Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants. Section Editor Steven A Abrams, MD

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1 Page 1 of 18 Official reprint from UpToDate UpToDate Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants Authors Ronald J Wong, BA Vinod K Bhutani, MD, FAAP Section Editor Steven A Abrams, MD Deputy Editor Melanie S Kim, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug This topic last updated: Aug 08, INTRODUCTION Almost all newborn infants develop a total serum or plasma bilirubin (TB) value greater than 1 mg/dl (17.1 micromol/l), which is the upper limit of normal for adults. As TB increases, it causes neonatal jaundice, the yellowish discoloration of the skin and/or conjunctiva caused by bilirubin deposition in half of all newborn infants. Neonates with severe hyperbilirubinemia (defined as a TB >25 mg/dl [428 micromol/l]) are at risk for bilirubin-induced neurologic dysfunction (BIND), which occurs when bilirubin crosses the blood-brain barrier and binds to brain tissue. The clinical manifestations of neonatal unconjugated hyperbilirubinemia including risk factors for severe hyperbilirubinemia in term and late preterm infants are reviewed here. The pathogenesis, etiology, evaluation, prevention, and treatment of this disorder are discussed separately. (See "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn" and "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants" and "Treatment of unconjugated hyperbilirubinemia in term and late preterm infants".) DEFINITIONS Neonatal hyperbilirubinemia in infants 35 weeks gestational age (GA) is defined as total serum or plasma bilirubin (TB) >95 th percentile on the hour-specific Bhutani nomogram (figure 1) [1]. Severe neonatal hyperbilirubinemia is defined as a TB >25 mg/dl (428 micromol/l). It is associated with an increased risk for bilirubin-induced neurologic dysfunction (BIND), which occurs when bilirubin crosses the blood-brain barrier and binds to brain tissue. (See 'Neurologic manifestations' below.) Acute bilirubin encephalopathy (ABE) is used to describe the acute manifestations of BIND. (See 'Acute bilirubin encephalopathy' below.) Kernicterus is used to describe the chronic and permanent sequelae of BIND. (See 'Kernicterus' below.) OVERVIEW The administration of Rh(D) immunoglobulin to Rhesus (Rh)-negative mothers in the late 1960s dramatically decreased the incidence of neonatal Rh isoimmune hemolytic disease. Thus, the risk of kernicterus was reduced from its peak in the 1950s through the 1970s. Nevertheless, isolated cases of kernicterus, a preventable condition, continue to be reported [2,3]. (See 'Epidemiology' below.) Since the association between hyperbilirubinemia and kernicterus was first identified in infants with erythroblastosis fetalis more than 50 years ago [4-6], there has been a debate on what degree and duration of hyperbilirubinemia causes bilirubin-induced neurologic dysfunction (BIND). Additional factors such as the rate of rise of total serum or plasma bilirubin (TB), the proportion of unbound (or "free") bilirubin, and the permeability of the blood-brain barrier affect the potential for neurotoxicity. (See 'Neurologic manifestations' below.) Limited data based upon case reports suggest that kernicterus is unlikely to occur in healthy term infants with TB 20 mg/dl (342 micromol/l) [2,7]. This is illustrated in a report of 61 cases of readmitted patients (before seven days of age) that were voluntarily reported to the Pilot Kernicterus Registry [2]. The median TB on readmission was 39 mg/dl (667 micromol/l), range 21.5 to 50 mg/dl (368 to 855

2 Page 2 of 18 micromol/l) [2]. A review of the literature in 2002 of 123 cases reported similar results; more than 90 percent of infants had TB >25 mg/dl (428 micromol/l). Based upon these data, the management of unconjugated hyperbilirubinemia in term and late preterm infants is focused on two key elements: th Prevention of hyperbilirubinemia, defined as TB >95 percentile for hours-of-age on the Bhutani nomogram [8], by identifying at-risk infants and beginning preventative therapeutic interventions (eg, phototherapy) as needed [3] Reduction of TB in infants with severe hyperbilirubinemia (See "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants" and "Treatment of unconjugated hyperbilirubinemia in term and late preterm infants".) EPIDEMIOLOGY Total serum/plasma bilirubin (TB) In the neonate, TB values vary substantially among institutions because of differences in racial composition, hemolytic conditions, or breastfeeding practices. (See "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Epidemiology' and "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn", section on 'Neonatal jaundice'.) These factors may contribute to the observed global variations in the incidence of hyperbilirubinemia (TB >20 mg/dl [342 micromol/l]). In studies of term or late preterm infants from a large Northern California health maintenance organization (HMO), the following incidences of severe hyperbilirubinemia at different TB values were reported from birth data collected between 1995 and 1998 [9,10]: TB >20 mg/dl (342 micromol/l): 2 percent [10] TB >25 mg/dl (428 micromol/l): 0.14 percent [10] TB >30 mg/dl (513 micromol/l): 0.01 percent [9] The risk of TB >20 mg/dl (342 micromol/l) was lower in infants born to mothers who self-reported as African American than in those who were Caucasian (0.9 versus 1.5 percent, relative risk [RR] 0.62, 95% CI ) [11]. However, the risk of severe hyperbilirubinemia, defined as TB >30 mg/dl (513 micromol/l), was higher in African-American infants (0.13 versus 0.03 percent, RR 4.2, 95% CI ). In a later cohort of infants from the same HMO born between 1995 and 2011 (n = 525,409), 47 infants were identified with severe hyperbilirubinemia resulting in an incidence of 8.6 per 100,000 births [12]. The etiology was not identified in 33 patients, and 10 of 25 patients tested for glucose- 6-phosphate dehydrogenase (G6PD) activity were found to be deficient. Four patients had acute bilirubin encephalopathy (ABE). This included three infants with G6PD deficiency with TB levels >40 mg/dl (684 micromol/l), in whom cerebral palsy (CP) and sensorineural hearing loss (SNHL) developed in two patients, and SNHL only in one patient. (See "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn", section on 'Increased production'.) In a Danish population-based study from 2000 to 2007, the incidence of "extreme" hyperbilirubinemia (defined as a TB 26.3 mg/dl or 450 micromol/l) was percent of infants born at gestational age (GA) 35 weeks [13]. Of the 224 identified infants with extreme hyperbilirubinemia, three had advanced bilirubin encephalopathy and a peak TB level greater than 35 mg/dl (599 micromol/l), which was due to hemolysis either from ABO incompatibility or G6PD deficiency. All three patients developed kernicterus. Two other infants had moderate bilirubin

