Neonatal JaundiceMarch, 2015

Pediatric Continuity Clinic CurriculumOnyekachukwu Osakwe

Objectives• Recognize the common findings in newborns with hyperbilirubinemia.

• Describe bilirubin metabolism

• Distinguish between direct and indirect hyperbilirubinemia

• Develop differential diagnoses for each type

• Understand the clinical significance of hyperbilirubinemia

• Understand the management options

Hyperbilirubinemia – Why do we care?

• Hyperbilirubinemia in infants ≥35 weeks gestation is defined as a total bilirubin >95th percentile on the hour-specific Bhutani nomogram.

• Hyperbilirubinemia with a total bilirubin >25 to 30 mg/dL 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.

• “Acute Bilirubin Encephalopathy” is a term used to describe the acute manifestations of BIND.

• “Kernicterus” is used to describe the chronic and permanent sequelae of BIND.

• Appropriate intervention is important to consider in every infant with severe hyperbilirubinemia. However, even if these infants are adequately treated, long-term neurologic sequelae (kernicterus) can sometimes develop.

Bhutani Normogram

• 4 day old, 3.5 kg female delivered at 38 weeks to a 24 year old B+ primiparous woman with gestational diabetes. The pregnancy was otherwise uneventful. The baby was discharged home after 2 days, at which time her weight was down 4% from birth weight and she had mild facial jaundice. She is breast fed every 3 hours and ha 2 wet diapers daily.

• On day 3, her parents gave her water on two occasions as she appeared hungry despite regular and frequent breast feeding attempts. In addition, they noted worsening jaundice, but failed to address it after being reassured by family members that jaundice is common. The urine is described as dark yellow in color and the stools appear dark green.

• Exam: T 37.6, P 158, RR 45, BP 66/42. Weight 2.8 kg (25%ile), length 50 cm (75%ile), head circumference 34 cm (75%ile). The infant is irritable. The anterior fontanel is slightly sunken, the oral mucosa is tacky, and there is jaundice to the lower extremities. No cephalohematoma or bruising. The sclera of both eyes are icteric. Muscle tone and activity are normal. The remainder of the physical exam is normal.

Items in bold are key in the history and physical examination of newborns with jaundice

Hyperbilirubinemia Risk FactorsThe following are risk factors for developing severe hyperbilirubinemia in infants 35 or more weeks gestational age – in approximate order of importance

• Total serum bilirubin or Transcutaneous bilirubin in high risk zone

• Jaundice in the first 24 hours

• ABO incompatibility with positive direct Coombs, known hemolytic disease

• Gestational age 35-36 weeks

• Prior sibling had phototherapy

• Cephalohematoma or bruising

• Exclusive breastfeeding especially with poor feeding or weight loss

• East Asian Race

Neurotoxicity Risk Factors

The following are neurotoxicity risk factors that increase the risk stratification for newborns with hyperbilirubinemia

• Isoimmune Hemolytic Disease

• G6PD deficiency

• Asphyxia

• Significant lethargy

• Temperature instability

• Sepsis

• Acidosis

• Albumin <3.0 g/dL

You are seeing a newborn at 96 hours after birth for his initial health supervision visit. The 2,500 gram neonate was born to a 34-year-old gravida 2, para 2 woman by induced vaginal delivery at 36 weeks’ gestation because of maternal chronic hypertension. The maternal blood type was A+ and antibody negative. He was exclusively breastfed in the hospital and was discharged at 72 hours after birth. His total serum bilirubin at discharge was 13 mg/dL

The mother describes the infant as sleep but breastfeeding every 3 to 4 hours for 10 to 15 minutes. He has had 4 wet diapers and 1 stool since being discharged home yesterday. His weight today is 2,350 grams and his viral signs are normal. Physical examination is notable for a somewhat sleepy infant with jaundice to his knees. His total serum bilirubin is 17 mg/dL, and you decide to initiate phototherapy.

Of the following, you advise the mother that the MOST significant reason her son is at risk for severe hyperbilirubinemia is because his

A. gestational age is 36 weeksB. pre-discharge bilirubin value was an intermediate riskC. sex is maleD. sibling had neonatal jaundiceE. weight loss is excessive

Major and Minor Risk Factors• Late preterm gestation (34 weeks to 36 weeks, 6 days) is considered a major risk factor for

severe hyperbilirubinemia. Late preterm infants have a decreased ability to process unconjugated bilirubin when compared with term infants.

