Severe Neonatal Hyperbilirubinemia and Kernicterus: Are These Still Problems in the Third Millennium?

Despite efforts to eliminate permanent and irreversible brain damage due to bilirubin encephalopathy and kernicterus, these conditions continue to accompany us into the third millennium. This phenomenon occurs not only in developing countries with emerging medical systems, but in Westernized countries as well. Comprehensive guidelines to detect newborns with jaundice and treat those in whom hyperbilirubinemia has already developed have been formulated in several countries, but have not been successful in completely eliminating the problem. In this appraisal of the situation we review selected aspects of bilirubin encephalopathy and/or kernicterus. We highlight recent reports of severe hyperbilirubinemia and kernicterus, discuss some of the factors responsible for the continuing appearance of these conditions, and briefly review what can be done to decrease bilirubin-related morbidity and mortality to the minimum. Copyright © 2011 S. Karger AG, Basel Published online: October 3, 2011 Prof. Michael Kaplan Department of Neonatology, Shaare Zedek Medical Center PO Box 3235 Jerusalem 91031 (Israel) Tel. +972 2 655 5643, E-Mail kaplan @ cc.huji.ac.il © 2011 S. Karger AG, Basel 1661–7800/11/1004–0354$38.00/0 Accessible online at: www.karger.com/neo Presented at the International Symposium ‘Recent Advances in Neonatal Medicine’, Würzburg, 2011. D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /7 /2 01 7 2: 11 :1 7 A M Severe Neonatal Hyperbilirubinemia and Kernicterus Neonatology 2011;100:354–362 355 Much of the clinical material cited in this paper was published after the year 2000, and is thus relevant to current practice. It is not our intention to comprehensively appraise all aspects of kernicterus in this review. Rather, we wish to selectively relate to some aspects of why we continue to see cases of kernicterus, and what we can do to prevent, or minimize, these from occurring. Did the Pendulum Actually Swing? Some authors have referred to a disappearance and then resurgence of kernicterus during the last 2 decades [7, 8] . Hansen [3] has likened the situation to a recurrence of an unpleasant situation: ‘the specter walks again’. Undoubtedly, the advent of exchange transfusion, the subsequent introduction of phototherapy and prophylaxis of a major cause of kernicterus, Rh isoimmunization and its associated hemolysis resulted in a decrease in the number of cases of kernicterus in Westernized countries with advanced medical systems. However, there is some controversy as to whether the condition did, in fact, completely disappear for a while and then reappear. Though for a period there were few publications of cases of kernicterus from industrialized countries, one wonders what happened to the cases of kernicterus currently being seen, the result of conditions that have not been eliminated, including glucose6-phosphate dehydrogenase (G-6-PD) deficiency, direct antiglobulin titer (DAT)-positive ABO isoimmunization and late prematurity. While some cases, especially in the latter group, may have been prevented by longer hospital stays and a more aggressive therapeutic approach, it is difficult to comprehend a disappearance and then reappearance of kernicterus associated with ABO blood group heterospecificity or the sudden, unpredictable and exponential rises in serum bilirubin associated with G-6-PD deficiency [9, 10] . In favor of the resurgence theory, some case reports of kernicterus surfaced in the US after a period of relative ‘publication silence’ [11–13] and culminated in the publication of the provisional (2004) and subsequently final (2009) report of the Kernicterus Registry [14, 15] . In Denmark, in a search of medical registries, insurance and other records, and in direct approaches to each of the pediatric departments in that country, Ebbesen [16] could find no cases of kernicterus during the 20 years preceding 1994, but did uncover 6 cases between 1994 and 1998. Subsequently, during 2000–2001, Ebbesen et al. [17] identified 32 near-term and term infants in whom the serum total bilirubin (STB) values exceeded the indications for exchange transfusion, the median value for which was 450  mol/l (26.3 mg/dl). Twelve of these infants had signs and symptoms of central nervous system involvement including 11 with evidence of ABE. Many of the infants were readmitted after having been discharged as healthy; readmitted babies frequently had a higher incidence of clinical bilirubin encephalopathy than in those in whom the hyperbilirubinemia developed in hospital. This finding may have been due to higher STB concentrations in combination with prolonged exposure to toxic bilirubin levels. In the US, Burke et al. [18] used data from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample and Kids’ Inpatient databases to determine kernicterus time trends. They reported a 70% decrease in hospitalizations between 1988 and 2005 of neonates with a diagnosis of kernicterus. On the other hand, Brooks et al. [19] , using strict ICD9 codes for kernicterus from the California Department of Developmental Services, identified 25 cases of physician-confirmed strictly diagnosed kernicterus during the 10-year period of 1988–1997, equivalent to an incidence of 0.44 per 100,000 live births in California during this period. The incidence was constant during