditions to be considered

Certain conditions may cause nonphysiologic jaundice. In these infants, a baseline physiologic jaundice most likely occurs, which is then exaggerated, for example, by increased enterohepatic circulation in bowel atresia, bile stasis in choledochal cyst, or increased bilirubin production in hemolytic anemias. Such conditions include the following:

  • Bowel atresia

  • Hypertrophic pyloric stenosis

  • Choledochal cyst

  • Conjugated hyperbilirubinemia

  • Crigler-Najjar syndrome

  • Arias syndrome

  • Gilbert syndrome

  • Immune hemolytic anemia

  • Nonimmune hemolytic anemia

  • Congenital infections with cytomegalovirus or toxoplasmosis

Differential Diagnoses

 

Workup

Laboratory Studies

Bilirubin measurement may include the following:

  • Transcutaneous bilirubinometry can be performed using handheld devices that incorporate sophisticated optical algorithms. Use of such devices has been shown to reduce the need for blood sampling in infants with jaundice.[26] However, they cannot be used to monitor the progress of phototherapy.[27]

  • Transcutaneous bilirubinometry performs better than visual assessment. The latter is not a reliable technique for estimating levels of bilirubin,[28] but the complete absence of jaundice as judged by the eye in good lighting conditions has quite high accuracy as far as predicting which infants are unlikely to develop high total serum bilirubin levels.[29]

  • In infants with mild jaundice, transcutaneous bilirubinometry may be all that is needed to assure that total bilirubin levels are safely below those requiring intervention.

  • In infants with moderate jaundice, transcutaneous bilirubinometry may be useful in selecting patients who require phlebotomy or capillary blood sampling for serum bilirubin measurement.

  • In infants with extreme jaundice, transcutaneous bilirubinometry may be a useful tool to fast-track such infants to rapid and aggressive therapy.

  • Usually, a total serum bilirubin level test is the only one required in an infant with moderate jaundice who presents on the typical second or third day of life without a history and physical findings suggestive of a pathologic process. Measurement of bilirubin fractions (conjugated vs unconjugated) in serum is not usually required in infants who present as described above. However, in infants who have hepatosplenomegaly, petechiae, thrombocytopenia, or other findings suggestive of hepatobiliary disease, metabolic disorder, or congenital infection, early measurement of bilirubin fractions is suggested. The same may apply to infants who remain jaundiced beyond the first 7-10 days of life, and to infants whose total serum bilirubin levels repeatedly rebound following treatment.

Additional studies may be indicated in the following situations:

  • Infants who present with jaundice on the first or after the third day of life

  • Infants who are anemic at birth

  • Infants who otherwise appear ill

  • Infants in whom serum bilirubin levels are elevated enough to trigger treatment

  • Infants in whom significant jaundice persists beyond the first 2 weeks of life

  • Infants in whom family, maternal, pregnancy, or case histories suggest the possibility of a pathologic process

  • Infants in whom physical examination reveals findings not explained by simple physiologic hyperbilirubinemia

In addition to total serum bilirubin levels, other suggested studies may include the following, particularly if the rate of rise or the absolute bilirubin concentration is approaching the need for phototherapy:

  • Blood type and Rh determination in mother and infant

  • Direct antiglobulin test (DAT) in the infant (direct Coombs test)

  • Hemoglobin and hematocrit values

  • Serum albumin levels: This appears to be a useful adjunct in evaluating risk of toxicity levels because albumin binds bilirubin in a ratio of 1:1 at the primary high-affinity binding site.

  • Nomogram for hour-specific bilirubin values: This is a useful tool for predicting, either before or at the time of hospital discharge, which infants are likely to develop high serum bilirubin values. Infants identified in this manner require close follow-up monitoring and repeated bilirubin measurements. The predictive ability has been shown both for bilirubin values measured in serum and for values measured transcutaneously. The nomogram has also been shown to work well for DAT-positive infants with AB0 incompatibility.[30] A positive DAT test result did not add any value to the clinical management of these infants beyond that already obtained by an hour-specific bilirubin value plotted onto the nomogram.

  • Measurement of end-tidal carbon monoxide in breath: End-tidal carbon monoxide in breath (ETCO) may be used as an index of bilirubin production. Measurement of ETCO may assist in identifying individuals with increased bilirubin production and, thus, at increased risk of developing high bilirubin levels. An apparatus has been developed that makes measuring ETCO simple (CoSenseTM ETCO Monitor, Capnia, Palo Alto, CA, USA).

  • Peripheral blood film for erythrocyte morphology

  • Reticulocyte count

  • Conjugated bilirubin levels: Measuring bilirubin fractions may be indicated in the circumstances described above. Note that direct bilirubin measurements are often inaccurate, are subject to significant interlaboratory and intralaboratory variation, and are generally not a sensitive tool for diagnosing cholestasis unless repeated measurements confirm the presence of an elevated conjugated bilirubin.

  • Liver function tests: Aspartate aminotransferase (ASAT or SGOT) and alanine aminotransferase (ALAT or SGPT) levels are elevated in hepatocellular disease. Alkaline phosphatase and γ-glutamyltransferase (GGT) levels are often elevated in cholestatic disease. A γ-GT/ALAT ratio of more than 1 is strongly suggestive of biliary obstruction. However, it does not distinguish between intrahepatic and extrahepatic cholestasis.

  • Tests for viral and/or parasitic infection: These may be indicated in infants with hepatosplenomegaly, petechiae, thrombocytopenia, or other evidence of hepatocellular disease.

  • Reducing substance in urine: This is a useful screening test for galactosemia, provided the infant has received sufficient quantities of milk.

  • Blood gas measurements: The risk of bilirubin CNS toxicity is increased in acidosis, particularly respiratory acidosis.

  • Bilirubin-binding tests: Although they are interesting research tools, these tests have not found widespread use in clinical practice. Although elevated levels of unbound ("free") bilirubin are associated with an increased risk of bilirubin encephalopathy, unbound bilirubin is but one of several factors that mediate/modulate bilirubin toxicity.

  • Thyroid function tests

Imaging Studies

Ultrasonography: Ultrasonography of the liver and bile ducts is warranted in infants with laboratory or clinical signs of cholestatic disease.

Radionuclide scanning: A radionuclide liver scan for uptake of hepatoiminodiacetic acid (HIDA) is indicated if extrahepatic biliary atresia is suspected. At the author's institution, patients are pretreated with phenobarbital 5 mg/kg/d for 3-4 days before performing the scan.

Other Tests

Auditory and visually evoked potentials are affected during ongoing significant jaundice; however, no criteria have been established that allow extrapolation from evoked potential findings to the risk of kernicterus. Data suggest that the probability of a bilateral "refer" on an automated auditory brainstem response (AABR) study increases with unbound bilirubin concentrations.[31] Because unbound bilirubin concentrations may be more closely correlated with bilirubin neurotoxicity, a "refer" finding may indicate an increased risk of bilirubin neurotoxicity. A "refer" AABR result obtained shortly after admission of an infant with significant jaundice seems to argue for immediate and aggressive treatment.

