Sections

Overview

Background

Jaundice is the most common condition that requires medical attention and hospital readmission in newborns.^[1]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 IXα (Z,Z) is neurotoxic and can cause death in newborns and lifelong neurologic sequelae in infants who survive (kernicterus).^[1]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.^[2]

Next: Pathophysiology

Pathophysiology

Neonatal physiologic jaundice results from simultaneous occurrence of the following two phenomena^[3]:

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.^{[4, 5]}
Hepatic excretory capacity is low, 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.^[6]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), 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). Owing to 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. Albumin-bound bilirubin increases postnatally with age and is reduced in infants who are ill.

The presence of endogenous and exogenous binding competitors (eg, certain drugs) also reduces 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,^{[7, 8]}and fetal excretion of bilirubin occurs primarily through the maternal organism.

When it reaches the liver, bilirubin is transported into liver cells, where it binds to ligandin.^[6]Uptake of bilirubin into hepatocytes increases with increasing ligandin concentrations. Ligandin concentrations are low at birth but rapidly rise 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.^[9]Interactions between the Gilbert genotype and hemolytic anemias such as glucose-6-phosphatase dehydrogenase (G6PD) deficiency, hereditary spherocytosis, or ABO hemolytic disease also appear to raise 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 OATP2 correlates with a three-fold increased risk for developing marked neonatal jaundice. Combination of the OATP2 gene polymorphism with a variant UDPGT1A1 gene further increases this risk to 22-fold.^[10]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.^[11]As the impact of these genetic variants is more fully understood, development of a genetic test panel for the risk of severe and/or prolonged neonatal jaundice may become feasible.^{[9, 12]}

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 breastfeeding, inadequate fluid and nutrient intake often leads to significant postnatal weight loss in the infant. Such infants have an elevated 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.^[13]

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^[14]or OATP2 genes. Other data have also shown that breast milk jaundice correlates with higher levels of epidermal growth factor, both in breast milk and in infants' serum.^[15]Although there is no consensus on the mechanism(s) that causes this phenomenon,^[13]evidence suggests that supplementation with breast milk substitutes that contain protein hydrolysates may reduce the degree of breast milk jaundice (see "Other therapies" under Medical Care). Data further suggest that the difference between breastfed and formula-fed infants may be less pronounced with some modern formulas.

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).^[16]

Nonimmune hemolytic disorders (spherocytosis, G-6-PD deficiency) may also cause increased jaundice,^[17]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, three novel mutations in genes encoding either alpha or beta spectrin (SPTA1 or SPTB) were found in three unrelated neonates with nonimmune hemolytic jaundice.^[18]

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 a pathologic process (eg, Rh 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.

Next: Pathophysiology

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 UDPGT.^[6]

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 breastfeeding jaundice, breast milk jaundice, and in several metabolic and endocrine disorders.

Risk factors for increased nenatal jaundice include the following^[19]:

Lower gestational age (ie, the risk increases with each additional week less than 40 wk)
Jaundice in the first 24 hours after birth
Predischarge transcutaneous bilirubin (TcB) or total serum bilirubin (TSB) concentration close to the phototherapy threshold
Hemolysis from any cause, if known or suspected based on a rapid rate of increase in the TSB or TcB of over 0.3 mg/dL per hour in the first 24 h or more than 0.2 mg/dL per hour thereafter.
Phototherapy before discharge
Parent or sibling requiring phototherapy or exchange transfusion
Family history or genetic ancestry suggestive of inherited red blood cell disorders, including G6PD deficiency
Exclusive breastfeeding with suboptimal intake
Scalp hematoma or significant bruising
Down syndrome
Macrosomic infant of a diabetic mother

Further risk factors to consider also include^[20]:

Race/ethnicity: The incidence is higher in East Asians and American Indians and is lower in Africans/African Americans.
Geography: A higher incidence occurs 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: There is a higher incidence in infants with mutations/polymorphisms in the genes that code for enzymes and proteins involved in bilirubin metabolism. Combinations of genetic variants appear to exacerbate neonatal jaundice.^{[3, 9, 10, 11, 21, 22]}
Maternal factors: Use of some drugs may increase the incidence, whereas others lower the incidence of neonatal jaundice. Some herbal remedies taken by the lactating mother may apparently exacerbate jaundice in the infant.
Congenital infection

Next: Pathophysiology

Epidemiology

United States data

An estimated 50% of term and 80% of preterm infants develop jaundice, typically 2-4 days after birth.^[5]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.^[20]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 healthcare providers, which varies widely and depends both on observer attention and on infant characteristics such as race and gestational age.^{[20, 23]}

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).^[24]In a 2003 US study, 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 suggested for considering phototherapy.^[25]

In 2022, the AAP raised the phototherapy thresholds by a narrow range in the updated clinical practice guidelines for the management of hyperbilirubinemia.^{[19, 26]}(See Guidelines.)