the study period and was not significantly different between the periods 1988–1993 and 1994–1997. The same authors studied the issue on a national US basis by extracting mortality data due to kernicterus from the Centers for Disease Control and Prevention databases. Thirty-one infant deaths with kernicterus as an underlying cause were reported from 1979 to 2006. The kernicterus death incidence during the first 14 years of the study period was not significantly different from that of the second study time epoch. Whether there was or was not a disappearance and resurgence of kernicterus is still not clear. What is important is that, in the year 2011, kernicterus is still with us and making a major contribution to neonatal and childhood mortality and morbidity, as will be seen in the following sections. Kernicterus in the Third Millennium Developing Countries While undoubtedly a tragedy, it is not surprising that kernicterus continues to occur in developing countries, with as yet underdeveloped health services, or in war zones. Perhaps the most devastating of recent reports emanates from Baghdad, Iraq, where there has been a severe breakdown of medical services [20] . Of 162 infants adD ow nl oa de d by : 54 .7 0. 40 .1 1 11 /7 /2 01 7 2: 11 :1 7 A M Kaplan /Bromiker /Hammerman Neonatology 2011;100:354–362 356 mitted for severe hyperbilirubinemia [STB up to 770 mol/l (45 mg/dl)], 22% had advanced ABE, 12% died within 48 h of admission and 21% had posticteric sequelae. Almost all babies were ! 10 days old. Evidence of advanced ABE at the time of admission increased the risk for the adverse outcome of kernicterus or death eightfold. Some other reports from developing countries since the year 2000 derive from Nigeria [115 babies with ABE, of whom 42 (36.5%) died] [21] , Oman [14 cases of whom 4 (28.5%) died] [22] and Turkey [10 G-6-PD-deficient neonates, of whom 5 (50%) developed kernicterus] [23] . In Kuwait and the United Arab Emirates, newborns with kernicterus were reported following henna applications to their skin [24] . Westernized Countries Recent comprehensive reports from Westernized countries emanate from the US [15] , Canada [25] , the UK and Ireland [26] , and Denmark [27] . The US-based Kernicterus Registry provides a record of 125 infants who actually developed kernicterus. The Canadian, UK and Ireland, and Danish studies also included infants with extreme hyperbilirubinemia but without ABE and, in the case of the Canadian survey, infants who had undergone exchange transfusion. The latter 3 surveys were all performed subsequent to the year 2000. Abnormal neurological signs attributable to bilirubin toxicity were seen in 20, 13 and 39% of the Canadian, UK and Ireland, and Danish groups, respectively. Overall, the most common etiologic entities found were ABO blood group heterospecificity (not necessarily DAT-positive) and G-6PD deficiency, both overrepresented relative to their frequency in the respective background population groups. A striking feature is the readmission of many infants who had been discharged as healthy from birth hospitalization. Breastfeeding played a prominent role in those Danish infants in whom no other etiological cause for hyperbilirubinemia could be found. Black ethnicity and minority groups were also overrepresented, relative to the home population, in the US and UK/Ireland groups. In a survey of 109 level III neonatal units in Italy, 16 cases of kernicterus were reported during the decade preceding 2010 [28] . Eleven of these cases were in term infants, while 5 were found in preterms. Similarly, between 2003 and 2005, a national surveillance system in Germany uncovered 11 cases of kernicterus [29] . Among this group, late prematurity and readmission of previously healthy babies were common. Clinical Picture of Kernicterus Acute Bilirubin Encephalopathy Newborns with ABE present a clinical picture very different from the chronic form, as recently reviewed [2] . The features associated with severe hyperbilirubinemia include, in the early stages, lethargy and poor feeding. These signs are nonspecific for bilirubin encephalopathy and if not suspected by the treating physician, may lead to delay in diagnosis and timely institution of therapy. As the disease process progresses, muscle tone may fluctuate between hypoand hypertonia and a high-pitched cry develops. Later, spasm of the extensor muscles with back arching, opisthotonus, retrocollis and impairment of upward gaze resulting in the ‘setting sun sign’ appear, while fever, seizures, apnea and death may complete the picture [2] . Sgro et al. [30] recently documented the clinical picture of 32 newborns whose STB ranged from 426–773 mol/l (24.9–45.2 mg/dl) and who had neurological findings at the time of admission. Cardinal clinical features included hypotonia, poor suck, lethargy and abnormal auditory-evoked responses. Opisthotonus, retrocollis, apnea, seizures, irritability and hypertonia were found, but to a lesser extent. Not surprisingly, infants in the highest peak bilirubin level group [ 1 550  mol/l (32 mg/dl)] who presented within the first 2 days of life or who had exchange transfusion were at higher risk for presenting with signs of bilirubin encephalopathy. The authors suggest that the rapid increase in serum bilirubin in those with early presentation may have potentiated an increased risk of ABE. Chronic Kernicterus The clinical picture of