Brainstem auditory-evoked potentials should be obtained in the aftermath of severe neonatal jaundice to exclude sensorineural hearing loss. In physiologic jaundice, auditory-evoked potentials return to normal with the resolution of hyperbilirubinemia. However, in patients with significant neonatal jaundice or kernicterus, auditory-evoked potentials and functional hearing may remain abnormal.

The phonetic characteristics of the infant's cry are changed in significant neonatal jaundice; however, computerized analyses of these phonetic characteristics are not used in clinical practice.

Histologic Findings

Organs, including the brain, are yellow in any individual with significant jaundice; however, the yellow color does not always indicate CNS toxicity. This distinction was not always clearly understood in older descriptions of so-called "low-bilirubin kernicterus." At present, this has contributed to confusion and uncertainty regarding therapeutic guidelines and intervention levels.

See Kernicterus for a more detailed description.

 

Treatment

Approach Considerations

Surgical care is not indicated in infants with physiologic neonatal jaundice. Surgical therapy is indicated in infants in whom jaundice is caused by bowel or external bile duct atresia.

For infants with physiologic neonatal jaundice, no consultation is required. Gastroenterologists and surgeons may be consulted regarding infants with jaundice resulting from hepatobiliary or bowel disease.

Medical Care

Phototherapy, intravenous immune globulin (IVIG), and exchange transfusion are the most widely used therapeutic modalities in infants with neonatal jaundice. Although medications that impact bilirubin metabolism have been used in studies, drugs are not ordinarily used in unconjugated neonatal hyperbilirubinemia.

Note that neonatal jaundice is a frequent comorbidity in sickle cell disease.[86] These infants may be more vulnerable to blue light phototherapy-induced oxidative stress (eg, increased lipid peroxidation and superoxide dismutase, slight change in activity of catalase and glutathione) and proinflammatory cytokine elevations (tumor necrosis factor alpha, interleukin [IL]-1 and 6).[86]

Phototherapy

Phototherapy is the primary treatment in neonates with unconjugated hyperbilirubinemia.[3] This therapeutic principle was discovered rather serendipitously in England in the 1950s and is now arguably the most widespread therapy of any kind (excluding prophylactic treatments) used in newborns.

Phototherapy is effective because 3 reactions can occur when bilirubin is exposed to light, as follows:

  • Initially, photooxidation was believed to be responsible for the beneficial effect of phototherapy. However, although bilirubin is bleached through the action of light, the process is slow and is now believed to contribute only minimally to the therapeutic effect of phototherapy.

  • Configurational isomerization is a very rapid process that changes some of the predominant 4Z,15Z bilirubin isomers to water-soluble isomers in which one or both of the intramolecular bonds are opened (E,Z; Z,E; or E,E). In human infants, the 4Z,15E isomer predominates, and, at equilibrium conditions, the isomer constitutes about 20-25% of circulating bilirubin after a few hours of phototherapy.[32] This proportion is not significantly influenced by the intensity of light, nor by the character of the light source or use of "double phototherapy."[32]  Data have shown that formation of photoisomers is significant after as little as 15 minutes of phototherapy.[32]  More recent studies suggest that the initial rate of isomerization is inversely related to the hemoglobin level.[32]

  • Structural isomerization consists of intramolecular cyclization, resulting in the formation of lumirubin. This process is enhanced by increasing the intensity of light. During phototherapy, lumirubin may constitute 2-6% of the total serum bilirubin concentration.

The photoisomers of bilirubin are excreted in bile and, to some extent, in urine. The half-life of lumirubin in serum is much shorter than that in E isomers, and lumirubin is the primary pigment found in bile during phototherapy.

Bear in mind when initiating phototherapy that lowering of the total serum bilirubin concentration may be only part of the therapeutic benefit. Because photoisomers, by virtue of their water-soluble nature, should not be able to cross the blood-brain barrier, phototherapy may reduce the risk of bilirubin-induced neurotoxicity as soon as the lights are turned on. At any given total serum bilirubin concentration, the presence of 20-25% of photoisomers means that only 75-80% of the total bilirubin may be present in a form that can enter the brain. Please note that although theoretically coherent, no experimental data support this speculation.

Phototherapy can be administered in a number of ways. To understand the benefits and limitations of the various approaches, some basic principles regarding wavelength and types of light are discussed below with comments and suggestions regarding each system.

First, wavelength must be considered. Bilirubin absorbs light primarily around 450-460 nm. However, the ability of light to penetrate skin is also important; longer wavelengths penetrate better. Thus, lamps with output predominantly in the blue region of the spectrum (460-490 nm) are probably most effective. In practice, light is used in the white, blue, turquoise, and green wavelengths.

Second, previously a dose-response relationship was thought to exist between the amount of irradiation and reduction in serum bilirubin up to an irradiation level of 30-40 µW/cm2/nm. Many older phototherapy units deliver much less energy, some at or near the minimally effective level, which appears to be approximately 6 µW/cm2/nm. On the other hand, newer phototherapy units, when properly configured and with the use of reflecting blankets and curtains may deliver light energy above 40 µW/cm2/nm. Recent data do not confirm that there really is a saturation level.[33] Thus, the relationship between irradiance and the 24-hour decrement in total serum bilirubin was linear up to 55 μW/cm2, and with no evidence of a saturation point.

Third, the energy delivered to the infant's skin decreases with increasing distance between the infant and the light source. This distance should not be greater than 50 cm (20 in) and can be less (down to 10 cm) provided the infant's temperature is monitored.

Fourth, the efficiency of phototherapy depends on the amount of bilirubin that is irradiated. Irradiating a large skin surface area is more efficient than irradiating a small area, and the efficiency of phototherapy increases with serum bilirubin concentration.

Fifth, the nature and character of the light source may affect energy delivery. Irradiation levels using quartz halide spotlights are maximal at the center of the circle of light and decrease sharply towards the perimeter of the circle. Large infants and infants who can move away from the circle's center may receive less efficient phototherapy.

Although green light theoretically penetrates the skin better, it has not been shown unequivocally to be more efficient in clinical use than blue or white light. Because green light makes babies look sick and is unpleasant to work in, green light has not gained widespread acceptance.

Blue fluorescent tubes are widely used for phototherapy.[88] Narrow-spectrum blue lamps (special blue) appear to work best, while ordinary blue fluorescent lamps are probably equivalent to standard white daylight lamps. Blue lights may cause discomfort in hospital staff members, which can be ameliorated by mixing blue and white tubes in the phototherapy unit.

White (daylight) fluorescent tubes are less efficient than special blue lamps; however, decreasing the distance between infants and lamps can compensate for the lower efficiency. Use of reflecting materials also helps. Thus, in LMICs where the cost of special blue lamps may be prohibitive, efficient phototherapy is accomplished with white lamps.

White quartz lamps are an integral part of some radiant warmers and incubators. They have a significant blue component in the light spectrum. When used as spotlights, the energy field is strongly focused towards the center, with significantly less energy delivered at the perimeter, as discussed above.

Quartz lamps are also used in single or double banks of 3-4 bulbs attached to the overhead heat source of some radiant warmers. The energy field delivered by these is much more homogeneous than that of spotlights, and the energy output is reasonably high. However, because the lamps are fixed to the overhead heater unit, the ability to increase energy delivery by moving lights closer to infants is limited.