International data

The international incidence varies with ethnicity and geography. There is a higher incidence in East Asians and American Indians and a lower one in Africans. Greeks living in Greece have a higher incidence than those of Greek descent living outside of Greece.^[20]

There is also a higher incidence in populations living at high altitudes. 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.^[27]

A study from Turkey reported significant jaundice in 10.5% of term infants and in 25.3% of near-term infants.^[28]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 term infants. In Denmark, 24 in 100,000 infants met exchange transfusion criteria, whereas 9 in 100,000 developed acute bilirubin encephalopathy.^[29]

In some LMICs, the incidence of severe neonatal jaundice may be as much as 100 times higher than that in higher-income countries.^{[16, 30]}Severe neonatal jaundice is 100-fold more frequent in Nigeria than in industrialized countries.^[30]

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, previously discussed above.^{[3, 10]}

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.^[20]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 G6PD deficiency.^{[16, 17]} 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).^[31]

It is important to recognize the possible impact of genetic polymorphisms on ethnic variation in incidence and severity. Thus, in a study of Taiwanese infants, Huang et al reported that neonates particularly at high risk for severe hyperbilirubinemia carry the 211 and 388 variants in the UGT1A1 and OATP2 genes and are breastfed.^[3]

Sex- and age-related demographics

Male infants are at higher risk of developing significant neonatal jaundice. 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.

Next: Pathophysiology

Prognosis

Prognosis of neonatal jaundice 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 relatively recent years may be due to the misconception that jaundice in the healthy full-term infant is not dangerous and can be disregarded. In a retrospective survey from the United Kingdom, most infants who were subsequently diagnosed with kernicterus had been discharged home from the birth hospital, and there was a delay between recognition of jaundice and readmission, with a range of 26-102 hours.^[32]Of further note, the majority of these infants had an underlying diagnosis which raised the risk of pathologic neonatal jaundice.

Morbidity/mortality

Kernicterus is the most important complication of neonatal jaundice. The incidence of kernicterus in North America and Europe ranges from 0.16 to 2.7 cases per 100,000 births.^{[33, 34]}Death from physiologic neonatal jaundice per se should not occur. Death from kernicterus may occur, particularly in countries with less developed medical care systems.^[16]In a study from rural Nigeria, 31% of infants with clinical jaundice tested had G6PD deficiency,—36% of these infants with G6PD deficiency died with presumed kernicterus compared with only 3% of the infants with a normal G6PD screening test result.^[35]

Please see Kernicterus for more information.

Next: Pathophysiology

Patient Education

Educate parents about neonatal jaundice and provide written information prior to discharge from the birth hospital. The parent information leaflet should preferably be available in several languages. Examples of such guidelines are available from the American Academy of Pediatrics^[36]and The Norwegian Pediatric Association.^[37]

A novel two-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.^[38]Of the 2,492 mother-infant pairs in the study, 347 (13.9%) selected dark yellow; the two-color icterometer missed only 1 of the 24 neonates who required phototherapy.

Several smartphone applications have been developed to assess neonatal jaundice (BiliCam, BiliScan, Picterus, and neoSCB)^[39]. These show promise for effectively screening newborns for neonatal jaundice. In a study comprising 530 newborns whose estimated bilirubin levels were calculated and compared with total serum bilirubin levels, the use of two decision rules resulted in the application providing accurate estimates of total serum bilirubin levels.^[40]

