Unconjugated hyperbilirubinemia in neonates is due to either physiologic or pathologic causes. Over 75% of neonatal unconjugated hyperbilirubinemia is due to physiologic causes. Physiologic jaundice is also referred to as non-pathologic jaundice, and it is mild and transient. This occurs because of differences in the metabolism of bilirubin in the neonatal period leading to an increased bilirubin load. The increased bilirubin load in the newborn arises from increased production of bilirubin due to a higher mass of red blood cells with a decreased lifespan in the neonate, a decreased bilirubin clearance from a deficiency of the uridine diphosphate glucuronosyltransferase (UGT) enzyme, which in the newborn has the activity of about 1% of the adult liver, and increased enterohepatic circulation.
Physiologic jaundice usually occurs on days 2 to 4, peaks between 4 to 5 days, and resolves in 2two weeks. Physiologic jaundice never occurs in the first 24 hours.
Similarly, the causes of pathologic unconjugated hyperbilirubinemia are also due to increased bilirubin production, decreased bilirubin clearance, and increased enterohepatic circulation. Pathologic jaundice may occur in the first 24 hours of life and is characterized by a rapid rate of rising in the bilirubin level more than 0.2 mg/dl per hour or 5 mg/dl per day.
Causes of increased bilirubin production in pathologic jaundice are immune-mediated hemolysis such as ABO and Rhesus incompatibility, non-immune mediated causes such as cephalhematoma, red blood cell membrane defects like hereditary spherocytosis and elliptocytosis, enzyme defects like glucose-6-phosphate dehydrogenase (G6PD) deficiency and pyruvate kinase.
ABO incompatibility occurs in mother’s with blood group O who have anti-A and anti-B IgG antibodies that cross the placenta and cause hemolysis in newborns with blood group A or B. In Rhesus (Rh) incompatibility, an Rh-negative mother who has been exposed to Rh-positive blood from a previous pregnancy becomes sensitized, causing hemolysis in the fetus with Rh-positive blood. Using Rhogam (anti-D gamma globulin) as prophylaxis in a mother with prior exposure has decreased the incidence of Rh hemolysis, which, although less common than ABO incompatibility, is more severe.
The G6PD enzyme, found in red blood cells (RBCs), protects against oxidative injury by the production of NADPH (nicotinamide adenine dinucleotide phosphate hydrogenase) from NADP (nicotinamide adenine dinucleotide phosphate). With its deficiency, and in the presence of oxidant stressors like illness, certain drugs, dyes, and foods like fava beans, there is hemolysis of RBCs. The clinical presentation is varied depending on the variant of the GGPD, and some newborns may present with neonatal jaundice with severe hyperbilirubinemia or kernicterus. G6PD is an X-linked disorder leading to males mostly being affected and females mostly being asymptomatic carriers
Decreased bilirubin clearance occurs in inherited disorders such as Crigler-Najjar and Gilbert syndrome, as well as maternal diabetes and congenital hypothyroidism.
In Crigler-Najjar syndrome, there is either an absence of UGT activity (type 1) or low UGT activity (type 2), which leads to severe hyperbilirubinemia in the first days of life or less severe disease respectively. Neonates with Crigler-Najar 1 need liver transplantation or long-term use of phototherapy. Phenobarbital may be used in type 2 Crigler-Najjar.
There is a mutation of the UGT1A1 gene in Gilbert syndrome, causing decreased UGT production and unconjugated hyperbilirubinemia. Gilbert is usually diagnosed in the adolescent period, although presentation in the neonatal period may occur and is mostly inherited as an autosomal dominant condition. It can be diagnosed with genetic testing.
Decreased intestinal activity leads to increased enterohepatic circulation. Breastfeeding jaundice, breast milk jaundice, and intestinal obstruction are common conditions associated with increased enterohepatic circulation, leading to unconjugated hyperbilirubinemia.
Breastfeeding jaundice, also known as breastfeeding failure jaundice, occurs in the first week of life and is due to failure of adequate intake of breast milk leading to dehydration and sometimes hypernatremia. Breastfeeding failure leads to decreased intestinal motility and decreases the elimination of bilirubin in the stool or meconium.