• Both term and late preterm infants have similar amounts of hemoglobin degradation. Hepatic immaturity (decreased bilirubin uptake and conjugation) contributes to the increase in incidence, severity, and duration of neonatal hyperbilirubinemia in late preterm infants.

• The AAP guidelines for phototherapy and exchange transfusion reflect lower total serum bilirubin thresholds for infants who are born at less than 36 weeks, 6 days’ gestation

• Minor risk factors for hyperbilirubinemia include: male gender, the predischarge bilirubin values in the high-intermediate risk zone, and the previous sibling with jaundice.

• Exclusive breastfeeding, especially if not going well or associated with excessive weight loss of more than 8% to 10%, is considered a major risk. The infant described in this vignette does not have excessive weight loss

Non-Pathologic Jaundice• Newborns have increased turnover of red blood cells - they have more red blood cells

(hematocrit between 50 to 60%) and fetal red blood cells have a shorter life span (approximately 85 days) than those in adults

• Bilirubin clearance is decreased in newborns, mainly due to the deficiency of the enzyme uridine diphosphogluconurate glucuronosyltransferase (UGT1A1). UGT activity in term infants does not reach adult levels until 14 weeks of age.

• There is an increase in the enterohepatic circulation of bilirubin, further increasing the bilirubin load in the infant.

• A combination of the above generally result in the low-risk unconjugated (indirect-reacting) bilirubinemia that occurs in nearly all newborns.

• Primary neonatal jaundice resolves within the first one to two weeks after birth - usually by the fifth day in Caucasian and African-American infants, and by the 10th day in Asian infants.

Hyperbilirubinemia – Pathologic Jaundice

Hyperbilirubinemia is defined as a total serum or plasma bilirubin >95th percentile on the hour-specific nomogram. It can be caused by certain pathologic conditions or by exaggeration of the mechanisms responsible for neonatal jaundice. The following features suggest severe hyperbilirubinemia:

• Jaundice recognized in the first 24 hours (a MEDICAL EMERGENCY) - usually caused by increased bilirubin production due to hemolysis.

• Total serum bilirubin greater than the hour-specific 95th percentile.

• Rate of total serum bilirubin rise greater than 0.2 mg/dL per hour.

• Jaundice in a term newborn after two weeks of age.

• Direct (conjugated) bilirubin concentration >1 mg/dL if the total bilirubin is <5 mg/dL, or more than 20 percent of the total bilirubin if the total bilirubin is >5 mg/dL. An increase in direct (conjugated) bilirubin is suggestive of cholestasis.

Causes of HyperbilirubinemiaIncreased production — The most common cause of pathologic indirect hyperbilirubinemia is increased bilirubin production due to hemolytic disease processes that include the following:

• Isoimmune-mediated hemolysis (eg, ABO or Rh(D) incompatibility)

• Inherited red blood cell membrane defects (eg, hereditary spherocytosis and elliptocytosis).

• Erythrocyte enzymatic defects (eg, glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, and congenital erythropoietic porphyria).

• Sepsis is a known cause of hemolysis. - likely due increased oxidative stress.

• Other causes include polycythemia or sequestration of blood within a closed space, which occurs in cephalohematoma.

• Macrosomic infants of diabetic mothers also have increased bilirubin production due to either polycythemia or ineffective erythropoiesis.

Causes of HyperbilirubinemiaDecreased clearance — Inherited defects in the gene that encodes UGT1A1, which catalyzes the conjugation of bilirubin with glucuronic acid. This reduces hepatic bilirubin clearance.

• Crigler-Najjar syndrome type I - autosomal recessive inheritance. The most severe form. UGT activity is absent, and severe hyperbilirubinemia develops in the first 2 to 3 days after birth. Lifelong phototherapy is required.

• Crigler-Najjar syndrome type II - less severe than is CN-I. UGT activity is low, but detectable. May present with jaundice, but often responds to phenobarbital treatment. Usually autosomal recessive, but can be autosomal dominant.

• Gilbert syndrome - the most common. It results from a reduced production of UGT. Breast milk jaundice during the second week after birth may be due to the concurrent neonatal manifestation of Gilbert syndrome.

• These conditions usually are identified by metabolic screening programs; however, infants may develop severe and prolonged jaundice before screening results become available.