Fiberoptic lights are also used in phototherapy units. These units deliver high energy levels, but because spectral power (ie, irradiance multiplied by the size of the irradiated area) is related to the size of the lighted field, the smaller "pads" are less efficient than larger wrap-around blankets. Drawbacks of fiberoptic phototherapy units may include noise from the fan in the light source and a decrease of delivered energy with aging and/or breakage of the optic fibers. Some new fiberoptic units now incorporate photodiodes as a light source. Advantages of fiberoptic phototherapy include the following:

  • Low risk of overheating the infant

  • No need for eye shields

  • Ability to deliver phototherapy with the infant in a bassinet next to the mother's bed

  • Simple deployment for home phototherapy

  • The possibility of irradiating a large surface area when combined with conventional overhead phototherapy units (double/triple phototherapy)

Light-emitting diode (LED) lights are found in most newer phototherapy units. Advantages include low power consumption, low heat production, and a much longer life span of the light-emitting units (20,000 hours) compared with older light sources. Blue LED lights have a narrow spectral band of high-intensity light that overlaps the absorption spectrum of bilirubin. Trials comparing LED phototherapy to other light sources were recently reviewed by the Cochrane Collaboration and by Tridente and DeLuca. The authors of these reviews conclude that the efficacy of LED lights in reducing total serum bilirubin levels is comparable to that of conventional light sources (fluorescent or halogen lamps).[34, 35]  Formation of bilirubin photoisomers also appears comparable between LEDs and blue fluorescent lamps.[32]

"Double" and "triple" phototherapy, which implies the concurrent use of 2 or 3 phototherapy units to treat the same patient, has often been used in the treatment of infants with very high levels of serum bilirubin. The studies that appeared to show a benefit with this approach were performed with old, relatively low-yield phototherapy units. Newer phototherapy units provide much higher levels of irradiance. Whether double or triple phototherapy also confers a benefit with the newer units, has not been tested in systematic trials. However, because recent studies appear to rule out the existence of a saturation point (see discussion above), the utility of double or triple phototherapy in extreme jaundice should not be discounted.[32]

The purpose of treating neonatal jaundice is to avoid neurotoxicity. Thus, indications for treatment have been based on clinical studies of infants who developed kernicterus. Historical data, much of which was derived from infants with hemolytic jaundice, appeared to suggest that total serum bilirubin levels greater than 350 µmol/L (20 mg/dL) were associated with increased risk of neurotoxicity, at least in full-term infants.

As treatment of premature infants became more widespread and increasingly successful during the last half of the 20th century, autopsy findings and follow-up data suggested that immature infants were at risk of bilirubin encephalopathy at lower total serum bilirubin levels than mature infants. Treatment was initiated at lower levels for these infants.

Until the 1940s, a truly effective treatment was not available. At that time, exchange transfusion was shown to be feasible and was subsequently used in the treatment of Rh-immunized infants with severe anemia, hyperbilirubinemia, or hydrops. However, exchange transfusion is not without risk for the infant, and only with the discovery of phototherapy did neonatal jaundice start to become an indication for treatment on a wider scale. Once phototherapy was shown to be an apparently innocuous treatment, lights were turned on at lower serum bilirubin values than those that had triggered exchange transfusion.

Exchange transfusion became the second-line treatment when phototherapy failed to control serum bilirubin levels. However, data have shown that treatment with IVIG in infants with Rh or ABO isoimmunization can significantly reduce the need for exchange transfusions.[36, 37] At the author's institution, a tertiary center where exchange transfusions used to be frequent, currently only 0-2 such procedures per year are performed, and IVIG has replaced exchange transfusion as the second-line treatment in infants with isoimmune jaundice.[38]  In a recent 1-year prospective national survey of NICU phototherapy practices in Norway, Mreihil and collaborators found that only 6 exchange transfusions had been performed in a birth population of 60.000 infants (Mreihil K et al, preliminary data).

Clearly, the scientific data on which current therapeutic guidelines are based have very significant shortcomings. Unfortunately, because the endpoint of bilirubin neurotoxicity is permanent brain damage, a randomized study to reassess the guidelines is ethically unthinkable.

In most neonatal wards, total serum bilirubin levels are used as the primary measure of risk for bilirubin encephalopathy. Numerous people would prefer to add a test for serum albumin at higher bilirubin levels because bilirubin entry into the brain, a sine qua non for bilirubin encephalopathy, increases when the bilirubin-albumin ratio exceeds unity. Tests for bilirubin-albumin binding or unbound bilirubin levels are used by some but have failed to gain widespread acceptance. New analytical tools for measurement of unbound bilirubin have greatly simplified the process, but the effect on clinical practice remains to be seen.

Numerous guidelines for the management of neonatal jaundice have been published, and even more appear to be in local use without submission for critical review. In a survey published in 1996, the author analyzed clinical practices in this field based on responses from 108 neonatal intensive care units (NICUs) worldwide.[39] The survey revealed a significant disparity in guidelines.

The image below shows a box-and-whisker plot of the range of serum bilirubin values that trigger phototherapy and exchange transfusion, respectively, in these NICUs. Evidently, an infant might receive an exchange transfusion in one NICU for a serum bilirubin level that would not trigger phototherapy in many other NICUs. This disparity illustrates how difficult it has been to translate clinical data into sensible treatment guidelines.

The graph represents indications for phototherapy The graph represents indications for phototherapy and exchange transfusion in infants (with a birthweight of 3500 g) in 108 neonatal ICUs. The left panel shows the range of indications for phototherapy, whereas the right panel shows the indications for exchange transfusion. Numbers on the vertical axes are serum bilirubin concentrations in mg/dL (lateral) and mmol/L (middle). In the left panel, the solid line refers to the current recommendation of the American Academy of Pediatrics (AAP) for low-risk infants, the line consisting of long dashes (- - - - -) represents the level at which the AAP recommends phototherapy for infants at intermediate risk, and the line with short dashes (-----) represents the suggested intervention level for infants at high risk. In the right panel, the dotted line (......) represents the AAP suggested intervention level for exchange transfusion in infants considered at low risk, the line consisting of dash-dot-dash (-.-.-.-.) represents the suggested intervention level for exchange transfusion in infants at intermediate risk, and the line consisting of dash-dot-dot-dash (-..-..-..-) represents the suggested intervention level for infants at high risk. Intensive phototherapy is always recommended while preparations for exchange transfusion are in progress. The box-and-whisker plots show the following values: lower error bar = 10th percentile; lower box margin = 25th percentile; line transecting box = median; upper box margin = 75th percentile; upper error bar = 90th percentile; and lower and upper diamonds = 5th and 95th percentiles, respectively.

In 2004, the AAP published new guidelines for the management of hyperbilirubinemia in healthy full-term newborns.[40] These guidelines have been plotted on the image above.

The 2004 AAP guidelines represent a significant change from the 1994 guidelines.[40] Thus, the emphasis on preventive action and risk evaluation is much stronger. An algorithm aids in the assessment of risk and the decision about further management and follow-up (see the image below). The committee that wrote the guidelines has carefully assessed the strength of the scientific evidence on which the guidelines are based.

