Kernicterus Position

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Kernicterusis a condition where very high bilirubin levels in the blood are deposited in the brain tissue causing irreversible damage to the brain. In the newborn, early diagnosis and treatment of jaundice or conditions that lead to jaundice may help prevent kernicterus.

Bilirubin encephalopathy (BE) is caused by very high levels of bilirubin. Bilirubin is a yellow pigment that is created as the body gets rid of old red blood cells. High levels of bilirubin in the body can cause the skin to look yellow (jaundice).

If the level of bilirubin is very high or a baby is very ill, the substance will move out of the blood and collect in the brain tissue if it is not bound to albumin (protein) in the blood. This can lead to problems such as brain damage and hearing loss. The term "kernicterus" refers to the yellow staining caused by bilirubin. This is seen in parts of the brain on autopsy.

This condition most often develops in the first week of life, but may be seen up until the third week. Some newborns with Rh hemolytic disease are at high risk for severe jaundice that can lead to this condition. Rarely, BE can develop in seemingly healthy babies.

Treating jaundice or conditions that may lead to it can help prevent this problem. Infants with the first signs of jaundice have bilirubin level measured within 24 hours. If the level is high, the infant should be screened for diseases that involve the destruction of red blood cells (hemolysis).

All newborns have a follow-up appointment within 2 to 3 days after leaving the hospital. This is very important for late preterm or early term babies (born more than 2 to 3 weeks before their due date).

Hamati AI, Felker MV. Neurological complications of systemic disease: children. In: Jankovic J, Mazziotta JC, Pomeroy SL, Newman NJ, eds. Bradley and Daroff's Neurology in Clinical Practice. 8th ed. Philadelphia, PA: Elsevier; 2022:chap 59.

Reviewed by: Charles I. Schwartz, MD, FAAP, Clinical Assistant Professor of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, General Pediatrician at PennCare for Kids, Phoenixville, PA. Also reviewed by David C. Dugdale, MD, Medical Director, Brenda Conaway, Editorial Director, and the A.D.A.M. Editorial team.

Milder degrees of hyperbilirubinemia not leading to a clinical presentation of acute encephalopathy may also be neurotoxic and cause less severe long-term complications. This remains controversial; however, if there are bilirubin concentrations at which subtle cerebral injury can occur, the thresholds are unknown [13]-[15]. The collaborative perinatal project, examining 54,795 live births in the United States, was unable to find any consistent association between peak TSB concentrations below critical levels and IQ or other adverse outcomes [12]. Therefore, prevention of acute encephalopathy remains the justification for the prevention, detection and treatment of severe hyperbilirubinemia [16][17].

The incidence of acute encephalopathy is uncertain, but it continues to occur. The Canadian Paediatric Surveillance Program (CPSP) recently reported 258 full-term infants over a two-year period (2002 to 2004) who either required exchange transfusion or had critical hyperbilirubinemia (excluding infants with rhesus isoimmunization) [18]. Twenty per cent of these infants had at least one abnormal neurological sign at presentation, and 5% had documented hearing loss or significant neurological sequelae at discharge. During this period, the live birth rate in Canada was approximately 330,000 per year, leading to a calculated minimal incidence of this degree of severity of hyperbilirubinemia of approximately four in 10,000 live births. If we assume that the entire 20% of infants with neurological findings at presentation had acute bilirubin encephalopathy, the incidence of this complication would be one in 10,000 live births, an incidence similar to that of phenylketonuria. The incidence of chronic encephalopathy is also uncertain, but it has been estimated to be approximately one in 100,000 [19][20]. This situation occurs despite the fact that a large number of infants already receive intensive preventive therapy [11]. The CPSP report [18] noted that 13 of the infants continued to have important neurological abnormalities at final discharge, suggesting a chronic bilirubin encephalopathy incidence of one in 50,000, similar to the frequency reported from a Danish study [21].

Acute bilirubin encephalopathy was first recognized in infants with rhesus hemolytic disease; this etiology is now largely avoidable and, consequently, has become rare. Reports [22][23] indicate that acute bilirubin encephalopathy continues to occur in otherwise healthy infants with, and occasionally without, identifiable risk factors. Prevention of this rare but serious disease requires appropriate clinical assessment, interpretation of TSB concentration and treatment, which must include all systems involved in the provision of health care and community support.

Several risk factors have been identified for the development of severe hyperbilirubinemia in the newborn (Table 1). These risk factors are all common and the attributable risk of each is therefore very low. They are of limited use in directing surveillance, investigation or therapy by themselves, but can be useful in combination with timed TSB analysis. It should also be noted that although a large number of studies have demonstrated an increased risk of severe hyperbilirubinemia with breastfeeding, one study [24] found that exclusive breastfeeding was associated with a lower incidence of hyperbilirubinemia. This may represent cultural differences in the approach to breastfeeding and the support mechanisms in place.