Causes of HyperbilirubinemiaIncreased enterohepatic circulation - The major causes of increased enterohepatic circulation of bilirubin are

• Breastfeeding failure jaundice

• Breast milk jaundice

• Impaired intestinal motility caused by functional or anatomic obstruction.

Breast Milk Jaundice• Breast milk jaundice has been traditionally defined as the persistence of “physiologic jaundice”

beyond the first week of age. It typically presents after the first three to five days of life, peaking within two weeks after birth, and progressively declined to normal levels over 3 to 12 weeks

• The cause is yet to be determined. Beta-glucuronidase is one proposed substance that de-conjugates intestinal bilirubin, increasing absorption (increasing enterohepatic circulation). Another mechanism that has been proposed is polymorphic mutation of the UGT1A1 gene.

• Affected infants commonly have TB levels >5 mg/dL for several weeks after delivery. Although it may not require intervention, it should be monitored to ensure that it remains unconjugated and does not increase.

• If TB levels begin to increase or there is a significant component of conjugated bilirubin, evaluation for other causes of hyperbilirubinemia should be performed.

• If after evaluation, breast milk intake is the only remaining viable factor, breastfeeding can continue with the expectation of resolution by 12 weeks of age and that the hyperbilirubinemia is in the safe zone.

Breast Feeding Jaundice• Breastfeeding failure jaundice typically occurs within the first week of life, as lactation failure

leads to inadequate intake with significant weight and fluid loss resulting in hypovolemia and hyperbilirubinemia.

• Decreased intake also causes slower bilirubin elimination and increased enterohepatic circulation that contribute to elevated TB

• Suboptimal breastfeeding compared with formula feeding is associated with an increased risk of jaundice and kernicterus.

• In a review of cases from the Pilot Kernicterus Registry, 59 of 61 infants with kernicterus were breastfed. Of the two infants who were formula-fed, both were found to have G6PD deficiency.

• The primary mechanism for the increased likelihood of kernicterus and jaundice with breast versus formula feeding is the failure to successfully initiate breastfeeding – TB is only marginally higher in successfully breastfed compared with formula-fed infants.

Breast Feeding Jaundice - Prevention

• Initiation of successful breastfeeding is one of the mainstays of preventing hyperbilirubinemia.

• During the first postpartum week, mothers should nurse whenever the infant shows signs of hunger or when four hours have elapsed since the last feeding - results in 8 to 12 feedings in 24 hours.

• During the birth hospitalization, problems with breastfeeding should be addressed at that time. A documented plan for management after discharge should be communicated to both the parents and primary care provider.

• At discharge, a primary care appointment should be scheduled so that the infant-mother dyad is evaluated 24 to 48 hours after discharge, and post-discharge lactation resources provided.

• At the follow-up appointment, supplementation with banked human milk or commercial infant formula is recommended when the infant has lost more than 7-10 percent of his/her birth weight or exhibits signs of dehydration, or mother's milk supply remains limited.

Prevention and Treatment of Severe Hyperbilirubinemia

• Two advances in medical care had a significant impact on the need for treatment and the way in which hyperbilirubinemia is managed. The administration of Rh (D) immunoglobulin to Rh-negative mothers in the late 1960s dramatically decreased the incidence of neonatal Rh isoimmune hemolytic disease. At about the same time, the introduction of phototherapy in the United States significantly reduced the need for exchange transfusions and the risk of severe hyperbilirubinemia.

• Universal screening of all term and late preterm infants identifies at-risk infants for hyperbilirubinemia

• Therapeutic interventions for infants with hyperbilirubinemia include:– Phototherapy– Exchange transfusion– Improving the frequency and efficacy of breastfeeding or supplementing inadequate

breastfeeding with formula

Prevention and Treatment of Severe Hyperbilirubinemia

• Pharmacologic agents include: – Intravenous immunoglobulin (inhibit hemolysis)– Phenobarbital (increase conjugation and excretion of bilirubin)– Ursodeoxycholic acid (increase bile flow)– Metalloporphyrins (inhibit formation of bilirubin)

• Currently only IVIG is used to treat unconjugated hyperbilirubinemia.