Algorithm for the management of jaundice in the ne Algorithm for the management of jaundice in the newborn nursery.

Practitioners in North America are advised to follow the 2004 AAP guidelines. Although the 2004 AAP guidelines do not provide guidance for treatment of jaundice in the smaller and more premature/immature infants, a group of US experts recently published their suggestions for management of jaundice in preterm infants younger than 35 weeks' gestation.[41]

Clinicians in different ethnic or geographic regions should consider tailoring these guidelines as pertinent to their own populations and must consider factors that are unique to their medical practice settings. Such factors may include racial characteristics, prevalence of congenital hemolytic disorders, prevalence of genetic variants, and environmental concerns. Such adaptation of guidelines should also take into consideration how healthcare delivery systems are organized, as this is likely affect both in-hospital delivery of care as well as follow-up. At present, the wisest course of action may be to apply local guidelines, assuming that these have been successful in the prevention of kernicterus..

With this background and the clear understanding that this is meant only as an example, the image below shows the chart currently in use in all pediatric departments in Norway. These guidelines are the result of a 2006 consensus in the Neonatal Subgroup of the Norwegian Pediatric Society. The similarities between the Norwegian chart and the 2004 AAP guidelines are apparent.

Guidelines for management of neonatal jaundice cur Guidelines for management of neonatal jaundice currently in use in all pediatric departments in Norway. The guidelines were based on previously used charts and were created through a consensus process in the Neonatal Subgroup of the Norwegian Pediatric Society. These guidelines were adopted as national at the fall meeting of the Norwegian Pediatric Society. The reverse side of the chart contains explanatory notes to help the user implement the guidelines. A separate information leaflet for parents was also created.

The Norwegian chart suggests intervention limits for premature/immature infants. For infants of less than 1000 gram birthweight, these guidelines propose starting phototherapy at 100 µmol/L (6 mg/dL) at age 24 hours, increasing gradually to 150 µmol/L (8.8 mg/dL) at age 4 days, and remaining steady thereafter at that level. This compares with a range of 85 µmol/L (5 mg/dL) to 171 µmol/L (10 mg/dL) used in a Neonatal Research Network (NRN) phototherapy trial in infants of less than 1000 gram birthweight. The intervention level depended on postnatal age and whether the infant was allocated to conservative or aggressive phototherapy.[42]

In a post hoc analysis of the NRN data, which compared infants who had not received any phototherapy with those who had received such treatment, the subgroup of infants with birthweights of 501-750 grams who had not received any phototherapy had a significantly higher rate of mental developmental index of less than 50.[43] However, it should be noted that in the original trial analysis, mortality in the aggressive phototherapy group at 501- to 750-g birthweight was 5 percentage points higher than in the conservative group, which, although not significant with the statistical approach chosen for analysis, appeared to offset the possible developmental gain in survivors.[42] Recently these data were reanalyzed using Bayesian statistics[44] and showed that aggressive phototherapy significantly increased the risk of death in the sickest (being on mechanical ventilation at 24 h) and smallest infants (≤750 g birthweight), while at the same time reducing impairment/severe impairment.

Key points in the practical execution of phototherapy include maximizing energy delivery and the available surface area. Also consider the following:

  • The infant should be naked except for diapers (use these only if deemed absolutely necessary and cut them to minimum workable size), and the eyes should be covered to reduce risk of retinal damage.

  • Check the distance between the infant's skin and the light source. With fluorescent lamps, the distance should be no greater than 50 cm (20 in). This distance may be reduced down to 10-20 cm (4-8 in) if temperature homeostasis is monitored to reduce the risk of overheating. Note that this does not apply to quartz lamps.

  • Cover the inside of the bassinet with reflecting material; white linen works well. Hang a white curtain around the phototherapy unit and bassinet. These simple expedients can multiply energy delivery by several fold.

  • When using spotlights, ensure that the infant is placed at the center of the circle of light, since photoenergy drops off towards the circle's perimeter. Observe the infant closely to ensure that the infant doesn't move away from the high-energy area. Spotlights are probably more appropriate for small premature infants than for larger near-term infants.

  • Older data suggested that phototherapy was associated with increased insensible water loss; therefore, many clinicians have routinely added a certain percentage to the infant's estimated basic fluid requirements. Newer data suggest that if temperature homeostasis is maintained, fluid loss is not significantly increased by phototherapy. At the author's institution, routine fluid supplementation for infants under phototherapy has not been used for more than a decade and is not recommended in national guidelines. Rather, the infant is monitored for weight loss, urine output, and urine specific gravity. Fluid intake is adjusted accordingly. In infants who are orally fed, the preferred fluid is milk because it serves as a vehicle to transport bilirubin out of the gut.

  • Timing of follow-up serum bilirubin testing must be individualized. In infants admitted with extreme serum bilirubin values (>500 µmol/L or 30 mg/dL), monitoring should occur every hour or every other hour. Reductions in serum bilirubin values of 85 µmol/L/h (5 mg/dL/h) have been documented under such circumstances. In infants with more moderate elevations of serum bilirubin, monitoring every 6-12 hours is probably adequate.

  • Expectations regarding efficacy of phototherapy must be tailored to the circumstances. In infants in whom serum bilirubin concentrations are still rising, a significant reduction of the rate of increase may be satisfactory. In infants in whom serum bilirubin concentrations are close to their peak, phototherapy should result in measurable reductions in serum bilirubin levels within a few hours. In general, the higher the starting serum bilirubin concentration, the more dramatic the initial rate of decline.

  • Discontinuation of phototherapy is a matter of judgment, and individual circumstances must be taken into consideration. In practice, phototherapy is discontinued when serum bilirubin levels fall 25-50 µmol/L (1.5-3 mg/dL) below the level that triggered the initiation of phototherapy. Serum bilirubin levels may rebound after treatment has been discontinued, and follow-up tests should be obtained within 6-12 hours after discontinuation.

  • Indications for prophylactic phototherapy are debatable. Phototherapy probably serves no purpose in an infant who is not clinically jaundiced. In general, the lower the serum bilirubin level, the less efficient the phototherapy. It seems more rational to apply truly effective phototherapy once serum (and skin) bilirubin has reached levels at which photons may do some good.

  • Wherever phototherapy is offered as a therapeutic modality, a device for measuring the irradiance delivered by the equipment used should be readily at hand. This assists in configuring the phototherapy set-up to deliver optimal efficiency. Some recommend this routinely, every time phototherapy is initiated, and use this as a tool to focus staff attention on maximizing energy delivery.

Generally, phototherapy is very safe and may have no serious long-term effects in neonates; however, the following adverse effects and complications have been noted:

  • Insensible water loss may occur, but data suggest that this issue is not as important as previously believed. Rather than instituting blanket increases of fluid supplements to all infants receiving phototherapy, the author recommends fluid supplementation tailored to the infant's individual needs, as measured through evaluation of weight curves, urine output, urine specific gravity, and fecal water loss.