Clinical Presentation

Mitra S, Rennie J. Neonatal jaundice: aetiology, diagnosis and treatment. Br J Hosp Med (Lond). 2017 Dec 2. 78 (12):699-704. [QxMD MEDLINE Link].
Hansen TW. Pioneers in the scientific study of neonatal jaundice and kernicterus. Pediatrics. 2000 Aug. 106 (2):E15. [QxMD MEDLINE Link].
Huang MJ, Kua KE, Teng HC, Tang KS, Weng HW, Huang CS. Risk factors for severe hyperbilirubinemia in neonates. Pediatr Res. 2004 Nov. 56 (5):682-9. [QxMD MEDLINE Link].
Christensen RD, Yaish HM. Hemolytic disorders causing severe neonatal hyperbilirubinemia. Clin Perinatol. 2015 Sep. 42 (3):515-27. [QxMD MEDLINE Link].
Woodgate P, Jardine LA. Neonatal jaundice: phototherapy. BMJ Clin Evid. 2015 May 22. 2015:0319. [QxMD MEDLINE Link]. [Full Text].
Hansen TWR, Wong RJ, Stevenson DK. Molecular physiology and pathophysiology of bilirubin handling by the blood, liver, intestine, and brain in the newborn. Physiol Rev. 2020 Jul 1. 100 (3):1291-346. [QxMD MEDLINE Link]. [Full Text].
Macias RI, Marin JJ, Serrano MA. Excretion of biliary compounds during intrauterine life. World J Gastroenterol. 2009 Feb 21. 15 (7):817-28. [QxMD MEDLINE Link]. [Full Text].
Itoh S, Okada H, Koyano K, et al. Fetal and neonatal bilirubin metabolism. Front Pediatr. 2022. 10:1002408. [QxMD MEDLINE Link]. [Full Text].
Riordan SM, Bittel DC, Le Pichon JB, et al. A hypothesis for using pathway genetic load analysis for understanding complex outcomes in bilirubin encephalopathy. Front Neurosci. 2016. 10:376. [QxMD MEDLINE Link]. [Full Text].
Yusoff S, Van Rostenberghe H, Yusoff NM, et al. Frequencies of A(TA)7TAA, G71R, and G493R mutations of the UGT1A1 gene in the Malaysian population. Biol Neonate. 2006. 89 (3):171-6. [QxMD MEDLINE Link].
Memon N, Weinberger BI, Hegyi T, Aleksunes LM. Inherited disorders of bilirubin clearance. Pediatr Res. 2016 Mar. 79 (3):378-86. [QxMD MEDLINE Link]. [Full Text].
Watchko JF, Lin Z. Genetics of neonatal jaundice. In: Stevenson DK, Maisels MJ, Watchko JF, eds. Care of the Jaundiced Neonate. New York: McGraw-Hill; 2012. 1-27.
Flaherman VJ, Maisels MJ, Academy of Breastfeeding Medicine. ABM clinical protocol #22: guidelines for management of jaundice in the breastfeeding infant 35 weeks or more of gestation-revised 2017. Breastfeed Med. 2017 Jun. 12 (5):250-7. [QxMD MEDLINE Link].
Fujiwara R, Maruo Y, Chen S, Tukey RH. Role of extrahepatic UDP-glucuronosyltransferase 1A1: advances in understanding breast milk-induced neonatal hyperbilirubinemia. Toxicol Appl Pharmacol. 2015 Nov 15. 289 (1):124-32. [QxMD MEDLINE Link]. [Full Text].
Kumral A, Ozkan H, Duman N, Yesilirmak DC, Islekel H, Ozalp Y. Breast milk jaundice correlates with high levels of epidermal growth factor. Pediatr Res. 2009 Aug. 66 (2):218-21. [QxMD MEDLINE Link].
Olusanya BO, Kaplan M, Hansen TWR. Neonatal hyperbilirubinaemia: a global perspective. Lancet Child Adolesc Health. 2018 Aug. 2 (8):610-20. [QxMD MEDLINE Link].
Kaplan M, Bromiker R, Hammerman C. Hyperbilirubinemia, hemolysis, and increased bilirubin neurotoxicity. Semin Perinatol. 2014 Nov. 38 (7):429-37. [QxMD MEDLINE Link].
Christensen RD, Agarwal AM, Yaish HM, Reading NS, O'Brien EA, Prchal JT. Three novel spectrin variants in jaundiced neonates. Clin Pediatr (Phila). 2018 Jan. 57 (1):19-26. [QxMD MEDLINE Link].
[Guideline] Kemper AR, Newman TB, Slaughter JL, et al. Clinical practice guideline revision: management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2022 Sep 1. 150 (3):e2022058859. [QxMD MEDLINE Link]. [Full Text].