3 Page 3 of 18 encephalopathy and their neurologic condition normalized over four to five days. One of the patients with moderate disease had ABO incompatibility. In a prospective population-based study in the United Kingdom and Ireland between 2003 and 2005, the incidence of "severe" hyperbilirubinemia (defined as a TB >30 mg/dl or 513 micromol/l) was 7 per 100,000 live births [14]. The mean GA of the 108 identified infants was 38.2 weeks. Eighty percent of the patients were breastfed, two-thirds were male, and about half were from a minority ethnic background. Fourteen infants developed ABE, including three infants who died. In a prospective population-based study from Australia performed between 2010 and 2013, the incidence of "extreme" hyperbilirubinemia (defined as a TB 26.3 mg/dl or 450 micromol/l) for newborns greater than 34 weeks GA was 9.4 per 100,000 infants [15]. In this cohort, the main identifiable cause of extreme hyperbilirubinemia was due to hemolytic disease (eg, ABO blood group incompatibility, G6PD deficiency, and Rhesus [Rh] isoimmunization). However, about half of the cases were identified as "idiopathic" and most occurred in infants of East Asian ethnicity, suggesting a genetic predisposition. (See 'Risk factors' below.) The higher reported incidence in the United States compared with Western Europe and Nova Scotia may reflect the greater number of infants born of mothers who are East Asian or African American. In a study that compared data from the Canadian Paediatric Surveillance Program (CPSP) with previously published reports, the incidence of severe hyperbilirubinemia in Canada declined from 0.04 to 0.01 percent over a 10-year period from 2002 through 2004 to 2011 through 2013 [16]. In this study, severe neonatal hyperbilirubinemia was defined as peak TB >25 mg/dl (425 mmol/l) or an exchange transfusion in a term infant 60 days of age. Kernicterus Kernicterus is the chronic and permanent neurologic sequelae of bilirubin-induced neurologic dysfunction (BIND). Although there had been concerns that the incidence of kernicterus was rising, the risk of kernicterus appears to be stable based on population studies. This was illustrated by a study that used diagnosis codes from data collected by the California Department of Developmental Services to identify patients with kernicterus born between 1988 and 1997, and death certificate data from the National Center for Health Statistics (NCHS) to examine kernicterus mortality trends [17]. The following findings were noted: Twenty-five cases with a strict diagnosis of kernicterus were identified over the 10-year period resulting in an overall incidence of 0.44 per 100,000 live births averaged per year when reported for the entire study period. The incidence of kernicterus was higher in boys than in girls (0.71 versus 0.30 per 100,000 live births per year). The death rate due to kernicterus was 0.28 deaths per one million live births, which remained stable throughout the study period from 1979 to Determining the incidence of kernicterus is confounded by absence of population-based data, reports of select patients who are admitted at varying stages of ABE, and variable timeliness to intervention. Similar incidences of kernicterus per 100,000 live births have been reported in the United States (0.44) as were reported in population-based studies in Germany (0.63) and Denmark (0.40), but a higher rate was seen in Canada [17-19]. In a report that used prospective data from the CPSP from 2007 to 2008, 20 cases of kernicterus (eg, chronic bilirubin encephalopathy) were identified resulting in an incidence of 2.3 cases per 100,000 live births [19]. Causes of neonatal hyperbilirubinemia included alloimmune hemolytic disease due to ABO incompatibility or other red blood cell antibodies (n = 7), G6PD deficiency (n = 5), and sepsis (n = 2). Fifteen patients had an abnormal brain magnetic resonance imaging (MRI) study during the neonatal period. Of the 14 patients with follow-up data, six patients had signs of neurologic impairment and/or developmental delay, five infants had choreoathetoid CP, and three were reported as healthy. It appears that the incidences of kernicterus and hyperbilirubinemia are decreasing.

4 Page 4 of 18 In one study using select reporting of nationally representative hospital discharge data in the United States, the hospitalization rate for newborns who were coded to have kernicterus by clinicians declined from 5.1 per 100,000 term neonates (patients 30 days of age) in 1988 to 1.5 per 100,000 neonates in 1994 [20]. In this report, a case of kernicterus, when reported, was defined by a diagnosis code and evidence of treatment with phototherapy or exchange transfusion, and data from late preterm infants were not included. Asian infants had a higher rate of hospitalization than other ethnic groups, as did preterm compared with term infants. A report from a multi-hospital healthcare system in the United States showed a declining rate of infants with extreme hyperbilirubinemia, defined as TB between 25 and 29.9 mg/dl (428 and 513 micromol/l) from 2002 to 2010 [21] (figure 2). No patient in this cohort developed kernicterus. RISK FACTORS In the 2004 American Academy of Pediatrics (AAP) Practice Guideline, the following major risk factors for severe hyperbilirubinemia (table 1) and bilirubin-induced neurologic dysfunction (BIND) were identified [1]: Predischarge total serum or plasma bilirubin (TB) or transcutaneous bilirubin (TcB) in a high-risk zone defined as >95 th percentile for age (figure 1). The risk for severe hyperbilirubinemia and the threshold for intervention based upon the hour-specific TB value may be determined using the newborn hyperbilirubinemia assessment calculator (calculator 1). (See "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Total serum or plasma bilirubin (TB)' and "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Transcutaneous bilirubin'.) Jaundice within the first 24 hours of life [22]. Hemolytic disease due to isoimmune-mediated hemolysis from blood group incompatibility or inherited red cell enzymatic deficiencies or membrane defects (eg, glucose-6-phosphate dehydrogenase [G6PD] deficiency). In addition, evidence of hemolysis is a major risk factor for severe hyperbilirubinemia (eg, elevated end-tidal carbon monoxide [CO], corrected for inhaled CO or end-tidal carbon monoxide concentration [ETCOc] levels). (See "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn", section on 'Increased production' and "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Endtidal carbon monoxide concentration'.) Gestational age (GA) 35 to 36 weeks [23,24]. (See "Late preterm infants".) Sibling who previously received phototherapy [24,25]. Cephalohematoma or significant bruising from birth trauma [23]. Exclusive breastfeeding, particularly if nursing is not going well and weight loss is excessive (>12 percent of birth weight [BW]) [23,24]. East Asian race. (See "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn", section on 'Ethnic variation in conjugation ability'.) Minor risk factors included [1] (table 1): TB in a high intermediate range (>75 th and 95 th percentile for age-in-hours) Jaundice observed before discharge [24] Macrosomic infant of a diabetic mother [26,27] Polycythemia Male gender [23] Maternal age 25 years [24]