  • As noted above, a reanalysis of the NRN trial of ”aggressive” versus ”conservative” phototherapy in premature infants of less than 1000 g birthweight showed that mortality was increased in the subgroup of sick 501- to 750-g birthweight infants receiving aggressive' phototherapy.[44] In a recent recommendation for treatment of hyperbilirubinemia in premature infants younger than 35 weeks’ gestation, the authors propose that initial irradiance should be reduced in the most vulnerable infants.[41] However, as pointed out in an editorial to this paper, extant data seem to be more compatible with the interpretation that duration of phototherapy is more dangerous than irradiance levels.[45] Thus, it may be argued that phototherapy should be short and efficient rather than less efficient and of longer duration. This question is still open to interpretation and discussion.

  • Phototherapy may be associated with loose stools. Increased fecal water loss may create a need for fluid supplementation.

  • Retinal damage has been observed in some animal models during intense phototherapy. In an NICU environment, infants exposed to higher levels of ambient light were found to have an increased risk of retinopathy. Therefore, covering the eyes of infants undergoing phototherapy with eye patches is routine. Care must be taken lest the patches slip and leave the eyes uncovered or occlude one or both nares.

  • The combination of hyperbilirubinemia and phototherapy can produce DNA-strand breakage and other effects on cellular genetic material. In vitro and animal data have not demonstrated any implication for treatment of human neonates. However, because most hospitals use (cut-down) diapers during phototherapy, the issue of gonad shielding may be moot.

  • Skin blood flow is increased during phototherapy, but this effect is less pronounced in modern servocontrolled incubators. However, redistribution of blood flow may occur in small premature infants. An increased incidence of patent ductus arteriosus (PDA) has been reported in these circumstances. The appropriate treatment of PDA has been reviewed.[46]

  • Hypocalcemia appears to be more common in premature infants under phototherapy lights. This has been suggested to be mediated by altered melatonin metabolism. Protective head covering may prevent phototherapy-induced hypocalcemia in icteric newborns younger than 35 weeks' gestational age.[85]  Concentrations of certain amino acids in total parenteral nutrition solutions subjected to phototherapy may deteriorate; thus, shield total parenteral nutrition solutions from light as much as possible.

  • Regular maintenance of the equipment is required because accidents have been reported, including burns resulting from a failure to replace UV filters.

Intravenous immune globulin

In relatively recent years, IVIG has been used for numerous immunologically mediated conditions. In the presence of Rh, ABO, or other blood group incompatibilities that cause significant neonatal jaundice, IVIG has been shown to significantly reduce the need for exchange transfusions. However, it must be recognized that some studies have failed to show efficacy. The reasons for this discrepancy have not been explained, but it should be noted that in the studies that failed to show significant effects, IVIG was used more or less prophylactically for all apparently immunized infants, whereas in the studies that reported benefits IVIG was used exclusively as a rescue therapy in infants headed for exchange transfusion. Also, one can speculate whether differences in the origin and characteristics of the IVIG preparation might play a role. If one particular IVIG preparation appears not to work, it may be worthwhile to try IVIG from a different source/manufacturer.

The 2004 AAP guidelines suggest a dose range for IVIG of 500-1000 mg/kg.[40]

The author routinely uses 500 mg/kg infused intravenously over a period of 2 hours for Rh or ABO incompatibility when the total serum bilirubin levels approach or surpass the exchange transfusions limits. The author has, on occasion, repeated the dose 2-3 times. In most cases, when this is combined with intensive phototherapy, avoiding exchange transfusion is possible. In the authors' institution, with about 750 NICU admissions per year, the use of exchange transfusions has decreased to 0-2 per year following the implementation of IVIG therapy for Rh and ABO isoimmunization.[38] The author does not use IVIG in the presence of hydrops. Anecdotally, IVIG appears less likely to be successful when the infant is anemic (Hb < 10 g/dL).

Exchange transfusion

Exchange transfusion is indicated for avoiding bilirubin neurotoxicity when other therapeutic modalities have failed or are not sufficient. In addition, the procedure may be indicated in infants with erythroblastosis who present with severe anemia, hydrops, or both, even in the absence of high serum bilirubin levels.

Exchange transfusion was once a common procedure. A significant proportion was performed in infants with Rh isoimmunization. Immunotherapy in Rh-negative women at risk for sensitization has significantly reduced the incidence of severe Rh erythroblastosis. Therefore, the number of infants requiring exchange transfusion is now much smaller, and even large NICUs may perform only a few procedures per year. As mentioned previously, the incidence of infants requiring exchange transfusion in Norway was in a prospective survey shown to be only 0.01% (Mrehil K et al, preliminary data). ABO incompatibility has become the most frequent cause of hemolytic disease in industrialized countries.

Early exchange transfusion has usually been performed because of anemia (cord hemoglobin < 11 g/dL), elevated cord bilirubin level (>70 µmol/L or 4.5 mg/dL), or both. A rapid rate of increase in the serum bilirubin level (>15-20 µmol/L /h or 1 mg/dL/h) was an indication for exchange transfusion, as was a more moderate rate of increase (>8-10 µmol/L/h or 0.5 mg/dL/h) in the presence of moderate anemia (11-13 g/dL).

The serum bilirubin level that triggered an exchange transfusion in infants with hemolytic jaundice was 350 µmol/L (20 mg/dL) or a rate of increase that predicted this level or higher. Strict adherence to the level of 20 mg/dL has been jocularly referred to as vigintiphobia (fear of 20).

Currently, most experts encourage an individualized approach, recognizing that exchange transfusion is not a risk-free procedure, that effective phototherapy converts 15-25% of bilirubin to nontoxic isomers, and that transfusion of a small volume of packed red cells may correct anemia. Administration of IVIG (500 mg/kg) has been shown to reduce red cell destruction and to limit the rate of increase of serum bilirubin levels in infants with Rh and ABO isoimmunization (see above).

Current AAP guidelines distinguish between 3 risk categories: low, intermediate, and high.[40] These correspond to 3 levels of suggested intervention, which increase from birth and plateau at age 4 days. Naturally, intervention levels associated with exchange transfusion are higher than those for phototherapy. Intensive phototherapy is strongly recommended in preparation for an exchange transfusion. In fact, intensive phototherapy should be performed on an emergency basis in any infant admitted for pronounced jaundice; do not await laboratory test results in these cases. Phototherapy has minimal side effects in this scenario, whereas the waiting period for laboratory test results and blood for exchange can take hours and could constitute the difference between intact survival and survival with kernicterus. If phototherapy does not significantly lower serum bilirubin levels, exchange transfusion should be performed.

Many believe that hemolytic jaundice represents a greater risk for neurotoxicity than nonhemolytic jaundice, although the reasons for this belief are not intuitively obvious, assuming that total serum bilirubin levels are equal. In animal studies, bilirubin entry into or clearance from the brain was not affected by the presence of hemolytic anemia.

The technique of exchange transfusion, including adverse effects and complications, is discussed extensively elsewhere. For more information, please consult Hemolytic Disease of Newborn.

