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]
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.
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.
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.
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]
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]
Neonatal jaundice typically 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, check the results of the newborn metabolic screen should for galactosemia and congenital hypothyroidism, further explore family history (see below), evaluate the infant's weight curve, elicit the mother's impressions as far as adequacy of breastfeeding, and assess the infant's stool color.
Family history
Obtain the following information:
Previous sibling(s) with jaundice in the neonatal period, particularly if the jaundice required treatment
Other family members with jaundice or a 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)
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.[41, 42] The 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. The cephalocuadal progression phenomenon has been verified with TcB measurements.[43]
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 laboratory test results (see Laboratory Studies under Workup). The potential need for exchange transfusion should not preclude the immediate initiation of phototherapy.[44, 45, 46]
Hepatosplenomegaly, petechiae, and microcephaly may be associated with hemolytic anemia, sepsis, and congenital infections and should trigger a diagnostic evaluation directed toward these diagnoses. Neonatal jaundice may be exacerbated in these situations.
Total serum bilirubin measurement has long been the standard method for quantitating serum bilirubin levels. The analysis is usually performed in venous or capillary blood, but it can also be performed in arterial blood on blood gas machines. The advantage of the latter is the much shorter turnaround time, reducing delay from clinical observation of jaundice to therapeutic action.
Transcutaneous bilirubinometry can be performed using handheld devices that incorporate sophisticated optical algorithms.[39] Use of such devices has been shown to reduce the need for blood sampling in infants with jaundice.[47] However, they cannot be used to monitor the progress of phototherapy.[48] Transcutaneous bilirubinometry performs better than visual assessment. The latter is not a reliable technique for estimating levels of bilirubin,[49] 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.[50]
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 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.
Newer point-of-care devices include image-based techniques using smartphone cameras and applications (eg, BiliCapture, BiliCam, BiliScan, Picterus, and neoSCB), as well as emerging blood-based point-of-care (POC) devices (eg, BiliStick, BiliSpec, BiliPAD, smartphone-based Nanosensor, and a sample-to-answer quantitative platform).[39]
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 the 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.[51] 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 ABO incompatibility.[52] However, 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 (ETCO): ETCO may be used as an index of bilirubin production. ETCO measurement 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 (CoSense ETCO Monitor).
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, subject to significant interlaboratory and intralaboratory variation, and 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.
Thyroid function tests
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.
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 hepatic iminodiacetic 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.
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.[53] 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.
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.
Surgical care is not indicated in infants with physiologic neonatal jaundice. However, operative intervention is indicated in infants whose jaundice is caused by bowel or external bile duct atresia.
For infants with physiologic neonatal jaundice, no consultation is required. Consult gastroenterologists and surgeons regarding infants with jaundice resulting from hepatobiliary or bowel disease.
Transfer
Infants in need of exchange transfusion who are 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 which 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 neurologic compromise, immediately initiate the most efficient phototherapy possible under the circumstances, and continue it until transfer commences.[54] 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, immediately start an infusion of intravenous immunoglobulin (IVIG) at 500 mg/kg, and continue it before and during transfer until completed (2 hours).[19, 55]
Even if the receiving hospital determines that an exchange transfusion should be performed, it is important to continue optimal phototherapy until the actual exchange procedure can commence. 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 reducing enterohepatic circulation of bilirubin, and it should be given unless clearly contraindicated by the clinical state of the infant.[56] Although none of these suggestions have been tested in randomized controlled trials under such scenarios, case reports, bilirubin photobiology, and expert opinion suggest that they may be beneficial and, at the very least, are unlikely to be harmful.