Hansen TW. Narrative review of the epidemiology of neonatal jaundice. Pediatr Med. 2021 May 28. 4:4-18. [Full Text].
Hua L, Shi D, Bishop PR, Gosche J, May WL, Nowicki MJ. The role of UGT1A1*28 mutation in jaundiced infants with hypertrophic pyloric stenosis. Pediatr Res. 2005 Nov. 58 (5):881-4. [QxMD MEDLINE Link].
Yamamoto A, Nishio H, Waku S, et al. Gly71Arg mutation of the bilirubin UDP-glucuronosyltransferase 1A1 gene is associated with neonatal hyperbilirubinemia in the Japanese population. Kobe J Med Sci. 2002 Aug. 48 (3-4):73-7. [QxMD MEDLINE Link].
Maisels MJ, Newman TB. The epidemiology of neonatal hyperbilirubinemia. In: Stevenson DK, Maisels MJ, Watchko JF, eds. Care of the Jaundiced Neonate. New York: McGraw-Hill; 2012. 97-113.
Maisels MJ, Gifford K. Normal serum bilirubin levels in the newborn and the effect of breast-feeding. Pediatrics. 1986 Nov. 78 (5):837-43. [QxMD MEDLINE Link].
Atkinson LR, Escobar GJ, Takayama JI, Newman TB. Phototherapy use in jaundiced newborns in a large managed care organization: do clinicians adhere to the guideline?. Pediatrics. 2003 May. 111 (5 Pt 1):e555-61. [QxMD MEDLINE Link].
Splete H. AAP updates hyperbilirubinemia guideline. MDedge. Available at https://medauth2.mdedge.com/content/aap-updates-hyperbilirubinemia-guideline. August 5, 2022; Accessed: August 30, 2022.
Moore LG, Newberry MA, Freeby GM, Crnic LS. Increased incidence of neonatal hyperbilirubinemia at 3,100 m in Colorado. Am J Dis Child. 1984 Feb. 138 (2):157-61. [QxMD MEDLINE Link].
Sarici SU, Serdar MA, Korkmaz A, et al. Incidence, course, and prediction of hyperbilirubinemia in near-term and term newborns. Pediatrics. 2004 Apr. 113 (4):775-80. [QxMD MEDLINE Link].
Ebbesen F, Andersson C, Verder H, et al. Extreme hyperbilirubinaemia in term and near-term infants in Denmark. Acta Paediatr. 2005 Jan. 94 (1):59-64. [QxMD MEDLINE Link].
Slusher TM, Olusaniya BO. Neonatal jaundice in low- and middle-income countries. In: Stevenson DK, Maisels MJ, Watchko JF, eds. Care of the Jaundiced Neonate. New York: McGraw-Hill; 2012. 263-73.
Linn S, Schoenbaum SC, Monson RR, Rosner B, Stubblefield PG, Ryan KJ. Epidemiology of neonatal hyperbilirubinemia. Pediatrics. 1985 Apr. 75 (4):770-4. [QxMD MEDLINE Link].
Rennie JM, Beer J, Upton M. Learning from claims: hyperbilirubinaemia and kernicterus. Arch Dis Child Fetal Neonatal Ed. 2019 Mar. 104 (2):F202-4. [QxMD MEDLINE Link].
Maisels MJ, Newman TB. Prevention, screening and postnatal management of neonatal hyperbilirubinemia. In: Stevenson DK, Maisels MJ, Watchko JF, eds. Care of the Jaundiced Neonate. New York: McGraw-Hill; 2012. 175-94.
Mreihil K, Benth JŠ, Stensvold HJ, et al, for the Norwegian NICU Phototherapy Study Group, Norwegian Neonatal Network. Phototherapy is commonly used for neonatal jaundice but greater control is needed to avoid toxicity in the most vulnerable infants. Acta Paediatr. 2018 Apr. 107 (4):611-9. [QxMD MEDLINE Link].
Slusher TM, Vreman HJ, McLaren DW, Lewison LJ, Brown AK, Stevenson DK. Glucose-6-phosphate dehydrogenase deficiency and carboxyhemoglobin concentrations associated with bilirubin-related morbidity and death in Nigerian infants. J Pediatr. 1995 Jan. 126 (1):102-8. [QxMD MEDLINE Link].
Jaundice and your newborn. American Academy of Pediatrics. Available at https://publications.aap.org/patiented/article/doi/10.1542/peo_document197/80109/Jaundice-and-Your-Newborn. 2022;