Management of infants with extreme jaundice

Numerous cases have been reported in which infants have been readmitted to hospitals with extreme jaundice. In some cases, significant delays have occurred between the time the infant was first seen by medical personnel and the actual commencement of effective therapy.[47]

Any infant who returns to the hospital with significant jaundice within the first 1-2 weeks of birth should be immediately triaged with measurement of transcutaneous bilirubin. High values should result in immediate initiation of treatment. If such a measuring device is not available, or if the infant presents with any kind of neurological symptoms, the infant should be put in maximally efficient phototherapy as an emergency procedure, preferably by fast-tracking the infant to a NICU. Waiting for laboratory results is not necessary before instituting such therapy because no valid contraindications to phototherapy are possible in this scenario. Plans for an exchange transfusion do not constitute an argument for delaying or not performing phototherapy. Immediate benefit may be obtained within minutes, as soon as conversion of bilirubin into water-soluble photoisomers is measurable (see discussion above).

The need for intravenous hydration in such infants has been discussed. In the absence of clinical signs of dehydration, no evidence suggests that overhydration is helpful. If the infant is dehydrated, hydration should be given as clinically indicated. However, if the infant is able to tolerate oral feeding, oral hydration with a breast milk substitute is likely to be superior to intravenous hydration because it reduces enterohepatic circulation of bilirubin and helps "wash" bilirubin out of the bowel.

Every hospital in which babies are delivered, or which has an emergency department in which infants may be seen, should develop a protocol and triage algorithm for rapid evaluation and management of jaundiced infants. The objective of such a protocol should be rapid recognition of risk severity and reduction in the time to initiate appropriate treatment.

Infants admitted with signs of intermediate to advanced acute bilirubin encephalopathy (ABE) are in urgent need of treatment because reversibility may be possible, even in such cases. The term "crash-cart approach" has been used as a recommendation in such cases. The author, together with other European colleagues, has published a series that included 6 patients with signs of ABE who were urgently managed and appear to have escaped neurologic sequelae.[48]

In a review of the Kernicterus Registry, full recovery was noted in 8 of 11 cases treated with a crash-cart approach, which included effective phototherapy plus exchange transfusion; full recovery was not noted in cases in which delays had occurred.[47] In the Kernicterus Registry, reversal was not observed in cases treated with only phototherapy; the authors strongly recommend that exchange transfusion be performed in such cases.[47] In the European study, reversal was also seen in 2 patients who did not receive exchange transfusion.[48] In one of these cases, IVIG was used in lieu of exchange transfusion; in the other case, intensive phototherapy and intravenous albumin were used.

Other therapies

In infants with breast milk jaundice, interruption of breastfeeding for 24-48 hours and feeding with breast milk substitutes often helps to reduce the bilirubin level. Evidence suggests that the simple expedient of supplementing feeds of breast milk with 5 mL of a breast milk substitute reduces the level and duration of jaundice in breast milk–fed infants. Because this latter intervention causes less interference with the establishment of the breastfeeding dyad, the author prefers to use this approach rather than complete interruption of breast feeding in most cases.

Oral bilirubin oxidase can reduce serum bilirubin levels, presumably by reducing enterohepatic circulation; however, its use has not gained wide popularity. The same may be said for agar or charcoal feeds, which act by binding bilirubin in the gut. Bilirubin oxidase is not available as a drug, and for this reason, its use outside an approved research protocol probably is proscribed in many countries.

Prophylactic treatment of Rh-negative women with Rh immunoglobulin has significantly decreased the incidence and severity of Rh-hemolytic disease.

Diet

Breastfeeding concerns associated with neonatal jaundice are as follows:

  • Incidence and duration of jaundice have increased as breastfeeding has become more popular. The factors in breast milk that contribute to this phenomenon are unclear. In selected infants, interruption of breastfeeding and its replacement for 24-48 hours by a breast milk substitute may be indicated. This decision should always be discussed in person with the mother before implementation. The author's practice is now to first perform a trial of 5 mL of a hydrolyzed formula given after each breast meal. The author typically tries this for at least 1-2 days, with follow-up of bilirubin values. Only if this is unsuccessful does the author occasionally attempt interruption of breast feeding.

  • With increasing emphasis on breastfeeding, some new mothers may have difficulty admitting (even to themselves) to a lack of success in establishing lactation. Occasionally, infants of breastfeeding mothers are admitted to hospitals with severe jaundice. They typically weigh significantly less than their birthweight at a time when they should have regained and surpassed that weight. Presumably, the process is one of increased enterohepatic circulation, as bilirubin is left longer in the proximal gut for lack of milk to bind it and carry it onward and out. This condition is sometimes referred to as "breastfeeding jaundice." These infants may respond dramatically to phototherapy plus oral feedings of milk ad libitum.

Long-Term Monitoring

In the era of early discharge, newborns released within the first 48 hours of life need to be reassessed for jaundice within 1-2 days. The use of the hour-specific bilirubin nomogram may assist in selecting infants with a high likelihood of developing significant hyperbilirubinemia. The 2004 AAP guidelines emphasize the importance of universal systematic assessment for the risk of severe hyperbilirubinemia.[40]  Guidelines from the European Society for Pediatric Research reiterate the same principles.[24]

Neonatal jaundice is one of the most common reasons why neonates are brought to an emergency department after discharge from the birth hospital.[49]

Near-term infants are at higher risk than term infants of developing significant jaundice and merit closer surveillance.[50]

The question of universal bilirubin screening has received attention and is the subject of debate. Some data suggest that predischarge bilirubin screening reduces the number of infants with severe jaundice, as well as the rate of hospital readmissions.[51, 52]  Others have found that home nurse visiting was cost-effective and prevented readmissions for jaundice and dehydration.[53]  However, the cost-effectiveness of preventing kernicterus by universal screening has been questioned.[54]

Nevertheless, in an update to the 2004 AAP jaundice guidelines Maisels et al give a clear recommendation in favor of predischarge bilirubin screening, either by transcutaneous measurement or by serum analysis.[55]

These authors also recommend a more structured approach to management and follow-up according to the predischarge total serum bilirubin and transcutaneous bilirubin (TcB) levels, gestational age (see the Gestational Age from Estimated Date of Delivery calculator), and other risk factors for hyperbilirubinemia. These risk factors include the following:[55]

  • Predischarge total serum bilirubin or transcutaneous bilirubin level measurement in the high-risk or high-intermediate–risk zone

  • Lower gestational age

  • Exclusive breastfeeding, particularly if nursing is not going well and weight loss is excessive

  • Jaundice observed in the first 24 hours

  • Isoimmune or other hemolytic disease (eg, G-6-PD deficiency)

  • Previous sibling with jaundice

  • Cephalohematoma or significant bruising

  • East Asian race

Telephone consultations are not recommended because parental reports cannot be appropriately gauged. Recently, numerous infants have developed kernicterus, resulting, at least in part, from inadequate communication between practitioners or their representatives and parents.

The availability of new devices for transcutaneous measurement of bilirubin levels should facilitate follow-up evaluations of infants discharged before 48 hours of life.

Home phototherapy is used in an effort to limit the high cost of applying such therapy in hospitals. Note the following:

  • Home treatment can avoid or limit parent-child separation. Home treatment should be used with caution, since prevention of neurotoxicity is the goal. Some argue that an infant at risk for neurologic damage should not be at home.

  • With effective treatment strategies, the average duration of phototherapy in the regular neonatal nursery at the author's institution is less than 17 hours. Whether the effort and cost to set up home therapy is worthwhile is debatable. This assessment may be different in different socioeconomic and health financing circumstances.