kernicterus in its chronic form has been well described [2] . Affected individuals may display a dystonic or athetoid movement disorder, an auditory processing disturbance which may be associated with hearing loss, motor ocular impairment of upward gaze, enamel dysplasia of the teeth, and hypotonia and ataxia due to cerebellar involvement. The 25 above-mentioned California cases of strict definition kernicterus serve to provide a glum picture of these severely disadvantaged children [19] . Seventy-two percent were male. At a mean (SD) age of 7.8 (3.9) years, 60% did not walk at all, and only 16% were able to walk unaided. A feeding tube was in place in 12%, while only 52% could self-feed orally. Severe or profound mental retardation, or severe disablement precluding testing or completion of testing was found in 36%, while only 32% had no evidence of mental retardation. Epilepsy was found in 20%. Severe, D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /7 /2 01 7 2: 11 :1 7 A M Severe Neonatal Hyperbilirubinemia and Kernicterus Neonatology 2011;100:354–362 357 profound or untestable visual impairment was documented in a quarter of the cases. Severe, profound or untestable hearing impairment was a feature affecting 56% of the group, with only 36% having normal hearing. Motor spasticity was seen in 32%, ataxia and dyskinesis in 12% each, and hypotonia in 8%. Does ABE Necessarily Predict Chronic Disease? There is some evidence to suggest that the occurrence of ABE may not necessarily translate into permanent neurological sequelae. Harris et al. [31] identified 6 exclusively or partially breastfeeding term and near-term infants from 1993 to 1996 who were readmitted to hospital within the first week of life. Five infants had bilirubin values 1 513  mol/l (30 mg/dl) and abnormal neurologic signs were already present at the time of admission in 5 infants. Three of the 4 infants who had initial MRIs had increased signal intensity in the basal ganglia consistent with kernicterus, while 2 had abnormal audito ry-evoked responses. Infants were treated aggressive ly with phototherapy, intravenous fluids and, in 5 of the 6, exchange transfusions. At follow-up examinations between 3 months and 2 years, the clinical signs had resolved in all but 1 infant. Four infants had a subsequently normal MRI and only 1 had residual hearing impairment. Hansen et al. [32] recently reported 6 infants from 4 European countries who presented with symptoms and signs commensurate with intermediate-to-advanced acute phase bilirubin encephalopathy. Clinical features included seizures, shrill cry, pronounced muscular hypotonia, apnea, anorexia and opisthotonos/retrocollis. In 2 of the 4 infants who had had an MRI performed, findings typical of kernicterus were found. Subsequently, complete normalization was observed in 4 of the 6 infants. The 5th had hearing loss while the 6th had severe residual neurological sequelae. Similarly, 3 of 11 surviving newborns with bilirubin encephalopathy in the UK and Ireland survey were found to be normal on follow-up [26] . The virtual absence of long-term neurological deficits attributable to bilirubin disease, except for 1 infant, in the above-mentioned Danish infants who were available for follow-up is also noteworthy [27] . However, it must be recognized that only 28% of those originally included were available for these follow-up studies. STB versus Serum Unbound Bilirubin in the Prediction of Kernicterus The correlation between increasing STB concentrations and the development of kernicterus in Rh isoimmunized babies with severe hemolysis was described many years ago [33] . More recently, in the post-Rh isoimmunization era, it has become clear that the serum total bilirubin value correlates poorly with the subsequent development of kernicterus. There is also no single cutoff point above which an infant will categorically develop bilirubin encephalopathy and/or kernicterus, or below which a baby will remain safe [34–36] . Many factors, including prematurity or the presence of hemolysis, may interact with the total bilirubin to precipitate or prevent the development of kernicterus. The unbound bilirubin fraction, i.e. the fraction which is not bound to serum albumin, has a greater propensity for traversing the bloodbrain barrier and entering the basal nuclei than that which is attached to bilirubin. Thus, the unbound fraction may predict subsequent bilirubin-induced neurologic dysfunction, bilirubin encephalopathy or kernicterus to a greater extent than the total bilirubin value [37] . Unfortunately, unbound bilirubin determination is not available as a clinical tool, and, for practical purposes, we have to rely on the total serum bilirubin both to monitor babies for hyperbilirubinemia and for therapeutic decision-making. Unbound bilirubin values may be used in the future to determine the risk of an individual baby developing kernicterus and to decide on therapeutic procedures. Of practical implication, suggesting the need for cautious evaluation of hyperbilirubinemic neonates who have undergone abdominal surgery, may be the recent finding of hypoalbuminemia associated with increased unbound bilirubin, the latter both individually and relative to total serum bilirubin, in neonates who had undergone abdominal surgery compared with controls in whom surgery had not been performed [38] . Some Specific Conditions with a High Propensity for