Phototherapy, 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.[57] Affected 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).[57]
Phototherapy is the primary treatment in neonates with unconjugated hyperbilirubinemia.[5, 19, 58] 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 three 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.[59] This proportion is not significantly influenced by the intensity of light, nor by the character of the light source or use of "double phototherapy."[59] Data have shown that formation of photoisomers is significant after as short as 15 minutes of phototherapy.[59] More recent studies suggest that the initial rate of isomerization is inversely related to the hemoglobin level.[59, 60]
Structural isomerization consists of intramolecular cyclization, resulting in the formation of lumirubin. This process is enhanced by increasing the light intensity. During phototherapy, lumirubin may constitute 2-6% of the total serum bilirubin (TSB) 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 TSB 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 TSB concentration, the presence of 20-25% of photoisomers means that only 75-80% of the total bilirubin would be present in a form that can enter the brain. Please note that, although theoretically coherent, no experimental data are as yet available to support this speculation.[59, 61]
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 more. Thus, lamps with output predominantly in the blue region of the spectrum (460-490 nm) are probably most effective. Indeed, data from Ebbesen's group showed that blue–green light-emitting diode (LED) light (≈478 nm) was 31% more efficient than standard blue LED light (≈459 nm) as measured by the decline in TSB.[62]
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. However, newer phototherapy units, when properly configured and with the use of reflecting blankets and curtains, may deliver light energy above 40 µW/cm2/nm. Data have not confirmed that, for practical purposes, there really is a saturation level.[63, 64] Indeed, the relationship between irradiance and the 24-hour decrement in TSB was linear up to 55 μW/cm2, and with no evidence of a saturation point within that range.[63]
Third, according to the laws of physics, the energy delivered to the infant's skin decreases with increasing distance between the infant and the light source. That distance should not be greater than 50 cm (20 in) and can be less (down to 10 cm with LED lamps) provided the infant's temperature is monitored. Note that quartz halide lamps must NOT be brought this close!
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. This implies that covering of the infant's skin during phototherapy should be minimal (use eye protection and the smallest practicable size of diapers). Spectral power (ie, irradiance multplied by the size of the irradiated area) is a key concept in phototherapy.
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 toward the circle perimeter. Large infants and infants who can move away from the circle's center may receive less efficient phototherapy.
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 can be accomplished with white lamps.[65, 66]
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 toward 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 is related to the size of the illuminated 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 newer 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)
The opportunity not to interfere with mother-infant binding to the same extent as with traditional overhead units.
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 have been reviewed by the Cochrane Collaboration and by Tridente and DeLuca. The authors of these reviews conclude that the efficacy of LED lights in reducing TSB levels is comparable to that of conventional light sources (fluorescent or halogen lamps).[67, 68] Formation of bilirubin photoisomers also appears comparable between LEDs and blue fluorescent lamps.[59]
"Double" and "triple" phototherapy, which implies the concurrent use of two or three 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 more 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.[59]
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 TSB levels greater than 350 µmol/L (20 mg/dL) were associated with an 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, magnetic resonance images, and follow-up data suggested that immature infants were at risk of bilirubin encephalopathy at lower TSB levels than mature infants. Treatment was therefore initiated at lower levels for these infants. Several conditions may render the brains of premature infants vulnerable to bilirubin entry and toxicity, such as hypoalbuminemia, co-morbid CNS insult(s), infection, inflammation, and acidocis.[69]
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 a second-line treatment when phototherapy failed to control serum bilirubin levels. This procedure is performed with decreasing frquency in industrialized countries, secondary to the introduction of prophylactic treatment for Rh isoimmunization. Data from LMICs show that the procedure is still quite commonly performed in that setting.[16] Intravenous immuneglobulin has been proposed as a way to avoid exchange transfusions in hemolytic disease of the newborn (see below).
Unfortunately, the scientific data on which current therapeutic guidelines are based have very significant shortcomings. However, because of the extreme rarity of kernicterus in industrialized countries, the number that would need to be enrolled for a randomized, controlled study is clearly unachieveable. Furthermore, because the endpoint of bilirubin neurotoxicity is permanent brain damage, a randomized study to reassess the guidelines is ethically unthinkable.
In most neonatal wards, TSB levels are used as the primary measure of risk for bilirubin encephalopathy. Many 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 clinicians but these have failed to gain widespread acceptance. Newer analytical tools for measurement of unbound bilirubin have greatly simplified the process, but the effect on clinical practice remains to be seen.
In 2022, the American Academy of Pediatrics (AAP) published new guidelines for the management of hyperbilirubinemia in healthy full-term newborns.[19] These more recent guidelines involve some changes from the 2004 guidelines[70] and the 2009 update.[71] Thus, the phototherapy thresholds have been raised by a narrow range considered by the AAP committee to be safe. Newer research has been taken into consideration as far as revising the risk-based approach based on the hour-specific biliubin concentration, as well as how one should rapidly address very elevated bilirubin concentrations. As has been true of previous guidelines, the AA[ Committee has been careful in assessing the strength of the scientific evidence on which the guidelines are based.