Neonatal Group of the Norwegian Pediatric Association. Jaundice in newborn infants - an explanation for parents. Available at https://www.legeforeningen.no/contentassets/32664d0928704f5a81d644160df9568c/gulsott-foreldreinformasjon-engelsk-versjon.pdf. Revised 2016;
Olusanya BO, Slusher TM, Imosemi DO, Emokpae AA. Maternal detection of neonatal jaundice during birth hospitalization using a novel two-color icterometer. PLoS One. 2017. 12 (8):e0183882. [QxMD MEDLINE Link]. [Full Text].
Thomas M, Greaves RF, Tingay DG, et al. Current and emerging technologies for the timely screening and diagnosis of neonatal jaundice. Crit Rev Clin Lab Sci. 2022 Aug. 59 (5):332-52. [QxMD MEDLINE Link]. [Full Text].
Taylor JA, Stout JW, de Greef L, et al. Use of a smartphone app to assess neonatal jaundice. Pediatrics. 2017 Sep. 140 (3):e20170312. [QxMD MEDLINE Link]. [Full Text].
Knudsen A. The influence of the reserve albumin concentration and pH on the cephalocaudal progression of jaundice in newborns. Early Hum Dev. 1991 Jan-Feb. 25 (1):37-41. [QxMD MEDLINE Link].
Purcell N, Beeby PJ. The influence of skin temperature and skin perfusion on the cephalocaudal progression of jaundice in newborns. J Paediatr Child Health. 2009 Oct. 45 (10):582-6. [QxMD MEDLINE Link].
Kamphuis ASJ, Bekhof J. Cephalocaudal progression of neonatal jaundice assessed by transcutaneous bilirubin measurements. Early Hum Dev. 2021 Sep. 160:105418. [QxMD MEDLINE Link].
[Guideline] Bhutani VK, Maisels MJ, Stark AR, Buonocore G, and the Expert Committee for Severe Neonatal Hyperbilirubinemia, European Society for Pediatric Research, et al. Management of jaundice and prevention of severe neonatal hyperbilirubinemia in infants >or=35 weeks gestation. Neonatology. 2008. 94 (1):63-7. [QxMD MEDLINE Link].
Bhutani VK, Johnson LH, Jeffrey Maisels M, et al. Kernicterus: epidemiological strategies for its prevention through systems-based approaches. J Perinatol. 2004 Oct. 24 (10):650-62. [QxMD MEDLINE Link].
Hansen TW, Nietsch L, Norman E, et al. Reversibility of acute intermediate phase bilirubin encephalopathy. Acta Paediatr. 2009 Oct. 98 (10):1689-94. [QxMD MEDLINE Link].
Mishra S, Chawla D, Agarwal R, Deorari AK, Paul VK, Bhutani VK. Transcutaneous bilirubinometry reduces the need for blood sampling in neonates with visible jaundice. Acta Paediatr. 2009 Dec. 98 (12):1916-9. [QxMD MEDLINE Link].
Bhutani VK, Gourley GR, Adler S, Kreamer B, Dalin C, Johnson LH. Noninvasive measurement of total serum bilirubin in a multiracial predischarge newborn population to assess the risk of severe hyperbilirubinemia. Pediatrics. 2000 Aug. 106 (2):E17. [QxMD MEDLINE Link].
Keren R, Tremont K, Luan X, Cnaan A. Visual assessment of jaundice in term and late preterm infants. Arch Dis Child Fetal Neonatal Ed. 2009 Sep. 94 (5):F317-22. [QxMD MEDLINE Link].
Riskin A, Tamir A, Kugelman A, Hemo M, Bader D. Is visual assessment of jaundice reliable as a screening tool to detect significant neonatal hyperbilirubinemia?. J Pediatr. 2008 Jun. 152 (6):782-7, 787.e1-2. [QxMD MEDLINE Link].
Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics. 1999 Jan. 103 (1):6-14. [QxMD MEDLINE Link].
Schutzman DL, Sekhon R, Hundalani S. Hour-specific bilirubin nomogram in infants with ABO incompatibility and direct Coombs-positive results. Arch Pediatr Adolesc Med. 2010 Dec. 164 (12):1158-64. [QxMD MEDLINE Link].
Ahlfors CE, Parker AE. Unbound bilirubin concentration is associated with abnormal automated auditory brainstem response for jaundiced newborns. Pediatrics. 2008 May. 121 (5):976-8. [QxMD MEDLINE Link].