Breast milk jaundice occurs late in the first week, peaks in the second, and usually resolves by 12 weeks of age. It is due to inhibition of UGT activity and a factor in breast milk with a beta-glucuronidase-like activity that deconjugates conjugated bilirubin in the intestines leading to increased enterohepatic circulation.
Conjugated hyperbilirubinemia is always pathologic and is due to defects in bile formation or transport, obstruction to its flow, or to systemic conditions that may affect the liver.
Conditions causing conjugated hyperbilirubinemia due to hepatobiliary disease include biliary atresia, choledochal cysts, idiopathic neonatal hepatitis, and Alagille syndrome.
Inborn errors of metabolism like galactosemia, metabolic disorders such as tyrosinemia and genetic disorders like a-1 antitrypsin deficiency present as conjugated hyperbilirubinemia.
Systemic infections like “TORCH” (toxoplasmosis, other-syphilis, varicella-zoster, rubella, cytomegalovirus, and herpes simplex) infections and systemic conditions like sepsis, shock, and birth asphyxia may also present with conjugated hyperbilirubinemia. Urinary tract infections in the neonatal period and prolonged use of parenteral nutrition in premature newborns are also known causes of conjugated hyperbilirubinemia.
Biliary atresia is the most common cause of conjugated neonatal hyperbilirubinemia. It involves both intra-hepatic and extra-hepatic bile ducts and classically presents around 2 to 4 weeks of life with pale stools. The initial evaluation is by ultrasonography that may show an absent gallbladder and the classic "triangular cord" sign. The absence of pale stools and ultrasonographic findings or the presence of the gallbladder, however, do not rule out biliary atresia. Ultrasonography is followed by percutaneous liver biopsy, which gives additional information and supports the diagnosis of biliary atresia or helps to differentiate biliary atresia from other causes. If the liver biopsy supports a diagnosis of biliary atresia, an open cholangiogram should be performed, followed by the definitive surgical intervention, the Kasai procedure (hepatoportoenterostomy) should be performed. For a better outcome, the Kasai procedure should be performed before eight weeks. Newborns suspected of biliary atresia should, therefore, be promptly referred for evaluation and management.
Choledochal cysts involve dilation of the intrahepatic and extra-hepatic bile duct. Ultrasonography can detect the cysts with normal or dilated intrahepatic bile ducts as opposed to sclerosed ducts in biliary atresia, although cystic biliary atresia may resemble choledochal cysts.
Alagille syndrome is caused by a genetic mutation leading to a paucity of interlobular bile ducts and hepatic manifestations, including jaundice and cirrhosis. Other clinical features are butterfly vertebrae, peripheral pulmonic stenosis, renal involvement, dysmorphic features, and posterior embryotoxon of the eye. Alagille syndrome is inherited in an autosomal dominant pattern.
Alpha-1-antitrypsin deficiency is a common genetic disorder that presents with cholestatic jaundice in infants who are homozygous for the PiZZ genotype. Accumulation of anti-trypsin polymers in the endoplasmic reticulum of hepatocytes of a patient with the PiZZ genotype leads to apoptosis, neonatal cholestasis, and cirrhosis later in childhood.
Newborns with galactosemia present with jaundice, cataracts, hepatomegaly, failure to thrive, renal tubular acidosis, and Escherichia coli sepsis after the ingestion of milk. Galactosemia is due to galactose-1-phosphate uridyl transferase (GALT) deficiency leading to the accumulation of toxic metabolites in multiple organs. The presence of reducing substances in urine suggests galactosemia, and GALT activity in the liver or erythrocytes confirms the diagnosis.