Infants who have been treated for hemolytic jaundice require follow-up observation for several weeks because hemoglobin levels may fall lower than seen in physiologic anemia. Erythrocyte transfusions may be required if infants develop symptomatic anemia.

Prevention

Prevention of severe neonatal jaundice is best achieved through attention to the risk status of the infant prior to discharge from the birth hospital, through parent education, and through careful planning of postdischarge follow-up.[24, 40]

A predischarge bilirubin measurement, obtained by transcutaneous or serum measurement and plotted into an hour-specific nomogram, has been shown to be a useful tool in distinguishing infants with a low risk of subsequently developing high bilirubin values.

Clinical risk factors include gestational age of less than 38 weeks, the use of oxytocin or vacuum during delivery, exclusive breast feeding, an older sibling with neonatal jaundice that required phototherapy, a rise of ≥ 6 mg/dL/d (≥ 100 μ mol/L/d) in total serum bilirubin levels, and hematomas or extensive bruising. Birth weight is also associated with risk of developing significant jaundice; the higher the birthweight in term infants, the higher the risk.

 

Medication

Medication Summary

Medications are not usually administered in infants with physiologic neonatal jaundice. However, in certain instances, phenobarbital, an inducer of hepatic bilirubin metabolism, has been used to enhance bilirubin metabolism. Several studies have shown that phenobarbital is effective in reducing mean serum bilirubin values during the first week of life. Phenobarbital may be administered prenatally in the mother or postnatally in the infant.

In populations in which the incidence of neonatal jaundice or kernicterus is high, this type of pharmacologic treatment may warrant consideration. However, concerns surround the long-term effects of phenobarbital on these children. Therefore, this treatment is probably not justified in populations with a low incidence of severe neonatal jaundice. Other drugs can induce bilirubin metabolism, but lack of adequate safety data prevents their use outside research protocols.

Intravenous immunoglobulin (IVIG) at 500 mg/kg has been shown to significantly reduce the need for exchange transfusions in infants with isoimmune hemolytic disease.[38] The mechanism is unknown but may be related to the way the immune system handles red cells that have been coated by antibodies. Published experience is still somewhat limited, but administration of immunoglobulin does not appear to be likely associated with greater risks for the infant than an exchange transfusion. Published data regarding efficacy are varied, perhaps having to do with different study sets-up, as studies that show effects of IVIG as far as reducing exchange transfusion have used this drug in a rescue modailty only. One may also speculate that the specific origin and characteristics of the IVIG preparation could play a role. Although speculative, lack of efficacy of a specific IVIG product may warrant trial of one from a different manufacturer or batch.

A new therapy currently under development consists of inhibition of bilirubin production through blockage of heme oxygenase. This can be achieved through the use of metal mesoporphyrins and protoporphyrins. Apparently, heme can be directly excreted through the bile; thus, inhibition of heme oxygenase does not result in accumulation of unprocessed heme. This approach may virtually eliminate neonatal jaundice as a clinical problem. However, before the treatment can be applied on a wide scale, important questions regarding the long-term safety of the drugs must be answered. Also, in light of data suggesting that bilirubin may play an important role as a free radical quencher, a more complete understanding of this putative role for bilirubin is required before wholesale inhibition of its production is contemplated.

Supplementation of probiotics appears to show promise for newborns with pathologic neonatal jaundice. A systematic review and meta-analysis of 13 randomized controlled trials involving 1,067 neonates with jaundice who received probiotics showed a reduction in total serum bilirubin levels after 3, 5, and 7 days, as well as a decrease in the time of jaundice fading, the duration of phototherapy, and length of hospitalization relative to neonates in the control group.[83]  The investigators did not find any reports of serious adverse events.

Zinc sulfate supplementation is a controversial potential approach for treating neonatal jaundice. A systematic review and meta-analysis comprising data from 645 neonates over 5 randomized controlled trials did not show any significant reductions in levels of total serum bilirubin on days 3 and 7, nor reductions in the incidence of bilirubinemia and phototherapy requirements, but zinc supplementation did result in a significantly shorter duration of phototherapy.[84]

 

Follow-up

Further Inpatient Care

Infants who have been treated for neonatal jaundice can be discharged when they are feeding adequately and have had 2 successive serum bilirubin levels demonstrating a trend towards lower values.

If the hospital does not routinely screen newborns for auditory function, ordering such tests prior to discharge is advisable in infants who have had severe jaundice.

The 2004 AAP guideline recommends a systematic risk assessment for hyperbilirubinemia risk in all infants before discharge.[40] Parents should be provided with verbal and written information about jaundice.

Transfer

Infants in need of exchange transfusion born at or admitted to facilities not capable of performing this procedure should be transferred to the nearest facility with such capability. In addition to complete records, the infant should be accompanied by a sample of maternal blood because this is needed by the blood bank to match blood.

However, in determining the best use of time before transfer, as well as the timing of the transfer, the following factors should be considered:

  • If the infant is in imminent danger of kernicterus, or is already exhibiting signs of neurological compromise, the most efficient phototherapy possible under the circumstances should be immediately initiated and should be continued until transfer commences. If fiberoptic or any other kind of phototherapy is technically feasible during transport, it should be continued throughout the duration of the transport.

  • If the hyperbilirubinemia is due to blood group isoimmunization, an infusion of intravenous immunoglobulin (IVIG) at 500 mg/kg should be immediately started and continued before and during transfer until completed (2 h).

Even if the receiving hospital determines that an exchange transfusion should be performed, continuing optimal phototherapy until the actual exchange procedure can commence is important. If fiberoptic phototherapy is available, the infant may be left on a fiberoptic mattress while the exchange is carried out. Oral hydration with a breast milk substitute may aid the clearance of bilirubin from the gut, thus inhibiting enterohepatic circulation of bilirubin, and should be given unless clearly contraindicated by the clinical state of the infant. Although none of these suggestions have been tested in randomized controlled trials, case reports, bilirubin photobiology, and expert opinion suggest that they may be beneficial and, at the very least, are unlikely to be harmful.

 

Questions & Answers

Overview

What is neonatal jaundice?

When was neonatal jaundice first identified?

What is the pathogenesis of neonatal jaundice?

What is the role of bilirubin in the pathophysiology of neonatal jaundice?

What is the role of endogenous and exogenous binding competitors in the pathogenesis of neonatal jaundice?

What is the role of ligandin in the pathogenesis of neonatal jaundice?

What is the role of uridine diphosphoglucuronyltransferase (UDPGT) in the pathogenesis of neonatal jaundice?

What is the role of bilirubin conjugation in the pathogenesis of neonatal jaundice?

Which infants are at an increased risk of significant hyperbilirubinemia and neonatal jaundice?

What is the enterohepatic circulation cycle and which infants have an increased risk of developing jaundice through this mechanism?

What is breast milk jaundice and which genetic factors increase the risk of developing it?

Which factors increase the risk for neonatal jaundice?

What are the challenges to measuring total serum bilirubin values in neonatal jaundice?

What is difference between physiologic and pathologic neonatal jaundice?

What is the role of bilirubin clearance in the etiology of breast feeding jaundice?