5 Page 5 of 18 The ability of the AAP major risk factors to predict hyperbilirubinemia was illustrated in a retrospective nested case-control study of a large cohort of 285,295 newborn infants born with a BW 2000 g at a GA 34 weeks between 1995 and 2004 [28]. In this study, 62 infants (0.4 percent) were identified with a TB 25 mg/dl (428 micromol/l) from a cohort of 17,986 infants (6.3 percent) with a TB between 17 and 22.9 mg/dl (291 to 392 micromol/l) at age 48 hours of life. Four randomly selected control cases within the identified cohort group were matched to the patients with TB 25 mg/dl (428 micromol/l). Lower GA, bruising, a family history of neonatal hyperbilirubinemia, a rapid rise of TB 6 mg/dl (103 micromol/l) per day, and exclusive breastfeeding were associated with a TB 25 mg/dl (428 micromol/l). In the nested control sample, inpatient phototherapy within eight hours of a qualifying TB was associated with a decreased risk for a TB 25 mg/dl (428 micromol/l). A population-based study using data from the Swedish Medical Birth Right Register of term infants ( 37 weeks GA) born from 1999 to 2012 identified the following as risk factors for severe hyperbilirubinemia: GA between 37 and 38 weeks, failed or successful vacuum extraction, macrosomic infants, obese mother, and being small for gestational age (SGA) [29]. In this cohort, planned cesarean delivery was associated with a reduced risk of hyperbilirubinemia. In this study, severe hyperbilirubinemia was defined as 20 mg/dl (342 micromol/l) before 2008 and 20.6 mg/dl (352 micromol/l) from 2008 and after. Although inherited deficiencies in hepatic conjugating capacity (eg, Crigler-Najjar or Gilbert syndromes) were not included in the AAP guideline or assessed in the Swedish study as risk factors, genetic predisposition may play a major role in severe hyperbilirubinemia, especially in Gilbert syndrome, which affects 9 percent of the general population [30,31]. This may in part explain why family history is a predictive risk factor for hyperbilirubinemia. The underlying decrease in bilirubin clearance of infants with Gilbert syndrome in combination with other factor(s) that increases TB can result in severe hyperbilirubinemia [32]. As an example, breastfed infants with Gilbert syndrome have a three- to fourfold increased risk for TB >20 mg/dl (342 micromol/l) compared with breastfed infants without Gilbert syndrome [33]. (See "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn", section on 'Gilbert syndrome'.) An alternative simpler approach of using the infant's discharge TB level and GA has been reported to accurately assess an infant's risk of developing significant hyperbilirubinemia [34]. Factors associated with decreased risk of severe hyperbilirubinemia include [1] (table 1): GA 41 weeks [23] Exclusive bottle-feeding [23,24] Neonatal discharge from the hospital after 72 hours [24,35] African American ethnicity, although there appears to be a subgroup of African American males with G6PD deficiency who remain at risk [36] These risk factors are used to assess the likelihood of developing clinically significant hyperbilirubinemia. The risk assessment and the age of the infant at the time of discharge from the hospital are used to determine the timing of appropriate follow-up (table 2). (See "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Risk assessment' and "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Follow-up'.) Readmission Risk for readmission for hyperbilirubinemia for term infants based on a large population-based Australian study included [37]: Early birth hospital discharge ( 2 days after birth). GA <39 weeks. Mother from an Asian country. Vaginal birth. First-time mother.

