*1.3.2 Neurotoxicity risk factors*

Of specific clinical importance is to recognize the risk factors associated with brain damage in newborn infants with significant hyperbilirubinemia. According to the 2009 AAP recommendation, neurotoxicity risk factors are isoimmune hemolytic disease, G6PD deficiency, asphyxia, sepsis, acidosis, and albumin <3.0 mg/dL [17]. The neurotoxicity risk factors are used in making the decision when to initiate phototherapy or perform an exchange transfusion. These interventions are recommended at a lower bilirubin threshold level in the presence of any of the neurotoxicity risk factors [17].

Prematurity represents a well-recognized predisposition to development of jaundice. In premature newborns the rise of the total serum bilirubin tends to be slightly slower but of longer duration than term newborns [18]. There is still insufficient amount of evidence-based data to provide recommendations for treatment in this group of patients. Recommendations are mainly based on consensus agreementbased guidelines on the safe spectrum of thresholds [19, 20]. Bilirubin neurotoxicity has been associated with prematurity; however, birth weight and gestation are not the sole variables predictive of the neuronal damage. Other factors such as the presence of a concurrent neonatal disease, sepsis, cholestasis, drugs that alter the albumin-bilirubin binding, or the use of total parenteral nutrition have been found to enhance the risk of neurotoxicity. Moreover, premature newborns have similar

**5**

*Neonatal Hyperbilirubinemia in Newborns of the Republic of North Macedonia*

an "undetermined etiology" group as done by certain authors [16].

but often more subtle clinical manifestations of acute bilirubin encephalopathy than term infants [21–23]. For all the abovementioned reasons, it is reasonable to observe premature newborns as a distinct entity of neonatal jaundice and not assign them to

This term refers to the neurologic consequences of the deposition of unconjugated bilirubin in brain tissue with subsequent damage and scarring of the basal ganglia and brainstem nuclei. Determinants of the neurotoxic effect of bilirubin are the duration of exposure and the concentration of bilirubin in the brain. Poor correlation exists between serum bilirubin level and bilirubin encephalopathy in the absence of hemolysis [9]. Other important determinants of bilirubin influx in the brain are the bilirubin-binding capacity of albumin and the integrity of the bloodbrain barrier. If the serum unconjugated bilirubin level exceeds the bilirubin-binding capacity of albumin, unbound lipid-soluble bilirubin crosses the blood-brain barrier. Conditions that alter the permeability of the blood-brain barrier such as sepsis, acidosis, hypoxia, hyperoxia, hypoperfusion, and hyperosmolality can potentiate bilirubin entry in the brain [2, 9]. Differentiating neurons are particularly sensitive to bilirubin-related injury; therefore, premature newborns are more susceptible to the effects of bilirubin deposition in the brain [9]. For the purpose of greater consistency when defining bilirubin-induced neurological damage, it has been recommended to separate the terms "acute bilirubin encephalopathy" and "kernicterus." The former is used to describe the acute manifestations of bilirubin toxicity in the first weeks of life, whereas the latter is reserved for the chronic and permanent clinical sequelae of bilirubin toxicity [4]. The exact bilirubin concentration associated with kernicterus in the healthy term infant is unpredictable. Toxicity levels may vary among ethnic groups, also with maturation of an infant, and in the presence of hemolytic disease. The clinician's concerns of possible bilirubin toxicity should rise in the presence of bilirubin >25 mg/dL (428 μmol/L) in the term newborn without hemolysis and > 20 mg/dL (342 μmol/L) in the term newborn with hemolysis [2]. The early phase of acute bilirubin encephalopathy is characterized by lethargy, hypotonia, and poor sucking. In the intermediate phase, irritability and hypertonia develop. The infant may develop a fever and high-pitched cry, which may alternate with drowsiness and hypotonia [4, 24]. The hypertonia is demonstrated by backward arching of the neck (retrocollis) and trunk (opisthotonos). The advanced phase is characterized by pronounced hypertonia, apnea, and fever, deep stupor to coma, sometimes seizures, and death. Features of chronic bilirubin encephalopathy (kernicterus) include athetoid cerebral palsy, hearing loss, visual and dental problems, and moreover

*DOI: http://dx.doi.org/10.5772/intechopen.87045*

intellectual and other handicaps [1, 2, 4, 5, 9, 10].

Laboratory evaluation of jaundice is directed by the age of the newborn. The first step in evaluation, for a newborn jaundiced in the first 24 hours of life, is to perform total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) measurement [2, 4, 10]. Transcutaneous bilirubin (TcB) can be a powerful and noninvasive screening tool for bilirubin estimation with reported close correlation to TSB measurement in different populations [10]. When jaundice appears excessive for newborn's age, a TSB should be obtained. In infants under phototherapy and TSB above the 75th percentile or rising rapidly (i.e., crossing percentiles), it is recommended to extend the diagnostic workout by performing additional tests such as complete blood count and smear, reticulocyte count, blood grouping, and Coombs

**1.4 Laboratory evaluation of jaundice**

*1.3.3 Kernicterus*

but often more subtle clinical manifestations of acute bilirubin encephalopathy than term infants [21–23]. For all the abovementioned reasons, it is reasonable to observe premature newborns as a distinct entity of neonatal jaundice and not assign them to an "undetermined etiology" group as done by certain authors [16].