A TSB concentration greater than 30 mol/L in umbilical cord blood [29] is statistically correlated with a peak neonatal TSB concentration greater than 300 mol/L, but the positive predictive value is only 4.8% for the term infant, rising to 10.9% in the late preterm infant, and the specificity is very poor (evidence level 1b).

Although bilirubin is derived from the breakdown of hemoglobin, routine umbilical cord blood hemoglobin or hematocrit measurement does not aid in the prediction of severe hyperbilirubinemia [30] (evidence level 2b).

ABO isoimmunization is a common cause of severe hyperbilirubinemia. Babies whose mothers are blood group O have an OR of 2.9 for severe hyperbilirubinemia (because most infants with jaundice due to ABO isoimmunization are blood group A or B infants born to a mother with group O blood)[31][32]. The need for phototherapy is increased in ABO-incompatible infants who are direct antiglobulin test (DAT [direct Coombs test])-positive compared with those who are DAT-negative [28][30]. Universal testing for incompatibility with blood grouping, and for isoimmunization using the DAT, on cord blood does not improve clinical outcomes compared with testing only infants whose mothers are group O [33][34] (evidence level 2b). Testing all babies whose mothers are group O does not improve outcomes compared with testing only those with clinical jaundice [35][36] (evidence level 2b). Therefore, it is reasonable to perform a DAT in clinically jaundiced infants of mothers who are group O and in infants with an elevated risk of needing therapy (ie, in the high-intermediate zone [Figure 1]). The results will determine whether they are low risk or high risk, and may therefore affect the threshold at which therapy would be indicated (Figure 2).

The usual antenatal screen for a panel of red cell antibodies occasionally identifies additional mothers who will deliver infants at increased risk of hemolysis. The significance of the various antibodies differs; in such infants, analysis of blood group and a DAT is usually required, closer follow-up and earlier therapy may be needed, and a consultation with a paediatric hematologist or neonatologist is suggested.

Newborns with glucose-6-phosphate dehydrogenase (G6PD) deficiency have an increased incidence of severe hyperbilirubinemia (evidence level 1b). Testing for G6PD deficiency in babies whose ethnic group or family history suggest an increased risk of G6PD deficiency is advised (eg, Mediterranean , Middle Eastern, African [37] or Southeast Asian origin). Although G6PD deficiency is an X-linked disease, female heterozygotes can have more than 50% of their red cells deficient in the enzyme because of random inactivation of the X chromosome. Females with greater proportions of their red cells affected have an increased risk of severe neonatal hyperbilirubinemia [38]; therefore, testing of both girls and boys who are at risk is advised [39]. G6PD deficiency increases the likelihood of requiring exchange transfusion in infants with severe hyperbilirubinemia; therefore, a test for G6PD deficiency should be considered in all infants with severe hyperbilirubinemia (evidence level 5). It should also be recognized that in the presence of hemolysis, G6PD levels can be overestimated and this may obscure the diagnosis [40]. Females in particular can have misleading results on the common screening tests [41]. G6PD-deficient newborns may require intervention at a lower TSB concentration because they are more likely to progress to severe hyperbilirubinemia [42][43]. Unfortunately, in many centres, it currently takes several days for a G6PD deficiency screening test result to become available. Improving the turnaround time for this test would improve care of the newborn. Because G6PD deficiency is a disease with lifelong implications, testing infants at risk is still of value.

Exhaled carbon monoxide is increased during hemolysis; however, prediction of severe hyperbilirubinemia is not improved by measuring the end-tidal carbon monoxide concentration [44] in addition to a timed TSB measurement (evidence level 1b).

The peak TSB concentration usually occurs between three and five days of life, at which time the majority of babies have already been discharged from hospital. At the usual age of discharge, TSB concentrations that are in a high-risk zone on the nomograms cannot be reliably detected by visual inspection, especially in infants with darker skin colours. To predict the occurrence of severe hyperbilirubinemia, it is therefore recommended that either TSB or TcB concentration be measured in all infants between 24 h and 72 h of life; if the infant does not require immediate treatment, the results should be plotted on the predictive nomogram to determine the risk of progression to severe hyperbilirubinemia. The TSB (or TcB) concentration and the predictive zone should be recorded, a copy should be given to the family at the time of discharge, and follow-up arrangements should be made for infants who are at higher risk (Table 4).

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