What are the risk factors for neonatal jaundice?

What is the incidence of neonatal jaundice in the US?

What is the global incidence of neonatal jaundice?

Does the incidence of neonatal jaundice vary among racial or ethnic groups?

Is there a gender predilection for neonatal jaundice?

Does the risk for neonatal jaundice vary by gestational age?

What is the prognosis of neonatal jaundice?

What is the incidence of kernicterus in neonatal jaundice?

How should parents be educated about neonatal jaundice?

How can parents detect early neonatal jaundice in their newborns?

Presentation

What is the timing for the appearance of neonatal jaundice?

What is the focus of family history in cases of neonatal jaundice?

What information is elicited from history of pregnancy and delivery in cases of neonatal jaundice?

Which details of postnatal history should be obtained for neonatal jaundice?

How is neonatal jaundice initially identified?

What is the significance of cephalocaudal progression in neonatal jaundice?

What are physical findings of neonatal jaundice?

What immediate actions should be taken if neurologic symptoms are present in neonatal jaundice?

Which conditions may exacerbate neonatal jaundice?

DDX

What are important considerations in healthy full-term neonates with neonatal jaundice?

Which conditions may cause nonphysiologic jaundice in neonates?

What are the differential diagnoses for Neonatal Jaundice?

Workup

How should bilirubin be measured in neonates?

Which conditions may require additional testing during evaluation of neonatal jaundice?

Which studies are performed if the rate of rise or the absolute bilirubin concentration is approaching the need for phototherapy for neonatal jaundice?

What is the role of ultrasonography in the evaluation of neonatal jaundice?

What is the role of radionuclide scanning in the evaluation of neonatal jaundice?

What is the role of an automated auditory brainstem response (AABR) study in the evaluation of neonatal jaundice?

What is the role of brainstem auditory evoked potentials (BAEPs) in the evaluation of neonatal jaundice?

Do phonetic characteristics of an infant&#39;s cry have a role in the evaluation of neonatal jaundice?

What do yellow organs indicate in the evaluation of neonatal jaundice?

Treatment

What are the indications for surgical care or specialist consultations in the management of neonatal jaundice?

When is double and triple phototherapy indicated for the treatment of neonatal jaundice?

What are the treatment options for neonatal jaundice?

What is the primary treatment for neonatal jaundice?

Why is phototherapy effective treatment for neonatal jaundice?

What are the benefits of phototherapy for the treatment of neonatal jaundice?

How is phototherapy administered for the treatment of neonatal jaundice?

Is green light more effective than blue or white light for the treatment of neonatal jaundice?

What are the advantages and disadvantages of blue fluorescent tubes in phototherapy for the treatment of neonatal jaundice?

What are the advantages and disadvantages of white (daylight) fluorescent tubes in phototherapy for the treatment of neonatal jaundice?

Are white quartz lamps effective phototherapy for the treatment of neonatal jaundice?

What are the advantages and disadvantages of using fiber optic lights in phototherapy for neonatal jaundice?

What are the advantages and disadvantages of using light-emitting diode (LED) lights in phototherapy for neonatal jaundice?

At what total serum bilirubin level is the risk of neurotoxicity increased in patients with neonatal jaundice?

Is the risk for bilirubin encephalopathy increased in premature infants with neonatal jaundice?

What is the historical role of exchange transfusion in the treatment of neonatal jaundice?

When is exchange transfusion indicated for the treatment of neonatal jaundice?

Why is scientific data from randomized studies limited for neonatal jaundice?

What is the primary measure of risk for bilirubin encephalopathy in neonatal jaundice?

What are the limitations of the available guidelines for the management of neonatal jaundice?

Does the serum bilirubin value that triggers phototherapy and exchange transfusion in neonatal intensive care units (NICUs) vary for the treatment of neonatal jaundice?

What is the emphasis of the AAP guidelines for the management of hyperbilirubinemia in healthy full-term newborns?

What are the recommended guidelines for the treatment of neonatal jaundice?

What are the Neonatal Subgroup of the Norwegian Pediatric Society guidelines for the treatment of neonatal jaundice?

What were the published results of the Neonatal Research Network (NRN) phototherapy trial for the treatment of neonatal jaundice?

What should be considered in the administration of phototherapy for the treatment of neonatal jaundice?

What are the possible adverse effects and complications of phototherapy for treating neonatal jaundice?

What is the role of IVIG in the treatment of neonatal jaundice?

What are the AAP guidelines for IVIG dosing in the treatment of neonatal jaundice?

When is an exchange transfusion indicated for the treatment of neonatal jaundice?

How common is exchange transfusion for the treatment of neonatal jaundice?

Why is an early exchange transfusion performed for the treatment of neonatal jaundice?

Which serum bilirubin level triggers an exchange transfusion in infants with hemolytic jaundice?

What should be considered when selecting treatment for neonatal jaundice?

What are the AAP guidelines for the treatment selection in neonatal jaundice?

What is the risk for neurotoxicity in hemolytic jaundice?

What are the techniques for exchange transfusion for neonatal jaundice?

What is the management of infants readmitted with extreme jaundice?

What is the role of hydration in the management of neonatal jaundice?

Are there protocols for the rapid evaluation and management of neonatal jaundice?

What is the crash-cart approach to treatment of acute bilirubin encephalopathy (ABE)?

What is the efficacy of a crash-cart approach to management of infants with extreme jaundice?

What is the role of breastfeeding in the management of neonatal jaundice?

Are oral bilirubin oxidase, agar or charcoal feeds effective treatments for neonatal jaundice?

Which prophylactic measure has decreased the incidence and severity of Rh-hemolytic disease in neonatal jaundice?

Can breastfeeding increase the risk of neonatal jaundice?

What are the guidelines recommendations for monitoring for neonatal jaundice in newborns released within the first 48 hours of life?

Which infants are at higher risk of developing significant jaundice?

What is the AAP guidelines recommendation for screening for neonatal jaundice prior to discharge?

What are the risk factors for hyperbilirubinemia in neonatal jaundice?

What is the efficacy of telephone consultations for monitoring of neonatal jaundice?

Have new devices for transcutaneous measurement of bilirubin levels facilitated monitoring for neonatal jaundice?

What is the role of home phototherapy for the treatment of neonatal jaundice?

What is the protocol for monitoring of infants who received treatment for hemolytic jaundice?

How is severe neonatal jaundice prevented?

Which tool is available for distinguishing infants with a low risk of subsequently developing neonatal jaundice?

What are clinical risk factors for neonatal jaundice?

Medications

Which medications are administered for infants with physiologic neonatal jaundice?

Is IVIG an effective treatment for neonatal jaundice?

What is the role of bilirubin production inhibition via metal mesoporphyrins and protoporphyrins in the treatment of neonatal jaundice?

What is the role of supplementation of probiotics in the treatment of neonatal jaundice?

What is the role of zinc sulfate supplementation in the treatment of neonatal jaundice?

Follow-up

When can infants treated for neonatal jaundice be discharged?

What is the protocol for transfer of infants with neonatal jaundice in need of exchange transfusion?

Should phototherapy be continued while exchange transfusion is performed for the treatment of neonatal jaundice?