6 Page 6 of 18 Breastfeeding at the time of birth hospital discharge. Of note, the study does not differentiate between suboptimal or successful initiation of breastfeeding at the time of discharge. CLINICAL MANIFESTATIONS The clinical manifestations of hyperbilirubinemia are due to bilirubin deposition in the skin (jaundice) and/or the brain (bilirubin-induced neurologic dysfunction [BIND]). Jaundice Jaundice is the yellow color produced by the deposition of bilirubin in the skin and subcutaneous tissues. Although an important, and time-honored clinical sign, the presence of jaundice is not a reliable method to assess total serum or plasma bilirubin (TB) concentration or identify infants at risk for rapidly rising bilirubin, especially in those with dark skin [2,38,39]. The examination for jaundice should be performed with adequate ambient light or under daylight fluorescent light. Pressing on the skin with a finger reduces local skin perfusion and facilitates detection of jaundice (picture 1). Jaundice usually progresses in a cephalocaudal direction, appearing first in the face with TB levels of 4 to 8 mg/dl (68 to 137 micromol/l). The entire body, including palms and soles, can appear jaundiced at TB >15 mg/dl (257 micromol/l) [40]. The presence or absence of conjunctival icterus may be useful to help decide which infants may need further assessment. In an observational study of 240 term or late preterm neonates, most infants with conjunctival icterus had TB 15 mg/dl (257 micromol/l) and all infants with this finding had TB levels >75th percentile (primarily greater than the 95 th percentile) on the hour-specific Bhutani nomogram (figure 1) [41]. Seven of the 76 infants with conjunctival icterus had a TB in the 10 to 14.9 mg/dl (171 to 255 micromol/l) range. In another study of 689 infants between 3 and 10 days of age seen in the follow-up after discharge from the nursery, conjunctival icterus did not correlate with significant hyperbilirubinemia, as 60 percent of those infants with icterus had a transcutaneous bilirubin (TcB) measurement of <13 mg/dl. However, the absence of conjunctival icterus was associated with a low probability of significant hyperbilirubinemia. Differences in the results of this and the previous study may be due to the use of TcB, which typically underestimates TB, and differences in the study population. (See "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Limitations of TcB'.)Based on available data, in our practice, TB or transcutaneous bilirubin (TcB) levels are measured in an infant with jaundice below the umbilicus or with conjunctival icterus. If there is uncertainty regarding the presence or extent of jaundice, a TB or TcB measurement is also performed. (See "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants".) Other findings on physical examination may suggest an increased risk for hyperbilirubinemia. These include pallor, enclosed hemorrhage (eg, cephalohematoma), bruising, and hepatosplenomegaly. Neurologic manifestations Bilirubin is a potential neurotoxin [42-50]. Term and late preterm infants are at risk for BIND when TB concentrations 25 mg/dl (428 micromol/l). In general, at this threshold, unconjugated bilirubin, which is not bound to albumin (also referred to as "free" or unbound bilirubin), can enter the brain and cause cell death by apoptosis (programmed cell death) and/or necrosis [48-50]. In vitro, animal cell culture studies suggested that lower levels of unconjugated bilirubin induce apoptosis and higher levels induce necrotic cell death [48]. Which mechanism predominates in infants with severe unconjugated hyperbilirubinemia who develop BIND remains uncertain [1]. BIND is a spectrum of subtle neurologic findings and sequelae [51], which can manifest as disorders in vision [52], hearing [53], gait [54], and speech, cognition, and language [55]. Acute bilirubin encephalopathy (ABE) may be reversible or result in permanent irreversible neurologic dysfunction (kernicterus). The brain regions most often affected include the basal ganglia and the brainstem nuclei for oculomotor and auditory function, accounting for the clinical features seen in infants with BIND [56]. Acute bilirubin encephalopathy ABE typically progresses through three phases [56]:

7 Page 7 of 18 In the early phase, the clinical signs may be subtle. The infant is sleepy but arousable, and when aroused has mild to moderate hypotonia and a high-pitched cry. If there is no intervention, the intermediate phase evolves with progression and persistence of hyperbilirubinemia. The infant can be febrile, lethargic with a poor suck, or irritable and jittery with a strong suck. The cry can be shrill and the infant is difficult to console. Mild to moderate hypertonia develops, beginning with backward arching of the neck (retrocollis) and trunk (opisthotonos) with stimulation. An emergent exchange transfusion at this stage might prevent permanent BIND. The advanced phase is characterized by apnea, inability to feed, fever, seizures, and a semicomatose state that progresses to coma. Hypertonicity presents as persistent retrocollis and opisthotonos with bicycling or twitching of the hands and feet. The cry is inconsolable, or may be weak or absent. Death is due to respiratory failure or intractable seizures. In a report based on prospective data from the voluntary Canadian Paediatric Surveillance Program (CPSP), 32 of 258 infants (12.4 percent) with severe hyperbilirubinemia (defined as a TB >24.8 mg/dl [424 micromol/l]) were diagnosed with ABE [57]. Twenty other infants had nonspecific neurologic findings that were not severe enough to confidently make the diagnosis of ABE. Infants with ABE had higher peak TB levels than those without ABE (29.7 versus 27.3 mg/dl [508 versus 467 micromol/l]). Infants with ABE who presented in the first 48 hours of life had lower TB levels than those who presented after 48 hours. This study was unable to determine whether there was a relationship between ABE and the etiology of hyperbilirubinemia, as an underlying cause was determined in only 41 percent of patients with ABE and 35 percent of patients without any neurologic abnormality. In an observational study, 249 Egyptian neonates were admitted to a public hospital neonatal intensive care unit (NICU) following unknown duration of hyperbilirubinemia after delivery at outlying facilities over a 12-month period (January to December 2008). Characteristics of this at-risk infant cohort included: gestational age (GA) >34 weeks, birth weight (BW) >2 kg, postnatal age <14 days, and admission TB 25 mg/dl (428 micromol/l). Of these, 44 (18 percent) were diagnosed with moderate or severe ABE, 55 (22 percent) with mild ABE, and the remaining infants were asymptomatic [58]. Although the median TB was lower in patients with no ABE symptoms (28.3 mg/dl [484 micromol/l]) and rose progressively for those with mild/moderate and severe ABE (32 to 33 and 36.5 mg/dl, [547 to 564 and 624 micromol/l]), the range of TB values was similar in all three groups. Of the 26 infants who died with evidence of ABE, 19 had a TB level 30 mg/dl (513 micromol/l). The seven infants who died with lower TB had evidence of severe hemolysis and included six with Rhesus (Rh) incompatibility. In this select cohort of patients, multiple regression analyses demonstrated that sepsis, Rh incompatibility, and incremental TB increases of 5 mg/dl (86 micromol/l) increased the risk of ABE. Brainstem auditory-evoked responses (BAER) can be used to detect neurologic effects of hyperbilirubinemia [59-61]. In one study, increased TB correlated with prolonged brainstem conduction time [60]. These abnormalities resolve as TB values decline. Changes in BAER also have been associated with elevated unbound bilirubin levels [62]. An abnormal BAER and normal otoacoustic emission (OAE) tests suggest that severe hyperbilirubinemia results in an auditory neuropathy. Infants who are at increased risk for ABE include those who were born <37 weeks GA, were breastfed, have hemolytic disease, and are discharged home before 48 hours. Close surveillance of these at-risk infants with timely intervention can prevent ABE. (See 'Risk factors' above and "Treatment of unconjugated hyperbilirubinemia in term and late preterm infants".) Kernicterus Kernicterus (the chronic and permanent sequelae of BIND) develops during the first year after birth [56]. Cognitive function usually is relatively spared. The major features of kernicterus include: Choreoathetoid cerebral palsy (CP; chorea, ballismus, tremor, and dystonia). (See "Hyperkinetic movement disorders in children".)