Hansen TW. Acute management of extreme neonatal jaundice--the potential benefits of intensified phototherapy and interruption of enterohepatic bilirubin circulation. Acta Paediatr. 1997 Aug. 86 (8):843-6. [QxMD MEDLINE Link].
Hansen TWR, Akkök CA, Watchko JF. International guidelines regarding the role of intravenous immunoglobulin in the management of RhD- and ABO-mediated haemolytic disease of the newborn-reconsidering the recommendations [letter]. Br J Haematol. 2022 Nov. 199 (3):452-3. [QxMD MEDLINE Link]. [Full Text].
Gourley GR, Li Z, Kreamer BL, Kosorok MR. A controlled, randomized, double-blind trial of prophylaxis against jaundice among breastfed newborns. Pediatrics. 2005 Aug. 116 (2):385-91. [QxMD MEDLINE Link].
Chaudhari H, Goyal S, Patil C. Neonates with sickle cell disease are vulnerable to blue light phototherapy-induced oxidative stress and proinflammatory cytokine elevations. Med Hypotheses. 2016 Nov. 96:78-82. [QxMD MEDLINE Link].
Hansen TWR, Maisels MJ, Ebbesen F, et al. Sixty years of phototherapy for neonatal jaundice - from serendipitous observation to standardized treatment and rescue for millions. J Perinatol. 2020 Feb. 40 (2):180-93. [QxMD MEDLINE Link].
Mreihil K, Madsen P, Nakstad B, Benth JŠ, Ebbesen F, Hansen TW. Early formation of bilirubin isomers during phototherapy for neonatal jaundice: effects of single vs. double fluorescent lamps vs. photodiodes. Pediatr Res. 2015 Jul. 78 (1):56-62. [QxMD MEDLINE Link].
Linfield DT, Lamola AA, Mei E, et al. The effect of hematocrit on in vitro bilirubin photoalteration. Pediatr Res. 2016 Mar. 79 (3):387-90. [QxMD MEDLINE Link].
McDonagh AF. Controversies in bilirubin biochemistry and their clinical relevance. Semin Fetal Neonatal Med. 2010 Jun. 15 (3):141-7. [QxMD MEDLINE Link].
Ebbesen F, Madsen PH, Rodrigo-Domingo M, Donneborg ML. Bilirubin isomers during LED phototherapy of hyperbilirubinemic neonates, blue-green (~478 nm) vs blue. Pediatr Res. 2024 Sep 4. [QxMD MEDLINE Link].
Vandborg PK, Hansen BM, Greisen G, Ebbesen F. Dose-response relationship of phototherapy for hyperbilirubinemia. Pediatrics. 2012 Aug. 130 (2):e352-7. [QxMD MEDLINE Link].
Ebbesen F, Donneborg ML. Clinical overview of phototherapy for neonatal hyperbilirubinaemia. Acta Paediatr. 2024 Oct. 113 (10):2199-202. [QxMD MEDLINE Link].
De Carvalho M, De Carvalho D, Trzmielina S, Lopes JM, Hansen TW. Intensified phototherapy using daylight fluorescent lamps. Acta Paediatr. 1999 Jul. 88 (7):768-71. [QxMD MEDLINE Link].
Djokomuljanto S, Quah BS, Surini Y, et al. Efficacy of phototherapy for neonatal jaundice is increased by the use of low-cost white reflecting curtains. Arch Dis Child Fetal Neonatal Ed. 2006 Nov. 91 (6):F439-42. [QxMD MEDLINE Link].
Kumar P, Chawla D, Deorari A. Light-emitting diode phototherapy for unconjugated hyperbilirubinaemia in neonates. Cochrane Database Syst Rev. 2011 Dec 7. 2011 (12):CD007969. [QxMD MEDLINE Link].
Tridente A, De Luca D. Efficacy of light-emitting diode versus other light sources for treatment of neonatal hyperbilirubinemia: a systematic review and meta-analysis. Acta Paediatr. 2012 May. 101 (5):458-65. [QxMD MEDLINE Link].
Watchko JF, Maisels MJ. The enigma of low bilirubin kernicterus in premature infants: why does it still occur, and is it preventable?. Semin Perinatol. 2014 Nov. 38 (7):397-406. [QxMD MEDLINE Link].