• In infants with isoimmune hemolytic disease and rising TB despite intensive phototherapy, IVIG may be administered to avoid the need for exchange transfusion

Prep QuestionA 9-day-old infant presents to the emergency department with jaundice. He was born at term by spontaneous vaginal delivery after an uncomplicated pregnancy. He was exclusively breastfed in the hospital and was discharged at 48 hours after birth with a total serum bilirubin value of 9.8 mg/dl. The mother reports increased spitting and fussiness over the past 24 hours with 6 wet diapers and 4 seedy yellow stools. On physical examination, his temperature is 37.8°C, his heart rate is 160 beats/min, and his respiratory rate is 50 breaths/min. The infant is fussy and has a soft anterior fontanelle, jaundice to the level of the lower extremities, and a liver edge at the right costal margin. Initial laboratory data include the following:

Blood test:Hemoglobin, 18.0 g/dL (180 g/L) Platelet count, 250 × 103/μL (250 × 109/L)White blood cell count, 25 × 103/μL (25 × 109/L), with 55% neutrophils, 20% band neutrophils, 15% lymphocytes, and 10% monocytesPeripheral blood smear, normal Reticulocyte count, 4%Total bilirubin, 16.0 mg/dL (273.66 μmol/L) Direct bilirubin, 3.8 mg/dL (65 μmol/L)

Urine test strip:pH, 7.0 Specific gravity, 1.010 2+ leukocyte esterase 1+ bilirubin 1+ nitratesReducing substances, negative

Prep QuestionOf the following, the MOST appropriate next step in the management of this boy is administration of

A. catheterize the urethra for urine cultureB. initiate intensive phototherapyC. obtain serum polymerase chain reaction testing for cytomegalovirusD. perform hepatic ultrasonographyE. switch to a soy-based formula

Sepsis and Hyperbilirubinemia• The clinical findings of fussiness and low-grade fever combined with an elevated

white blood cell count, increased band count, and abnormal urinalysis suggest a diagnosis of sepsis.

• The most appropriate next step is obtaining urine for culture as part of the septic workup. Conjugated hyperbilirubinemia is associated with bacterial sepsis, especially gram-negatives such as Escherichia coli.

• Viral and parasitic causes must be also be considered. Congenital infections that can be associated with cholestatic jaundice include cytomegalovirus (CMV), toxoplasmosis, rubella, herpes simplex virus, and syphilis.

Prep QuestionYou are assessing an infant who was born by spontaneous vaginal delivery at 37 weeks’ gestation to a 19-year-old primigravida who received no prenatal care. The growth parameters include a weight of 2,500 grams (10th percentile), head circumference of 30 cm (3rd percentile), and length of 46 cm (10th percentile). The physical examination is notable for faint facial jaundice, diffuse petechiae on the trunk and extremities, a 1/6 systolic murmur at the left sternal border, a liver edge palpable 2 centimeters below the right costal margin, and a spleen tip palpable 4 cm below the left costal margin

Of the following, the study MOST likely to lead to the correct diagnosis isA. blood culture for Listeria monocytogenesB. serology for parvovirus B19 IgMC. serology for Toxoplasma-specific IgMD. surface culture for herpes simplex virusE. urine culture for cytomegalovirus

Prep Question• The infant has physical findings that are most consistent with congenital

cytomegalovirus (CMV) disease and therefore should have a confirmatory urine culture for the virus.

• The clinical findings seen in an infant with symptomatic CMV infection include intrauterine growth retardation, jaundice, petechiae, hepatosplenomegaly, and, occasionally, blueberry muffin spots, chorioretinitis.

Prep QuestionYou are asked to see a 3½-week-old girl because of jaundice. The infant was the 3,200-g product of a full-term, uncomplicated pregnancy and delivery. She has been exclusively breastfed since birth, and “mild” jaundice was noted at the time of hospital discharge. The mother states that the infant has been feeding well but is concerned that her daughter’s “eyes are still yellow.” Physical examination demonstrates a vigorous infant whose weight is 3,520 g. Her skin appears jaundiced and the sclerae are icteric. Physical examination findings are normal except for a smooth liver edge palpated 1 cm below the right costal margin, with a total percussible span of 4 cm. Laboratory tests demonstrate the following:

Hemoglobin, 13.5 g/dL (135 g/L)White blood cells, 9,500/µL (9.5 × 109/L)Total bilirubin, 9.0 g/dL (153.9 µmol/L)Direct bilirubin, 4.2 mg/dL (71.8 µmol/L)Reticulocyte count, 1%Aspartate aminotransferase, 85 U/L; reference range, <40 U/LAlanine aminotransferase 125 U/L; reference range, <30 U/L

Prep QuestionOf the following, the MOST appropriate next test to order is

A. abdominal ultrasonographyB. hepatobiliary scintigraphyC. percutaneous liver biopsyD. serum α1-antitrypsin

E. serum immunoreactive trypsinogen

Cholestasis• In the newborn, the presence of jaundice beyond the first 2 weeks of life, regardless of the

method of feeding, should prompt investigation. The infant described has direct hyperbilirubinemia (see definition on slide 12).