8 Page 8 of 18 Sensorineural hearing loss (SNHL) commonly manifesting as auditory neuropathy (abnormal BAER with normal OAE). In a retrospective cohort study from a large multicenter health care system, SNHL based on chart review was found to be more frequently observed in patients who had TB 10 mg/dl (171 micromol/l) above the American Academy of Pediatrics (AAP) recommendation for exchange transfusion threshold (ETT) compared with controls with TB below the ETT [63]. In this study, all of the extremely hyperbilirubinemic infants were treated with phototherapy in a timely and effective manner consistent with the routine clinical practice of the birth hospitals in this healthcare system. (See "Hearing impairment in children: Etiology", section on 'Hyperbilirubinemia' and "Treatment of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Management approach' and "Treatment of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Exchange transfusion'.) Gaze abnormalities, especially limitation of upward gaze. Dental enamel dysplasia. Most infants who develop kernicterus have manifested some or all of the findings associated with ABE [2]. However, there are reported cases of infants who developed kernicterus with high TB, but without or with only a few signs of ABE [64,65]. In the previously mentioned report of 61 patients from the Pilot Kernicterus Registry who had been readmitted for hyperbilirubinemia, the following diagnoses were the major contributing causes of hyperbilirubinemia that resulted in kernicterus [2]: No etiology identified 20 patients Glucose-6-phosphate dehydrogenase (G6PD) deficiency 20 patients Hemolysis 9 patients Bruising from birth trauma 6 patients Infection 4 patients Crigler-Najjar Syndrome or galactosemia 3 patients All but one of the infants were breastfed. Sixteen infants had lost >10 percent of their BW at the time of hospital readmission. (See "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn".) Neurologic dysfunction and moderate hyperbilirubinemia It remains uncertain whether moderate hyperbilirubinemia may be associated with an increased risk of long-term neurologic dysfunction, as demonstrated by the following studies: In the already mentioned population-based study of 61,238 infants born between 1994 and 2000 from Nova Scotia, there were no differences in the composite outcome of CP, developmental delay, hearing and vision losses, autism, and attention deficit hyperactivity disorder (ADHD) between infants without hyperbilirubinemia (n = 52,240) and the 3431 infants with mild hyperbilirubinemia, defined as TB of 13.5 to 19 mg/dl (231 to 325 micromol/l), (adjusted relative risk [RR] 1.1, 95% CI ) or the 348 infants with severe hyperbilirubinemia, defined as TB >19 mg/dl (>325 micromol/l), (adjusted RR 1.1, 95% CI ). When the groups were analyzed for each outcome measure, only developmental delay was increased in those with moderate hyperbilirubinemia (adjusted RR 1.6, 95% CI ) and ADHD in those with severe hyperbilirubinemia (adjusted RR 1.9, 95% CI ) compared with infants without hyperbilirubinemia. Although not statistically significant, there appeared to be a trend of increased likelihood of autism in infants with hyperbilirubinemia compared with those without hyperbilirubinemia (adjusted RR 1.6, 95% CI ). Another prospective cohort study failed to find an increase in neurologic findings in 132 of 140 infants with TB levels 25 mg/dl (428 micromol/l) compared (blindly) with 372 matched controls who were either not jaundiced or had TB <22.8 mg/dl (390 micromol/l) at two to five years of age

9 Page 9 of 18 [66]. Infants with hyperbilirubinemia, who were treated with either phototherapy (136 cases) or exchange transfusions had a lower incidence of questionable or abnormal findings on neurological examination than control infants (17 versus 29 percent) [66]. In a subset analysis, nine patients with hyperbilirubinemia and a positive direct antiglobulin test (DAT or Coombs test) had lower scores on cognitive testing than other patients with hyperbilirubinemia with a negative DAT. In a case-control study, neonatal hyperbilirubinemia was not a risk factor for autism spectrum disorder for TB levels of 15 to 19.9 mg/dl (257 to 340 micromol/l, odds ratio [OR] 0.7, 95% CI ); 20 to 24.9 mg/dl (342 to 426 micromol/l, OR 0.7, 95% CI ); or 25 mg/dl (428 micromol/l, OR 1.1, 95% CI ) [67]. In contrast, a population-based study of 733,826 infants born alive in Denmark between 1994 and 2004 reported that neonatal jaundice was associated with an increased risk of psychological development disorders including infantile autism [68]. In this study, the exposure to jaundice and the diagnoses of psychological disorders were determined based on diagnostic coding from data retrieved from the Danish National Hospital Register. However, until there is convincing evidence that demonstrates moderate hyperbilirubinemia is associated with significant poor outcomes, recommendations regarding management should not be modified. (See "Treatment of unconjugated hyperbilirubinemia in term and late preterm infants".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5 th to 6 th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 th to 12 th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Jaundice in babies (The Basics)") Beyond the Basics topics (see "Patient education: Jaundice in newborn infants (Beyond the Basics)") SUMMARY Total serum/plasma bilirubin (TB) levels >1 mg/dl (17.1 micromol/l) occur in almost all newborn infants and present as jaundice. Infants with severe hyperbilirubinemia (TB >25 mg/dl [428 micromol/l]) are at risk for bilirubin-induced neurologic dysfunction (BIND), presenting acutely as acute bilirubin encephalopathy (ABE), and if inadequately treated, long-term neurologic sequelae (kernicterus). In the neonate, TB values vary because of differences in racial composition, breastfeeding practices, the prevalence of hemolytic conditions, and methodology of TB measurements. In California, reported incidences of hyperbilirubinemia for TB values >30 mg/dl (513 micromol/l), >25 mg/dl (428 micromol/l), and >20 mg/dl (342 micromol/l) were 0.01, 0.14, and 2 percent, respectively. (See 'Epidemiology' above and "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Methods to measure bilirubin'.) Infants remain at risk for severe hyperbilirubinemia and its sequelae of kernicterus, chronic BIND, because of increased prevalence of breastfeeding and early discharge of infants from the hospital with failure to set up timely follow-up and initiate successful breastfeeding. (See 'Epidemiology' above.)