[Guideline] American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004 Jul. 114 (1):297-316. [QxMD MEDLINE Link]. [Full Text].
Maisels MJ, Bhutani VK, Bogen D, Newman TB, Stark AR, Watchko JF. Hyperbilirubinemia in the newborn infant > or =35 weeks' gestation: an update with clarifications. Pediatrics. 2009 Oct. 124 (4):1193-8. [QxMD MEDLINE Link].
Maisels MJ, Watchko JF, Bhutani VK, Stevenson DK. An approach to the management of hyperbilirubinemia in the preterm infant less than 35 weeks of gestation. J Perinatol. 2012 Sep. 32 (9):660-4. [QxMD MEDLINE Link].
Hansen TW. Let there be light-but should there be less?. J Perinatol. 2012 Sep. 32 (9):649-51. [QxMD MEDLINE Link].
Maisels MJ. Phototherapy in the neonatal intensive care unit - quantity and quality. Acta Paediatr. 2018 Apr. 107 (4):551-3. [QxMD MEDLINE Link].
Tyson JE, Pedroza C, Langer J, et al, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Does aggressive phototherapy increase mortality while decreasing profound impairment among the smallest and sickest newborns?. J Perinatol. 2012 Sep. 32 (9):677-84. [QxMD MEDLINE Link]. [Full Text].
Madan JC, Kendrick D, Hagadorn JI, Frantz ID 3rd, and the National Institute of Child Health and Human Development Neonatal Research Network. Patent ductus arteriosus therapy: impact on neonatal and 18-month outcome. Pediatrics. 2009 Feb. 123 (2):674-81. [QxMD MEDLINE Link]. [Full Text].
Barekatain B, Badiea Z, Hoseini N. The effect of head covering in prevention of phototherapy-induced hypocalcemia in icterus newborns with gestational age less than 35 weeks. Adv Biomed Res. 2016. 5:176. [QxMD MEDLINE Link]. [Full Text].
Ebbesen F, Vreman HJ, Hansen TWR. Blue-green (~480 nm) versus blue (~460 nm) light for newborn phototherapy-safety considerations. Int J Mol Sci. 2022 Dec 27. 24 (1):461. [QxMD MEDLINE Link]. [Full Text].
Gottstein R, Cooke RW. Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn. Arch Dis Child Fetal Neonatal Ed. 2003 Jan. 88 (1):F6-10. [QxMD MEDLINE Link]. [Full Text].
Rübo J, Albrecht K, Lasch P, et al. High-dose intravenous immune globulin therapy for hyperbilirubinemia caused by Rh hemolytic disease. J Pediatr. 1992 Jul. 121 (1):93-7. [QxMD MEDLINE Link].
Huizing K, Røislien J, Hansen T. Intravenous immune globulin reduces the need for exchange transfusions in Rhesus and AB0 incompatibility. Acta Paediatr. 2008 Oct. 97 (10):1362-5. [QxMD MEDLINE Link].
Ergaz Z, Gross D, Bar-Oz B, Peleg O, Arad I. Carboxyhemoglobin levels in neonatal immune hemolytic jaundice treated with intravenous gammaglobulin. Vox Sang. 1995. 69 (2):95-9. [QxMD MEDLINE Link].
Hammerman C, Kaplan M, Vreman HJ, Stevenson DK. Intravenous immune globulin in neonatal ABO isoimmunization: factors associated with clinical efficacy. Biol Neonate. 1996. 70 (2):69-74. [QxMD MEDLINE Link].
Zwiers C, Scheffer-Rath ME, Lopriore E, de Haas M, Liley HG. Immunoglobulin for alloimmune hemolytic disease in neonates. Cochrane Database Syst Rev. 2018 Mar 18. 3 (3):CD003313. [QxMD MEDLINE Link]. [Full Text].
Lieberman L, Lopriore E, Baker JM, et al, for the International Collaboration for Transfusion Medicine Guidelines (ICTMG). International guidelines regarding the role of IVIG in the management of Rh- and ABO-mediated haemolytic disease of the newborn. Br J Haematol. 2022 Jul. 198 (1):183-95. [QxMD MEDLINE Link]. [Full Text].
Hansen TW, Oyasaeter S, Stiris T, Bratlid D. Effects of sulfisoxazole, hypercarbia, and hyperosmolality on entry of bilirubin and albumin into brain regions in young rats. Biol Neonate. 1989. 56 (1):22-30. [QxMD MEDLINE Link].