Thus, practitioners in North America are advised to follow the 2022 AAP guidelines. Figures 2 and 3 in those guidelines reflect recommended phototherapy indication levels for infants respectively without and with neurotoxicity risk factors, and according to gestational age.[19] The 2022 AAP guidelines do not provide guidance for treatment of jaundice in the smaller and more premature/immature infants. However, in 2012, a group of US experts published their suggestions for management of jaundice in preterm infants younger than 35 weeks' gestation—until an update is published, this remains the recommended reference.[72]
It seems that the 2004 AAP guidelines have been followed in many countries across the globe, and this is understandable considering the very careful work that went into those guidelines. However, clinicians in regions with differences in ethnic background, geography, as well as in how healthcare delivery is organized, need to consider how to tailor these (or other) guidelines to their own populations, and they must also 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. Differences in healthcare delivery systems may likely affect both in-hospital management as well as follow-up and primary care. Assuming that local/national guidelines have been successful in the prevention of kernicterus, the wisest course of action may be continue with these, until such time as adaptations may safely be judged to have very low risk of changing outcomes in a negative direction.
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 the 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: Do NOT bring quartz lamps that close to the infant.
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 toward 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 have 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. Infants should monitored for weight loss, urine output, and urine specific gravity, and fluid intake should be 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.
Individualize the timing of follow-up serum bilirubin testing. 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.[54] In infants with more moderate elevations of serum bilirubin, monitoring every 6-12 hours is probably adequate.[19]
Expectations regarding the efficacy of phototherapy must be tailored to the circumstances. In infants whose serum bilirubin concentrations are still rising, a significant reduction of the rate of increase may be satisfactory. In infants whose 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.[46, 54]
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.[19] Serum bilirubin levels may rebound after treatment has been discontinued, and follow-up tests should be obtained within 6-12 hours after discontinuation.[19]
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 bilirubin has reached levels at which photons may do some good. As prophylactic phototherapy necessarily increases the duration of exposure to phototherapy lights, there may be a particularly strong reason not to apply this practice in vulnerable, premature infants.[73, 74]
Wherever phototherapy is offered as a therapeutic modality, a device for measuring the irradiance delivered by the equipment used should be readily at hand.[19] 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:
As noted above, a reanalysis of the Neonatal Research Network 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.[75] In a recommendation for treatment of hyperbilirubinemia in premature infants younger than 35 weeks’ gestation, the authors proposed that initial irradiance should be reduced in the most vulnerable infants.[72] 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.[73] 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 a neonatal intensive care unit (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.[76]
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.[77] 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.
Several studies have discussed the possibility that longer term side effects may be associated with neonatal phototherapy. These include malignancy, allergic diseases, childhood epilepsy, diabetes type 1, and autism spectrum disorders. For a review with important references the reader is referred to Ebbesen et al.[78]
Data from several smaller studies have suggested that treatment with IVIG in infants with Rh or ABO isoimmunization can reduce the need for exchange transfusions.[79, 80, 81] There is also evidence that IVIG given to infants with severe Rh or ABO isoimmunization reduces the rate of hemolysis.[82, 83] However, in spite of this, there continues to be disagreement as to the potential role for IVIG in infants with Rh or ABO isoimmunization. Thus, both a 2018 Cochrane review[84] and a 2022 international recommendation[85] concluded that the quality of the studies which showed benfits of IVIG was insufficient to make a recommendation for its use in blood group isoimmunization. Both these publications placed their main emphasis on two randomized studies that failed to show benefit.
However, as pointed out in letters to the editor regarding the Cochrane review and the international recommendation, both of the randomized studies suffer from significant methodological shortcomings that speak to the biologic rationale rather than statistical design, and these detractors argue that therefore the emphasis on these two studies is misplaced.[55] The authors of the letters concur that additional study is needed, but until such data are available, the targeted use of IVIG for selected neonates with immune-mediated hemolytic disease of the newborn in whom the TSB is rising rapidly despite intensive phototherapy and/or the TSB level is within 35-50 μmol/L (≈2 to 3 mg/dL) of the exchange level and on course to surpass that level, is on balance more likely to provide benefit than harm and remains prudent.[55] The 2022 AAP jaundice guidelines suggest that IVIG (0.5 to 1 g/kg) over 2 hours may be provided to infants with isoimmune hemolytic disease (ie, positive DAT) whose TSB reaches or exceeds the escalation of care threshold.[19] The guidelines further point out that there is no evidence for a benefit of prophylatic use of IVIG in DAT+ neonates, and thus they discourage such use.