• Direct hyperbilirubinemia is a sign of either obstructive or functional cholestasis and ALWAYS requires additional evaluation. The initial step in this evaluation should be to image the biliary tract by means of an abdominal ultrasound examination. This study is usually diagnostic for choledochal cyst and, in many cases, may suggest a diagnosis of extrahepatic biliary atresia.

• Cholestasis is typically a presenting feature of neonatal liver disease because of the immaturity of the hepatobiliary excretory system. It may result from perinatal infection, as a sign of genetic and metabolic disorders, and from biliary structural abnormalities.

Prep QuestionA 2,000-g, 34-week-gestation female newborn was admitted to the neonatal intensive care unit at 3 days of age because of jaundice, lethargy, and vomiting. The pregnancy was complicated by illicit drug abuse and poor prenatal care. Delivery was by cesarean birth secondary to maternal preeclampsia, and the Apgar scores were 6 and 7 at one and five minutes, respectively. She initially fed well with cow milk–based formula but was noted to develop jaundice at 24 hours after birth; the baby became increasingly difficult to feed, with multiple episodes of postprandial emesis. Because of these symptoms, a sepsis workup was performed and the baby was started on intravenous antibiotics.Physical examination demonstrates a lethargic, jaundiced infant. She has a temperature of 37.0°C, pulse rate of 130 beats/min, respiratory rate of 20 breaths/min, blood pressure of 88/56 mm Hg, and oxygen saturation of 97% on room air. The liver is palpated 5 cm below the right costal margin. The remainder of the examination findings are normal. Laboratory studies are obtained and include the following results:

Total bilirubin, 15 mg/dL Direct bilirubin, 5.5 mg/dLAlanine aminotransferase, 205 U/L Aspartate aminotransferase, 170 U/LProthrombin time, 21 s Partial thromboplastin time, 39 s International normalized ratio, 1.95 Urine test strip, positive for reducing substances

Prep QuestionOf the following, the MOST appropriate next diagnostic test is

A. cell culture for cytomegalovirus from urineB. erythrocyte galactose-1-phosphate uridyltransferaseC. polymerase chain reaction for herpes simplex virus in cerebrospinal fluidD. serum a-1 antitrypsin measurement with protease inhibitor typingE. urine succinylacetone

Galactosemia and Hyperbilirubinemia

• When direct hyperbilirubinemia is diagnosed within the first few days after birth, particularly in association with other clinical symptoms, infectious and metabolic disorders must be considered. Thus, sepsis workup is an important first step in this neonate.

• Hepatic dysfunction with hepatomegaly and cholestasis during the first few days after birth (particularly within the first 24 hours after commencing feeding) suggest an inborn metabolic error.

• The associated finding of positive reducing substances in the urine indicate a carbohydrate metabolic disorder, the most prevalent being galactosemia. An erythrocyte cell galactose-1-phosphate uridyltransferase level will confirm the diagnosis.

• Once the newborn screening finds abnormalities pointing to this disorder, immediate changes should be made to the neonate’s diet until the diagnosis is confirmed to avoid potentially serious consequences.

Prep QuestionA 5-day-old term newborn is brought to the emergency department for the evaluation of jerking motions of his arms and legs. The newborn was delivered vaginally weighing 3,500 g and discharged to home 36 hours after delivery. He has been exclusively breastfed, with an increasingly poor suck, irritability, and decreased activity noted by the mother over the past 24 hours. Upon admission to the emergency department, his weight is 3,150 g and his vital signs are normal. A physical examination reveals an inconsolable, hypotonic newborn with marked jaundice that involves his legs and the palms of his hands. You note a brief jerking of his right arm, followed by bicycling movements of his upper and lower extremities.Of the following, the MOST likely cause of the jerking is

A. acute bilirubin encephalopathyB. benign neonatal myoclonusC. herpes simplex encephalitisD. hypocalcemiaE. hypoglycemia

Acute Bilirubin Encephalopathy (ABE)

• The newborn has marked jaundice of his legs and his palms, which suggests his serum bilirubin level is greater than 15 mg/dL.