Bilirubin comes from the breakdown in heme, which is produced from the breakdown of hemoglobin. Heme is converted to biliverdin, iron, and carbon monoxide by the enzyme heme oxygenase; biliverdin is then converted to bilirubin by biliverdin reductase. The conversion of heme to bilirubin takes place in the reticuloendothelial system. The unconjugated bilirubin is hydrophobic and is transported to the liver bound to albumin where it is conjugated by the enzyme uridine diphosphate-glucuronosyltransferase (UGT). Conjugated bilirubin, which is water-soluble, is excreted in bile and into the gastrointestinal (GI) tract and mostly excreted in feces after being metabolized by bacterial flora. Some conjugated bilirubin is deconjugated to unconjugated bilirubin and reabsorbed through the enterohepatic circulation.
Hyperbilirubinemia is total serum bilirubin more than the 95% on the Bhutani nomogram or above 1.5 mg/dl. Neonatal hyperbilirubinemia is classified as unconjugated/indirect hyperbilirubinemia, which is usually benign or conjugated/direct hyperbilirubinemia when the direct bilirubin is more than 20% of the total bilirubin with the total bilirubin above 5 mg/dl. Conjugated hyperbilirubinemia is always pathologic.
Severe neonatal hyperbilirubinemia is associated with neurologic dysfunction known as bilirubin-induced neurologic dysfunction (BIND). In severe hyperbilirubinemia, unconjugated bilirubin crosses the blood-brain barrier. It binds to the basal ganglia and brainstem nuclei, presenting either as an acute bilirubin encephalopathy or progresses to become a permanent neurologic dysfunction known as kernicterus.
History and Physical
The evaluation of the neonate with jaundice starts with a detailed history, including birth history, family history, the onset of jaundice, and maternal lab tests are important to help to differentiate between unconjugated and conjugated. If the newborn screen if available, it may give useful information.
The American Academy recommends universal screening of all newborns for jaundice and to identify risk factors for developing severe hyperbilirubinemia. Major risk factors in newborn over 35 weeks gestation include pre-discharge bilirubin in the high-risk zone, jaundice observed in the first 24 hours, blood group incompatibility, gestational age 35 to 36 weeks, a previous sibling who received phototherapy, cephalhematoma or significant bruising, exclusive breastfeeding and east Asian race. Prematurity is also a known risk factor for developing severe hyperbilirubinemia.
Minor risk factors are serum bilirubin in the high intermediate-range, macrosomic infant of a diabetic mother, polycythemia, male gender, and maternal age older than 25 years.
A complete examination of the neonate should include the general appearance, eye examination, abdominal examination taking note of any hepatomegaly, splenomegaly or ascites, neurological exam, and skin rashes.
Bilirubin levels may be assessed using a transcutaneous measurement device or taking blood for total serum or plasma level determination. Transcutaneous measurement decreases the frequency of blood tests for bilirubin but is limited by dark skin tone and if the neonate has received phototherapy. Also, if the transcutaneous bilirubin level exceeds the 95th percentile on the transcutaneous nomogram or 75% of the total serum bilirubin nomogram for phototherapy, the total serum bilirubin level should be measured.
Recommended labs to identify the hemolytic disease as a cause of unconjugated hyperbilirubinemia are the neonate’s blood group, Coombs test, complete blood cell (CBC), reticulocyte count, blood smear, and G6PD. In patients with conjugated hyperbilirubinemia, the serum aminotransferases should be ordered for evidence of hepatocellular injury, gamma-glutamyl transferase (GGTP) levels for evidence of hepatobiliary disease and prothrombin time and serum albumin to evaluate for hepatic synthetic function.
Imaging studies like ultrasonography and additional tests like TORCH titers, urine culture, viral cultures, serologic titers, amino acids, and the a-antitrypsin phenotype may be added depending on the suspected diagnosis for conjugated hyperbilirubinemia.
Treatment / Management
To prevent acute bilirubin encephalopathy and kernicterus, severe hyperbilirubinemia is treated with phototherapy, IV immunoglobulin, or exchange transfusion. There are nomograms available to determine bilirubin levels at which phototherapy and exchange transfusion are indicated.