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 shown in a prospective survey to be only 0.01%.[34] 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). Many experts currently encourage an individualized approach, recognizing that exchange transfusion is not a risk-free procedure, that effective phototherapy converts 15-25% of bilirubin to (presumably) nontoxic isomers, and that transfusion of a small volume of packed red blood cells may correct anemia. Administration of IVIG (500 mg/kg) has been shown to reduce red blood cell destruction and to limit the rate of increase of serum bilirubin levels in infants with Rh and ABO isoimmunization (see above).[82, 83]
The 2022 AAP guidelines discuss risk in two categories: 1) risk factors for developing high TSB levels, and 2) risk factors for neurotoxicity.[19] See Etiology for risk factors for the development of high TSB levels. Neurotoxicity risk factors include gestational age less than 38 weeks (this risk increases with the degree of prematurity); serum albumin below 3.0 g/dL; isoimmune hemolytic disease (ie, positive DAT), G6PD deficiency, or other hemolytic conditions; sepsis; and significant clinical instability in the previous 24 hours. Such clinical instability also likely includes respiratory failure with hypercapnia, as animal studies have shown that respiratory acidosis increases bilirubin entry into brain.[86]
Intervention levels associated with exchange transfusion are higher than those for phototherapy.[19] 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 (see below). Phototherapy has minimal side effects in this scenario, whereas the waiting period for laboratory test results and blood for the 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. Figures 5 and 6 in the 2022 AAP guidelines reflect the recommended exchange transfusion levels respectively without and with neurotoxicity risk factors, and according to gestational age.[19]
It has been believed that hemolytic jaundice represents a greater risk for neurotoxicity than nonhemolytic jaundice, and this is still reflected in most guidelines. However, the reasons for this belief are not intuitively obvious, assuming that TSB levels are equal. In animal studies, bilirubin entry into or clearance from the brain were not affected by the presence of hemolytic anemia.[87]
The technique of exchange transfusion, including adverse effects and complications, is discussed extensively elsewhere. For more information, please consult Hemolytic Disease of Newborn.
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.[32, 88]
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 (TcB). 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 neurologic 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 IV 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 IV hydration because it reduces enterohepatic circulation of bilirubin and helps "wash" bilirubin out of the bowel.[56]
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. In Norway, the national guidelines for management of neonatal jaundice dictate that whenever parents call with concerns about jaundice in an infant who had been discharged, they are to be told to come immediately to the hospital with the baby and to present themselves directly to the nursery from which the baby was discharged.[37]
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. A report from Europe showed that urgent intervention could reverse progression in infants presenting with intermediate ABE.[46] Similarly, 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. However, full recovery was not noted in cases in which delays had occurred.[88] 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.[88] In the European study, reversal was also seen in two patients who did not receive exchange transfusion.[46] In one of these cases, IVIG was used in lieu of exchange transfusion; in the other case, intensive phototherapy and IV albumin were used.
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 breastfeeding 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 reduced the incidence and severity of Rh-hemolytic disease.
Infants who have been treated for neonatal jaundice can be discharged when they are feeding adequately and have had two successive serum bilirubin levels demonstrating a trend toward 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 2022 AAP guideline recommends visual assessment for jaundice at least every 12 hours following delivery until discharge.[19] Parents should be provided with verbal and written information about jaundice, preferably also including procedures for contacting the birth hospital.[36, 37]
Breastfeeding concerns associated with neonatal jaundice are as follows:
The incidence and duration of jaundice have increased as breastfeeding has become more popular. A number of factors in breast milk have been thought to contribute to this phenomenon.[6] However, a review of this topic, which considered nutritional as well as bioactive factors (eg, enzymes and growth factors), concluded that the results were inconsistent and inconclusive for most of the substances of interest.[89] The authors concluded that the etiology of breast milk jaundice is likely to be multifactorial, and that no single constituent of breast milk could explain all the cases observed.
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/parents before implementation.[19] An initial trial of 5 mL of a hydrolyzed formula given after each breast meal may be attempted.[90] The author would usually try this for at least 1-2 days, with follow-up of bilirubin values. Only if this trial is unsuccessful does the author occasionally attempt interruption of breastfeeding.
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.