10 Page 10 of 18 The following major risk factors identify infants at risk for severe hyperbilirubinemia and BIND (table 1) (see 'Risk factors' above): Predischarge TB or transcutaneous bilirubin (TcB) >95 th percentile for age (figure 1) Jaundice within the first 24 hours of life Hemolytic disease Gestational age (GA) <37 weeks Sibling who previously received phototherapy Cephalohematoma or significant bruising [23] Exclusive breastfeeding, particularly if feeding is not going well East Asian race Clinical manifestations are due to bilirubin deposition in the skin (jaundice) and the brain. Jaundice is the yellow color produced by the deposition of bilirubin in the skin and subcutaneous tissues. Although an important and time-honored clinical sign, the presence of jaundice is not a reliable method for assessing the actual TB concentration or for identifying infants at risk for a rapidly rising bilirubin, especially in those with dark skin. If jaundice extends below the level of the umbilicus or if there is uncertainty regarding the presence or extent of jaundice, a TB or TcB measurement should be performed. (See 'Jaundice' above and "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants".) BIND can occur in otherwise healthy term infants when TB concentrations exceed 25 mg/dl (428 micromol/l) and is manifested as ABE that can be reversible or result in kernicterus, a chronic permanent condition. (See 'Neurologic manifestations' above.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004; 114: Johnson LH, Bhutani VK, Brown AK. System-based approach to management of neonatal jaundice and prevention of kernicterus. J Pediatr 2002; 140: Maisels MJ. What's in a name? Physiologic and pathologic jaundice: the conundrum of defining normal bilirubin levels in the newborn. Pediatrics 2006; 118: MOLLISON PL, CUTBUSH M. A method of measuring the severity of a series of cases of hemolytic disease of the newborn. Blood 1951; 6: HSIA DY, ALLEN FH Jr, GELLIS SS, DIAMOND LK. Erythroblastosis fetalis. VIII. Studies of serum bilirubin in relation to Kernicterus. N Engl J Med 1952; 247: HSIA DY, GELLIS SS. Studies on erythroblastosis due to ABO incompatibility. Pediatrics 1954; 13: Maisels MJ, Newman TB. Kernicterus in otherwise healthy, breast-fed term newborns. Pediatrics 1995; 96: Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics 1999; 103:6. 9. Newman TB, Liljestrand P, Escobar GJ. Infants with bilirubin levels of 30 mg/dl or more in a large managed care organization. Pediatrics 2003; 111:1303.

11 Page 11 of Newman TB, Liljestrand P, Escobar GJ. Combining clinical risk factors with serum bilirubin levels to predict hyperbilirubinemia in newborns. Arch Pediatr Adolesc Med 2005; 159: Wickremasinghe AC, Kuzniewicz MW, Newman TB. Black race is not protective against hazardous bilirubin levels. J Pediatr 2013; 162: Kuzniewicz MW, Wickremasinghe AC, Wu YW, et al. Incidence, etiology, and outcomes of hazardous hyperbilirubinemia in newborns. Pediatrics 2014; 134: Ebbesen F, Bjerre JV, Vandborg PK. Relation between serum bilirubin levels 450 μmol/l and bilirubin encephalopathy; a Danish population-based study. Acta Paediatr 2012; 101: Manning D, Todd P, Maxwell M, Jane Platt M. Prospective surveillance study of severe hyperbilirubinaemia in the newborn in the UK and Ireland. Arch Dis Child Fetal Neonatal Ed 2007; 92:F McGillivray A, Polverino J, Badawi N, Evans N. Prospective Surveillance of Extreme Neonatal Hyperbilirubinemia in Australia. J Pediatr 2016; 168: Sgro M, Kandasamy S, Shah V, et al. Severe Neonatal Hyperbilirubinemia Decreased after the 2007 Canadian Guidelines. J Pediatr 2016; 171: Brooks JC, Fisher-Owens SA, Wu YW, et al. Evidence suggests there was not a "resurgence" of kernicterus in the 1990s. Pediatrics 2011; 127: Bjerre JV, Petersen JR, Ebbesen F. Surveillance of extreme hyperbilirubinaemia in Denmark. A method to identify the newborn infants. Acta Paediatr 2008; 97: Sgro M, Campbell DM, Kandasamy S, Shah V. Incidence of chronic bilirubin encephalopathy in Canada, Pediatrics 2012; 130:e Burke BL, Robbins JM, Bird TM, et al. Trends in hospitalizations for neonatal jaundice and kernicterus in the United States, Pediatrics 2009; 123: Christensen RD, Lambert DK, Henry E, et al. Unexplained extreme hyperbilirubinemia among neonates in a multihospital healthcare system. Blood Cells Mol Dis 2013; 50: Newman TB, Liljestrand P, Escobar GJ. Jaundice noted in the first 24 hours after birth in a managed care organization. Arch Pediatr Adolesc Med 2002; 156: Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and prevention of extreme neonatal hyperbilirubinemia in a mature health maintenance organization. Arch Pediatr Adolesc Med 2000; 154: Maisels MJ, Kring E. Length of stay, jaundice, and hospital readmission. Pediatrics 1998; 101: Gale R, Seidman DS, Dollberg S, Stevenson DK. Epidemiology of neonatal jaundice in the Jerusalem population. J Pediatr Gastroenterol Nutr 1990; 10: Berk MA, Mimouni F, Miodovnik M, et al. Macrosomia in infants of insulin-dependent diabetic mothers. Pediatrics 1989; 83: Peevy KJ, Landaw SA, Gross SJ. Hyperbilirubinemia in infants of diabetic mothers. Pediatrics 1980; 66: Kuzniewicz MW, Escobar GJ, Wi S, et al. Risk factors for severe hyperbilirubinemia among infants with borderline bilirubin levels: a nested case-control study. J Pediatr 2008; 153: Norman M, Åberg K, Holmsten K, et al. Predicting Nonhemolytic Neonatal Hyperbilirubinemia. Pediatrics 2015; 136: Watchko JF. Vigintiphobia revisited. Pediatrics 2005; 115: Kadakol A, Sappal BS, Ghosh SS, et al. Interaction of coding region mutations and the Gilberttype promoter abnormality of the UGT1A1 gene causes moderate degrees of unconjugated hyperbilirubinaemia and may lead to neonatal kernicterus. J Med Genet 2001; 38: Watchko JF. Genetics and the risk of neonatal hyperbilirubinemia: commentary on the article by Huang et al. on page 682. Pediatr Res 2004; 56: Huang MJ, Kua KE, Teng HC, et al. Risk factors for severe hyperbilirubinemia in neonates. Pediatr Res 2004; 56: Keren R, Luan X, Friedman S, et al. A comparison of alternative risk-assessment strategies for predicting significant neonatal hyperbilirubinemia in term and near-term infants. Pediatrics 2008; 121:e170.