Hansen TW, Allen JW. Hemolytic anemia does not increase entry into, nor alter rate of clearance of bilirubin from rat brain. Biol Neonate. 1996. 69 (4):268-74. [QxMD MEDLINE Link].
Johnson L, Bhutani VK, Karp K, Sivieri EM, Shapiro SM. Clinical report from the pilot USA Kernicterus Registry (1992 to 2004). J Perinatol. 2009 Feb. 29 Suppl 1:S25-45. [QxMD MEDLINE Link].
Gao C, Guo Y, Huang M, He J, Qiu X. Breast milk constituents and the development of breast milk jaundice in neonates: a systematic review. Nutrients. 2023 May 10. 15 (10):[QxMD MEDLINE Link].
Gourley GR, Kreamer B, Cohnen M, Kosorok MR. Neonatal jaundice and diet. Arch Pediatr Adolesc Med. 1999 Feb. 153 (2):184-8. [QxMD MEDLINE Link].
Calado CS, Pereira AG, Santos VN, Castro MJ, Maio JF. What brings newborns to the emergency department?: A 1-year study. Pediatr Emerg Care. 2009 Apr. 25 (4):244-8. [QxMD MEDLINE Link].
Newman TB, Liljestrand P, Escobar GJ. Combining clinical risk factors with serum bilirubin levels to predict hyperbilirubinemia in newborns. Arch Pediatr Adolesc Med. 2005 Feb. 159 (2):113-9. [QxMD MEDLINE Link].
Bhutani VK, Johnson LH, Keren R. Diagnosis and management of hyperbilirubinemia in the term neonate: for a safer first week. Pediatr Clin North Am. 2004 Aug. 51 (4):843-61, vii. [QxMD MEDLINE Link].
Eggert LD, Wiedmeier SE, Wilson J, Christensen RD. The effect of instituting a prehospital-discharge newborn bilirubin screening program in an 18-hospital health system. Pediatrics. 2006 May. 117 (5):e855-62. [QxMD MEDLINE Link].
Paul IM, Phillips TA, Widome MD, Hollenbeak CS. Cost-effectiveness of postnatal home nursing visits for prevention of hospital care for jaundice and dehydration. Pediatrics. 2004 Oct. 114 (4):1015-22. [QxMD MEDLINE Link].
Suresh GK, Clark RE. Cost-effectiveness of strategies that are intended to prevent kernicterus in newborn infants. Pediatrics. 2004 Oct. 114 (4):917-24. [QxMD MEDLINE Link].
Bhutani VK, Johnson LH, Jeffrey Maisels M, et al. Kernicterus: epidemiological strategies for its prevention through systems-based approaches. J Perinatol. 2004 Oct. 24 (10):650-62. [QxMD MEDLINE Link].
Kuzniewicz MW, Wickremasinghe AC, Wu YW, et al. Incidence, etiology, and outcomes of hazardous hyperbilirubinemia in newborns. Pediatrics. 2014 Sep. 134 (3):504-9. [QxMD MEDLINE Link].
Mah MP, Clark SL, Akhigbe E, et al. Reduction of severe hyperbilirubinemia after institution of predischarge bilirubin screening. Pediatrics. 2010 May. 125 (5):e1143-8. [QxMD MEDLINE Link].
Stevenson DK, Wong RJ. Metalloporphyrins in the management of neonatal hyperbilirubinemia. Semin Fetal Neonatal Med. 2010 Jun. 15 (3):164-8. [QxMD MEDLINE Link].
Chen Z, Zhang L, Zeng L, et al. Probiotics supplementation therapy for pathological neonatal jaundice: a systematic review and meta-analysis. Front Pharmacol. 2017. 8:432. [QxMD MEDLINE Link]. [Full Text].
Yang L, Wu D, Wang B, Bu X, Tang J. The influence of zinc sulfate on neonatal jaundice: a systematic review and meta-analysis. J Matern Fetal Neonatal Med. 2018 May. 31 (10):1311-7. [QxMD MEDLINE Link].

Media Gallery

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 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.

of 3

#author-disclosures{display:block}#author-disclosures.modal-layer{position:relative}#author-disclosures .modal-content{max-height:none}#author-disclosures .close-modal{display:none}