Neonatal Jaundice 

  • Author: Thor WR Hansen, MD, PhD, MHA, FAAP; Chief Editor: Ted Rosenkrantz, MD   more...
 
Updated: Feb 1, 2012
 

Background

Jaundice is the most common condition that requires medical attention in newborns. 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 excessively rise, 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). 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 as kernicterus.

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Pathophysiology

Neonatal physiologic jaundice results from simultaneous occurrence of the following 2 phenomena:

  • 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.
  • 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, apparently by passive diffusion, 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. 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. 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.

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 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 developing countries.

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 10-15 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.

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.

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Epidemiology

Frequency

United States

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.

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).[1] 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.[2]

International

Incidence varies with ethnicity and geography. Incidence is higher in East Asians and American Indians and lower in blacks. 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.[3]

A study from Turkey reported significant jaundice in 10.5% of term infants and in 25.3% of near-term infants.[4] 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.

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.[5, 6]

Mortality/Morbidity

Kernicterus occurs in 1.5 of 100,000 births in the United States. 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.[7]

Race

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. Black infants are affected less often than white infants. For this reason, significant jaundice in a black 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).[8]

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.[5]

Sex

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.

Age

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

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Contributor Information and Disclosures
Author

Thor WR Hansen, MD, PhD, MHA, FAAP  Professor, Department of Neonatology, Women and Children's Division, Chair, Clinical Ethics Committee, Oslo University Hospital HC, Rikshospitalet, Norway

Thor WR Hansen, MD, PhD, MHA, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for the History of Medicine, American Pediatric Society, European Society for Paediatric Research, New York Academy of Sciences, Perinatal Research Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Oussama Itani, MD, FAAP, FACN  Clinical Associate Professor of Pediatrics and Human Development, Michigan State University; Medical Director, Department of Neonatology, Borgess Medical Center

Oussama Itani, MD, FAAP, FACN is a member of the following medical societies: American Academy of Pediatrics, American College of Nutrition, American College of Physician Executives, and American Heart Association

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Brian S Carter, MD, FAAP  Professor of Pediatrics (Neonatology), Vanderbilt University School of Medicine; Director, Neonatal Follow-up Program, Monroe Carell Jr Children's Hospital at Vanderbilt

Brian S Carter, MD, FAAP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Hospice and Palliative Medicine, American Academy of Pediatrics, American Society for Bioethics and Humanities, American Society of Law, Medicine & Ethics, National Hospice and Palliative Care Organization, Society for Pediatric Research, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Carol L Wagner, MD  Professor of Pediatrics, Medical University of South Carolina

Carol L Wagner, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American Medical Women's Association, American Public Health Association, American Society for Bone and Mineral Research, American Society for Clinical Nutrition, Massachusetts Medical Society, National Perinatal Association, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Ted Rosenkrantz, MD  Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine

Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Pediatric Society, Connecticut State Medical Society, Eastern Society for Pediatric Research, and Society for Pediatric Research

Disclosure: Nothing to disclose.

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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.
Algorithm for the management of jaundice in the newborn nursery.
Guidelines for management of neonatal jaundice currently in use in most 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.
 
 
 
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