• The clinical signs of ABE in the neonatal period represent a spectrum. The earliest findings are often subtle and nonspecific. Moderate ABE manifests with arching of the neck and trunk, increasing lethargy, decreased feeding, and irritability with a shrill cry.

• Intervention at these early phases may prevent the sequelae of kernicterus.

• Worsening signs include bicycling movements of the arms and legs, inconsolable crying, inability to eat, fever, seizures, and coma. Active intervention at this point is unlikely to affect the risk of the development of kernicterus.

• AAP guidelines recommend that infants showing signs of moderate to severe ABE be given an immediate exchange transfusion, even if the total serum bilirubin is falling.

• If suspected in the outpatient setting, infants with symptoms of ABE should be admitted directly to the hospital and NOT be referred to the emergency department where treatment may be delayed.

Prep QuestionYou are seeing a 2-week-old newborn in your office following discharge from the neonatal intensive care unit after treatment for indirect hyperbilirubinemia. The newborn was born at term after an unremarkable pregnancy, with prenatal screening notable for maternal blood type O positive and antibody negative. The newborn was jaundiced at less than 24 hours after birth. Evaluation at that time included blood type B positive and direct antiglobulin test positive. Intense phototherapy and intravenous immunoglobulin therapy was required, with the total bilirubin peaking at 18.2 mg/dL. At the time of hospital discharge, the hemoglobin was 12 g/dL, the total bilirubin was 10.2 mg/dL, and the direct bilirubin was 0.9 mg/dL. The mother asks if there are complications related to the jaundice that she needs to worry about.

Of the following, the most likely complication to be seen in this infant is

A. cholestatic liver diseaseB. hearing lossC. kernicterusD. late anemia of infancyE. malignant melanoma

Other Complications of Hyperbilirubinemia

• The newborn in this vignette has hemolytic disease of the fetus and newborn (HDFN) due to ABO incompatibility and is at increased risk of late anemia of infancy.

• Kernicterus and late anemia of infancy are the 2 major complications of HDFN.

• Late anemia of infancy is seen in the first month after birth and is attributed to continued destruction of the newborn’s RBCs by the circulating maternal immunoglobulin.

• Intrauterine or exchange transfusion may further exacerbate the anemia by suppressing erythropoiesis.

• At risk newborns should be monitored by serial hematocrit and reticulocyte counts after discharge from the hospital. Multiple dose treatment with IVIG has been suggested to decrease the ongoing hemolysis, decreasing the need for transfusion for late anemia of infancy

Summary• Total serum bilirubin levels >1 mg/dL occur in almost all term and near-term newborn infants.

• Infants with severe hyperbilirubinemia are at risk for BIND, presenting acutely as ABE and, if inadequately treated, long-term neurologic sequelae or kernicterus.

• Neonatal jaundice is primarily caused by normal neonatal alterations in bilirubin metabolism including increased bilirubin production, decreased bilirubin clearance, and increased enterohepatic circulation.

• Hyperbilirubinemia is caused by exaggeration of mechanisms that cause neonatal jaundice or by pathologic conditions that increase bilirubin production, decrease bilirubin clearance, or increase the enterohepatic circulation.

• Identification of the cause of neonatal hyperbilirubinemia is useful in determining whether therapeutic interventions can prevent severe hyperbilirubinemia.

• Breast milk jaundice, and impaired intestinal motility caused by functional or anatomic obstruction increase enterohepatic circulation of bilirubin.

References and Future Reading• American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of

hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114(1):297-316. DOI: 10.1542/peds.114.1.297.

• Lauer BJ, Spector ND. Hyperbilirubinemia in the newborn. Pediatr Rev. 2011;32(8):341-348. DOI: 10.1542/pir.32-8-341.

• Maisels MJ, Bhutani VK, Bogen D, Newman TB, Stark AR, Watchko JF. Hyperbilirubinemia in the newborn infant > 35 weeks’ gestation: an update with clarifications. Pediatrics. 2009;124(4):1193-1198. DOI: 10.1542/peds.2009-0329.

• Watchko JF. Hyperbilirubinemia and bilirubin toxicity in the late preterm infant. Clin Perinatol. 2006;33(4):839-852. DOI: 10.1016/j.clp.2006.09.002.