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.[19] The use of the hour-specific bilirubin nomogram may assist in selecting infants with a high likelihood of developing significant hyperbilirubinemia. The 2022 AAP guidelines recommend that TcB or TSB should be measured between 24 and 48 hours after birth or before discharge if that occurs earlier.[19] The 2022 guidelines also recommend that TSB should be measured if the TcB exceeds or is within 3 mg/dL of the phototherapy treatment threshold, or if the TcB is at least 15 mg/dL. If more than one TcB or TSB measure is available, the rate of increase may be used to identify infants at higher risk of subsequent hyperbilirubinemia. A rapid rate of increase (≥0.3 mg/dL per hour in the first 24 hours or ≥0.2 mg/dL per hour thereafter) is exceptional and suggests hemolysis. In this case, perform a DAT if not done previously.
Neonatal jaundice is one of the most common reasons why neonates are brought to an emergency department after discharge from the birth hospital.[91] Delays in or impediments to readmission seem to be involved in many cases of kernicterus.[32] Therefore, every hospital that takes care of deliveries and newborn infants should critically review their readmission procedures with a view to streamlining these.
Near-term infants are at higher risk than term infants of developing significant jaundice and merit closer surveillance.[19, 92]
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.[93, 94] Others have found that home nurse visiting was cost-effective and prevented readmissions for jaundice and dehydration.[95] The cost-effectiveness of preventing kernicterus by universal screening has been questioned.[96] However, the incidence of hazardous hyperbilirubinemia, defined as TSB of at least 30 mg/dL,[97] fell in at least three large US health systems after the adoption of universal predischarge bilirubin screening with closer post discharge follow-up.[94, 98, 99]
Maisels et al also recommended a more structured approach to management and follow-up according to the predischarge TSB and TcB levels, gestational age (see the Gestational Age from Estimated Date of Delivery calculator), and other risk factors for hyperbilirubinemia.[71] These risk factors include the following:
Predischarge TSB or TcB 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, G6PD deficiency)
Previous sibling with jaundice
Cephalohematoma or significant bruising
East Asian race
Telephone consultations are not recommended, because parental reports cannot be appropriately gauged. Numerous infants have developed kernicterus, resulting, at least in part, from inadequate communication between practitioners or their representatives and parents.
Home phototherapy is used in an effort to limit the high cost of applying such therapy in hospitals.
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 newborn nursery at the author's institution was less than 17 hours. It is debatable whether the effort and cost to set up home therapy is then worthwhile. 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 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.[19, 44]
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.
Risk factors for development of neonatal jaundice as well as for bilirubin neurotoxicity have been discussed earlier.
2022 AAP Hyperbilirubinemia Clinical Practice Guidelines
Updated guidelines on the management of hyperbilirubinemia in newborn infants of 35 or more weeks of gestation were published in August 2022 by the American Academy of Pediatrics (AAP) inPediatrics.[19, 26] Neonatal hyperbilirubinemia is common, and severe complications are rare; early identification of potential severe and devastating neurologic effects such as acute encephalopathy and kernicterus is crucial. Select strong or moderate recommendations are summarized below.
Prevention
Infants of mothers with unknown (due to no prenatal antibody screening) or positive maternal antibody screening should undergo direct antiglobulin testing (DAT) as well as blood typing via cord or peripheral blood.
Avoid oral supplementation with water or dextrose water for prevention of hyperbilirubinemia or for reducing bilirubin concentrations (strong recommendation).
Assessment and Monitoring
Total serum bilirubin (TSB) should be the definitive test for guiding phototherapy and escalating care, including exchange transfusion.
Visually assess all infants for jaundice a minimum of every 12 hours post delivery until discharge. Measure levels of TSB or transcutaneous bilirubin (TcB) as soon as possible for infants observed to be jaundiced less than 24 hours after birth (strong recommendation).
For identification of potential pathologic stasis, measure total and direct-reacting (or conjugated) levels of bilirubin in breastfed infants still jaundiced at age 3-4 weeks, as well as formula-fed infants still jaundiced at age 2 weeks.
Treatment
The AAP provides new TSB thresholds for intensive phototherapy on the basis of infants' gestational age, risk factors for hyperbilirubinemia neurotoxicity, and age in hours. (However, infants may be treated at lower levels, based on individual circumstances, family preferences, and shared decision-making with clinicians.)[19]
In the setting of inpatient phototherapy, measure TSB within 12 hours of initiation. Guide the timing of the first postphototherapy TSB measurement and the frequency of TSB monitoring during phototherapy based on infants' age, the presence of risk factors for hyperbilirubinemia neurotoxicity, and TSB level and trajectory.
In the setting of home phototherapy, measure TSB daily. Admit the infant for inpatient phototherapy with elevations of TSB, narrowing of the difference between the TSB and phototherapy threshold, or when the TSB level is at least 1 mg/dL above the phototherapy threshold.