12 Page 12 of Soskolne EI, Schumacher R, Fyock C, et al. The effect of early discharge and other factors on readmission rates of newborns. Arch Pediatr Adolesc Med 1996; 150: Kaplan M, Herschel M, Hammerman C, et al. Neonatal hyperbilirubinemia in African American males: the importance of glucose-6-phosphate dehydrogenase deficiency. J Pediatr 2006; 149: Lain SJ, Roberts CL, Bowen JR, Nassar N. Early discharge of infants and risk of readmission for jaundice. Pediatrics 2015; 135: Moyer VA, Ahn C, Sneed S. Accuracy of clinical judgment in neonatal jaundice. Arch Pediatr Adolesc Med 2000; 154: Tayaba R, Gribetz D, Gribetz I, Holzman IR. Noninvasive estimation of serum bilirubin. Pediatrics 1998; 102:E Knudsen A, Ebbesen F. Cephalocaudal progression of jaundice in newborns admitted to neonatal intensive care units. Biol Neonate 1997; 71: Azzuqa A, Watchko JF. Bilirubin Concentrations in Jaundiced Neonates with Conjunctival Icterus. J Pediatr 2015; 167: Chuniaud L, Dessante M, Chantoux F, et al. Cytotoxicity of bilirubin for human fibroblasts and rat astrocytes in culture. Effect of the ratio of bilirubin to serum albumin. Clin Chim Acta 1996; 256: Amato MM, Kilguss NV, Gelardi NL, Cashore WJ. Dose-effect relationship of bilirubin on striatal synaptosomes in rats. Biol Neonate 1994; 66: Hoffman DJ, Zanelli SA, Kubin J, et al. The in vivo effect of bilirubin on the N-methyl-D-aspartate receptor/ion channel complex in the brains of newborn piglets. Pediatr Res 1996; 40: Bratlid D. How bilirubin gets into the brain. Clin Perinatol 1990; 17: Dainat J, de Balbian Verster F, Zand R, Sellinger OZ. Age-dependent changes in the specificity of trna methyltransferases in the cerebellum of the icteric and nonicteric Gunn rat. Neurochem Res 1979; 4: Roger C, Koziel V, Vert P, Nehlig A. Regional cerebral metabolic consequences of bilirubin in rat depend upon post-gestational age at the time of hyperbilirubinemia. Brain Res Dev Brain Res 1995; 87: Hankø E, Hansen TW, Almaas R, et al. Bilirubin induces apoptosis and necrosis in human NT2-N neurons. Pediatr Res 2005; 57: Grojean S, Koziel V, Vert P, Daval JL. Bilirubin induces apoptosis via activation of NMDA receptors in developing rat brain neurons. Exp Neurol 2000; 166: Rodrigues CM, Solá S, Brites D. Bilirubin induces apoptosis via the mitochondrial pathway in developing rat brain neurons. Hepatology 2002; 35: Bhutani VK, Wong R. Bilirubin-induced neurologic dysfunction (BIND). Semin Fetal Neonatal Med 2015; 20: Good WV, Hou C. Visuocortical bilirubin-induced neurological dysfunction. Semin Fetal Neonatal Med 2015; 20: Olds C, Oghalai JS. Audiologic impairment associated with bilirubin-induced neurologic damage. Semin Fetal Neonatal Med 2015; 20: Rose J, Vassar R. Movement disorders due to bilirubin toxicity. Semin Fetal Neonatal Med 2015; 20: Wusthoff CJ, Loe IM. Impact of bilirubin-induced neurologic dysfunction on neurodevelopmental outcomes. Semin Fetal Neonatal Med 2015; 20: Volpe JJ. Neurology of the Newborn, 4th ed, WB Saunders, Philadelphia Sgro M, Campbell D, Barozzino T, Shah V. Acute neurological findings in a national cohort of neonates with severe neonatal hyperbilirubinemia. J Perinatol 2011; 31: Gamaleldin R, Iskander I, Seoud I, et al. Risk factors for neurotoxicity in newborns with severe neonatal hyperbilirubinemia. Pediatrics 2011; 128:e Vohr BR, Karp D, O'Dea C, et al. Behavioral changes correlated with brain-stem auditory evoked responses in term infants with moderate hyperbilirubinemia. J Pediatr 1990; 117: Gupta AK, Mann SB. Is auditory brainstem response a bilirubin neurotoxicity marker? Am J Otolaryngol 1998; 19:232.