Phototherapy is started based on risk factors and the serum bilirubin level on the nomogram. Bilirubin absorbs light optimally in the blue-green range (460 to 490 nm) and is either photoisomerized and excreted in the bile or converted into lumirubin and excreted in the urine. During phototherapy, the eyes of the newborn must be covered, and the maximum body surface area exposed to the light. It is important to maintain hydration and urine output as most of the bilirubin is excreted in the urine as lumirubin. The use of phototherapy is not indicated in conjugated hyperbilirubinemia and may lead to the “bronze baby syndrome” with grayish-brown discoloration of the skin, serum, and urine. After phototherapy is discontinued, there is an increase in the total serum bilirubin level known as the" rebound bilirubin." The "rebound bilirubin" level is usually lower than the level at the initiation of phototherapy and does not require reinitiation of phototherapy.
IV immunoglobulin is recommended for increasing bilirubin levels from iso-immune hemolysis despite phototherapy. IV immunoglobin is initiated when the bilirubin level is within 2 to 3 mg/dl of the exchange transfusion level.
Exchange transfusion is indicated if there is a risk of neurologic dysfunction with or without an attempt at phototherapy. It is used to removed bilirubin from the circulation, and in iso-immune hemolysis removes circulating antibodies and sensitized red blood cells as well. Exchange transfusions should take place in the training of the neonatal or pediatric intensive care unit (NICU/ PICU) by trained personnel. A double volume exchange blood transfusion (160 to 180 ml/kg) is performed, replacing the neonate’s blood in aliquots with crossed-matched blood. Complications that may arise from exchange transfusion are electrolyte abnormalities like hypocalcemia and hyperkalemia, cardiac arrhythmias, thrombocytopenia, blood-borne infections, portal vein thrombosis, graft versus host disease, and necrotizing enterocolitis (NEC).
Phototherapy should resume after exchange transfusion until the bilirubin reaches a level where it can be safely discontinued.
High levels of carotene may cause yellowish discoloration of the skin and may be mistaken to be hyperbilirubinemia. There is, however, no involvement of the sclera or mucosa in carotenemia. Carotenemia arises from the ingestion of carotenoid-containing foods like carrots, mangos, green leafy vegetables, sweet potatoes, apricots, and melons.
Newborns who develop severe hyperbilirubinemia are at risk for bilirubin-induced neurologic dysfunction (BIND) when bilirubin crosses the blood-brain barrier. Bilirubin binds primarily to the globus pallidus but also the hippocampus, cerebellum, and subthalamic nuclear bodies, causing neurotoxicity through apoptosis and necrosis. Acutely, this manifests as acute bilirubin encephalopathy (ABE) characterized by lethargy, hypotonia, and decreased suck and is reversible. Kernicterus, which is permanent, may develop if ABE progresses. It manifests as cerebral palsy, seizures, arching, posturing, and sensorineural hearing loss.
Enhancing Healthcare Team Outcomes
Neonatal jaundice is relatively common and has many causes. The first thing to appreciate is that many clinicians believe that jaundice in a newborn is a benign condition; the fact is that jaundice in a newborn is a serious disorder that can cause permanent brain damage. All clinicians who look after neonates must be aware of this fact. Because jaundice can present at any time after birth, the disorder is best managed by an interprofessional team. While many conditions that cause jaundice cannot be diagnosed right away, the key is to educate the parent. Parents need to be educated by the nurses, pediatricians, obstetricians, and the primary care provider that if there is a change in the infant's skin, stool, or urine color, the infant must be seen in the clinic. Today there is the 2-color icterometer, which can help parents identify jaundice. Nurses should train mothers on how to examine the skin and eyes of neonates. In addition, a smartphone app can also help parents assess jaundice. The key is to ensure that the infant is seen in the clinic to rule out any sinister cause of jaundice. Only with an interprofessional team approach can the morbidity of jaundice in neonates be reduced. Neonatal and low-risk nursery nurses are often the first to detect jaundice. They monitor treatments, educate parents, and keep the team apprised as to changes in condition. [Level 5]
Although neonatal jaundice is, in most cases, a mild and transient phenomenon, every newborn must be assessed predischarge for factors associated with increased risk of severe hyperbilirubinemia as per the American Academy of Pediatrics to improve patient outcomes. (Level 3)