To evaluate for anemia or obtain a baseline in case anemia develops in infants requiring phototherapy, measure hemoglobin concentration, hematocrit, or complete blood cell (CBC) count. For assessing the underlying cause(s) of hyperbilirubinemia in infants requiring phototherapy, obtain a DAT in infants of mothers with a positive antibody screen, a maternal O blood group regardless of Rh(D) status, or mothers who are Rh(D)-.
Measure glucose-6-phosphate dehydrogenase (G6PD) activity in any infant with jaundice of unknown cause in the setting of TSB elevations despite intensive phototherapy, sudden TSB increases or increases after an initial decline, or escalation of care.
Base repeat postphototherapy bilirubin measurement on the risk of rebound hyperbilirubinemia. Measuring TcB instead of TSB is an option if at least 24 hours have passed since the cessation of phototherapy.
Escalate care when an infant's TSB reaches or exceeds the escalation-of-care threshold (2 mg/dL below the exchange transfusion threshold) for infants without known risk factors for hyperbilirubinemia neurotoxicity, or for infants with rising TSB despite phototherapy or infants with at least one recognized risk factor for hyperbilirubinemia.
When escalation of care is required, obtain STAT levels of total and direct-reacting serum bilirubin, CBC, serum albumin and chemistries, as well as type and crossmatch.
Measure TSB at least every 2 hours from the initiation of escalation of care until the end of such escalation of care. When the TSB is below the threshold of escalation of care, follow the recommendations for monitoring infants on phototherapy.
Predischarge, provide all families with written and verbal education about neonatal jaundice.[36] Provide written information for ease of postdischarge care (eg, date, time, place of follow-up appointment; a prescription and follow-up appointment for TcB or TSB, as needed). Provide the infant's primary care provider with the birth hospitalization information (eg, last TcB or TSB and the age at measurement, any DAT results). If it is unclear who will provide the infant's follow-up care, provide such information to the families (strong recommendation).
For more information, please go to Conjugated Hyperbilirubinemia, Unconjugated Hyperbilirubinemia, and Phototherapy for Jaundice.
Medications are not usually administered in infants with physiologic neonatal jaundice. Phenobarbital, an inducer of hepatic bilirubin metabolism, has previously been used to enhance bilirubin metabolism. However, concern about the long-term effect of phenobarbital in early life has all but removed this drug from the list of therapeutic alternatives. 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 reduce the need for exchange transfusions in infants with isoimmune hemolytic disease.[19, 55] [81] A small number of cases of necrotizing enterocolitis following administration of immunoglobulin has been published, and comparisons of risk between IVIG versus exchange transfusion appear not to have been performed. Published data regarding efficacy are varied, perhaps having to do with different study set-ups, as studies that show effects of IVIG as far as reducing exchange transfusion have used this drug in a rescue modality only. Thus, IVIG is not recommended for prophlyactic use, and indeed is not warranted, as effective phototherapy will control hyperbilirubinemia in the majority of infants with hemolytic disease of the newborn.[34]
A newer therapy 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.[100] 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 1067 neonates with jaundice who received probiotics showed a reduction in total serum bilirubin (TSB) levels after 3, 5, and 7 days, as well as a reduction in the time of jaundice fading, the duration of phototherapy, and length of hospitalization relative to neonates in the control group.[101] 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 TSB levels 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.[102]
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?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?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?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's cry have a role in the evaluation of neonatal jaundice?What do yellow organs indicate in the evaluation of neonatal jaundice?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?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?
Thor WR Hansen, MD, PhD, MHA, FAAP, Professor, Department of Neonatology, Women and Children's Division, Director of Clinical Ethics, Oslo University Hospital HC, Rikshospitalet; Director of Pediatric Education, Faculty of Medicine, University of Oslo, Norway
Disclosure: Nothing to disclose.
Specialty Editors
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, University of Missouri-Kansas City School of Medicine; Attending Physician, Division of Neonatology, Children's Mercy Hospital and Clinics; Faculty, Children's Mercy Bioethics Center
Disclosure: Nothing to disclose.
Chief Editor
Muhammad Aslam, MD, Professor of Pediatrics, University of California, Irvine, School of Medicine; Neonatologist, Division of Newborn Medicine, Department of Pediatrics, UC Irvine Medical Center
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.
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.
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.
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.
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.
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;
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.