13 Page 13 of Agrawal VK, Shukla R, Misra PK, et al. Brainstem auditory evoked response in newborns with hyperbilirubinemia. Indian Pediatr 1998; 35: Ahlfors CE, Parker AE. Unbound bilirubin concentration is associated with abnormal automated auditory brainstem response for jaundiced newborns. Pediatrics 2008; 121: Wickremasinghe AC, Risley RJ, Kuzniewicz MW, et al. Risk of Sensorineural Hearing Loss and Bilirubin Exchange Transfusion Thresholds. Pediatrics 2015; 136: VAN PRAAGH R. Diagnosis of kernicterus in the neonatal period. Pediatrics 1961; 28: JONES MH, SANDS R, HYMAN CB, et al. Longitudinal study of the incidence of central nervous system damage following erythroblastosis fetalis. Pediatrics 1954; 14: Newman TB, Liljestrand P, Jeremy RJ, et al. Outcomes among newborns with total serum bilirubin levels of 25 mg per deciliter or more. N Engl J Med 2006; 354: Croen LA, Yoshida CK, Odouli R, Newman TB. Neonatal hyperbilirubinemia and risk of autism spectrum disorders. Pediatrics 2005; 115:e Maimburg RD, Bech BH, Vaeth M, et al. Neonatal jaundice, autism, and other disorders of psychological development. Pediatrics 2010; 126:872. Topic 4994 Version 38.0

14 Page 14 of 18 GRAPHICS Nomogram of hour-specific serum or plasma total bilirubin (TB) concentration in healthy term and near-term newborns The red, blue, and green lines denote the 95th, 75th, and 40th percentiles, respectively. Risk zones are designated according to percentile: high (TB 95th), high intermediate (95th >TB 75th), low intermediate (75th >TB 40th), and low (TB <40th). Infants with values in the high risk zone are at increased risk for the development of clinically significant hyperbilirubinemia requiring intervention. Reproduced with permission from Pediatrics, Vol. 114, Pages , Copyright 2004 by the AAP. Graphic Version 11.0

15 Page 15 of 18 Changes in the incidence of extreme hyperbilirubinemia in the Unite Comparison of the incidence of extreme hyperbilirubinemia (total serum bilirubin >25 mg/dl) fo born at one of the Intermountain Healthcare (IMHC) facilities from 2001 to 2010, historical data year Collaborative Perinatal Project of 41,324 singleton white and black births with birth weight in 1959 (prior to availability of phototherapy and most [85 percent] infants with total bilirubin > treated with an exchange transfusion), and from Northern California population (Newman et al) after the implementation of 1994 American Academy of Pediatrics (AAP) Guidelines. From: Brites D, Bhutani VK. Pathways involving bilirubin and other brain-injuring agents. In: Clinics in Medicine: Cerebral palsy: Science and clinical practice, Dan B, Mayston M, Paneht N, Rosenbloom L (E Press, London Copyright 2014 Mac Keith Press. Reproduced with permission of John Wiley & image has been provided by or is owned by Wiley. Further permission is needed before it can be down PowerPoint, printed, shared or ed. Please contact Wiley's permissions department either via ema permissions@wiley.com or use the RightsLink service by clicking on the 'Request Permission' link acco article on Wiley Online Library ( Graphic Version 1.0

16 Page 16 of 18 Risk factors for development of severe hyperbilirubinemia in infants of 35 or more weeks gestation (in approximate order of importance) Major risk factors Predischarge TB or TcB level in the high-risk zone Jaundice observed in the first 24 hours Blood group incompatibility with positive direct antiglobulin test, other known hemolytic disease (eg, G6PD deficiency), elevated ETCOc Gestational age 35 to 36 weeks Previous sibling received phototherapy Cephalohematoma or significant bruising Exclusive breastfeeding, particularly if nursing is not going well and weight loss is excessive East Asian race* Minor risk factors Predischarge TB or TcB level in the high intermediate-risk zone Gestational age 37 to 38 weeks Jaundice observed before discharge Previous sibling with jaundice Macrosomic infant of a diabetic mother Maternal age 25 years Male gender Decreased risk (these factors are associated with decreased risk of significant jaundice, listed in order of decreasing importance) TB or TcB level in the low-risk zone Gestational age 41 weeks Exclusive bottle feeding Black race* Discharge from hospital after 72 hours TB: total serum or plasma bilirubin; TcB: transcutaneous bilirubin; G6PD: glucose-6-phosphate dehydrogenase; ETCOc: end-tidal carbon monoxide concentration. * Race as defined by mother's description. Reproduced with permission from Pediatrics, Vol. 114, Pages , Copyright 2004 by the AAP. Graphic Version 15.0

17 Page 17 of 18 Recommended timing of follow-up visits for term and near term infants (>35 weeks gestation) Age infant discharged Less than 24 hours of age Between 24 and 47.9 hours of age Between 48 and 72 hours of age Timing of follow-up visit* 72 hours 96 hours 120 hours * Earlier follow-up visits and perhaps more frequent visits are required for infants who have risk factors for hyperbilirubinemia. If appropriate follow-up cannot be ensured, especially in infants with an increased risk for severe hyperbilirubinemia, then discharge should be delayed until appropriate follow-up can be ensured or the period of greatest risk has passed (72 to 96 hours). Graphic Version 2.0

18 Page 18 of 18 Jaundice newborn A) Physiologic jaundice. B) Pressing the color from the skin allows better recognition of the yellow of jaundice. Infant with bilirubin level of 13 mg/dl. C) Infant with no appreciable jaundice at chest level. A) Reproduced with permission from: O'Doherty N. Atlas of the Newborn, JB Lippincott, Philadelphia Copyright 1979 Lippincott Williams & Wilkins. B and C) Reproduced with permission from: Fletcher M. Physical Diagnosis in Neonatology, Lippincott-Raven Publishers, Philadelphia Copyright 1998 Lippincott Williams & Wilkins. Graphic Version 2.0 Contributor Disclosures Ronald J Wong, BA Nothing to disclose. Vinod K Bhutani, MD, FAAP Nothing to disclose. Steven A Abrams, MD Grant/Research/Clinical Trial Support: Mead-Johnson [Pediatric Nutrition (Preterm infant formulas)]. Consultant/Advisory Boards: MilkPrep [Childhood nutrition (Diary)]; Nestle Nutrition [Infant nutrition (Preterm infant formulas)]. Melanie S Kim, MD Nothing to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy