J.

Arab Neonatal Forum 2005; 2: 12-24

Kernicterus: A Preventable Neonatal Brain n!ur"

1 #ino$ K. B%utani& an$ 2'ois Jo%nson (e)artment o* Neonatal-(evelo)mental +e$icine& (e)artment o* Pe$iatrics& 'ucile Pac,ar$ -%il$ren.s /os)ital& 0tan*or$ 1niversit"& 0tan*or$& -A; 2(e)artment o* Pe$iatrics& Penns"lvania /os)ital& 1niversit" o* Penns"lvania 0c%ool o* +e$icine& P%ila$el)%ia& PA 1

Ke" 2or$s: ,ernicterus& bilirubin in$uce$ neurolo3ic $"s*unction& neonatal %")erbilirubinemia& ne4born !aun$ice 0ummar" Kernicterus, one of the most easily preventable causes of brain injury from severe neonatal jaundice, has re-emerged in the United States and other nations with well developed healthcare systems as a public and societal health concern. Kernicterus, in its usually recognized form, causes devastating disabilities including athetoid cerebral palsy ( !" and speech and hearing impairment. #t represents the severe manifestation of bilirubin induced neurologic dysfunction ($#%&" syndrome. 'his condition not only ran(s amongst the highest cost per new case (according to the enter of &isease ontrol)s *inancial $urden of &isability study in +,,-", but also results in profound and uncompromising grief for the family and loss to siblings of healthy, tal(ative playmates. .nd for the child with (ernicterus (usually remar(ably intelligent, but trapped in an uncontrollable body", grief and frustration are enormous. #n -//+ national healthcare organizations, including enters for &isease ontrol ( & ", the 0oint ommission for the .ccreditation of 1ealthcare 2rganizations (0. 12" and the .merican .cademy of !ediatrics (..!" issued alerts to all accredited hospitals and public health professionals in the United States and affiliated organizations that all healthy infants are at potential ris( of (ernicterus if their newborn jaundice is unmonitored and inade3uately treated. 4videntiary analysis of +-5 cases, from an informal !ilot Kernicterus 6egistry, documents that unmonitored or inade3uately treated severe hyperbilirubinemia results in (ernicterus in otherwise healthy term and near term infants. 2n the basis of this empirical evidence, the lapses in care and root causes have been associated with the occurrence of (ernicterus in these infants. 'he re-emergence of (ernicterus in the United States is the result of interacting phenomena including a" early hospital discharge (before e7tent of jaundice is (nown and signs of impending brain damage have appeared"8 b" lac( of ade3uate concern for the ris(s of severe jaundice in healthy term and near term newborns8 c" an increase in breast feeding without ade3uate instruction, monitoring and support8 d" medical care cost constraints leading to early discharge with loss of supervision8 e" paucity of educational materials to enable parents to participate in safeguarding their newborns8 and f" limitations within the healthcare systems to provide continuity of care. 'he current resources for clinical interventions that can drastically and efficiently reduce the increased bilirubin load, intensive phototherapy and e7change transfusions, are available for use in those infants with e7cessive hyperbilirubinemia. 1owever, these interventions leave a very narrow margin of safety for babies who have rapid or unrecognized increases in their bilirubin load. $ecause most babies are discharged before the hyperbilirubinemia reaches its pea( during the first wee( of life, preventive and system-based strategies offer a safer, (inder and gentler means to prevent $#%& including (ernicterus. ntro$uction Kernicterus incidence has not been measured as a clinical or public health inde7 even though it has long been recognized as the pathologic se3uela of severe hyperbilirubinemia. .lthough the condition is uncommon, the conse3uences are tragic, especially when it affects otherwise healthy term and near term infants. +-9 Kernicterus has become uncommon because of effective screening for and prevention of 6h incompatibility, a historically important cause, and the accessibility of phototherapy to treat hyperbilirubinemia due to increased production and:or decreased elimination of bilirubin. 55555555555555555555555555555555555 -ontact A$$ress: ;inod K $hutani, <&. , =5/ >elch 6d. ?9+5, Stanford, alifornia, ,@9/5-5=9+ ;oiceA (B5/" =-9-5=++*a7A (B5/" =-5-C95+, 4mailA bhutaniDstanford.edu *urthermore, adherence by clinicians to the guidelines from the .merican .cademy of !ediatrics (..!" concerning management of neonatal jaundice was e7pected to eliminate severe hyperbilirubinemia and prevent (ernicterus.@ Eittle contemporary information is available on the incidence or prevalence of (ernicterus or its conse3uences. 1owever, anecdotal cases continued to be seen by practicing pediatricians and neurologists and cumulative occurrence is not recorded as a matter of public record or medical literature. 'hat (ernicterus occurs in otherwise healthy infants is evident from +-5 cases of infants who had been discharged as healthy from their birthing hospitals and who were voluntarily reported to the !ilot Kernicterus 6egistry from +,,- to -//-.5,B 1owever, no cases of (ernicterus in infants with cerebral palsy were found in the retrospective database of the %orthern alifornia Kaiser !ermanente <edical are !rogram (K!< !" during a similar time period (+,,+ to

+-

Kernicterus: A Preventable Neonatal Brain n!ur" +,,C".= #n addition, among +++,//, infants in the K!< ! database, ++ (/./+F" developed total serum bilirubin ('S$" levels G9/mg:dE (when measured", and none apparently developed (ernicterus. C 2n the other hand, a &anish population-based study reports B cases of (ernicterus over a duration of 5 years for an estimated incidence of +A9C,/// well-babies cared for in &anish nurseries., !ediatricians who have managed babies with neonatal hyperbilirubinemia that progress to acute or chronic bilirubin encephalopathy often feel stigmatized and are disinclined to report, discuss, review or publish their e7perience. 'hus, the scope of the true incidences of overt (ernicterus as well as possible HsubtleI neurological deficits cannot be ascertained without an innovative and non-adversarial investigative approach. 'here is a societal e7pectation to provide a universally available safe birthing e7perience that includes a safe e7perience with newborn jaundice. 'hus, (ernicterus (or a 'S$ level J9/ mg:dE" is now considered a Hnever-eventI by the public health community.+/-+@ 'his review focuses on the clinical definitions of $#%&, its relationship with hyperbilirubinemia, bilirubin:albumin ratio and with a specific focus on KB!& deficiencyrelated neonatal hyperbilirubinemia. #n addition, the article briefly addresses the role of a systems strategy for a safer e7perience with newborn jaundice and the potential role of chemoprevention. A. Bilirubin n$uce$ Neurolo3ic ("s*unction 1. (eterminants o* Neuronal n!ur" b" Bilirubin 'he ris( of neuronal injury by bilirubin is primarily determined by the concentration of unbound or HfreeI unconjugated bilirubin ($f" and hydrogen ion (p1" in blood. $f can be measured indirectly or estimated by calculating the molar ratio of total serum bilirubin ('S$" to albumin. $ilirubin enters brain tissue as $f when the blood binding capacity is e7ceeded, or when other displacing substances, such as sulphonamides, compete for bilirubin binding sites on albumin. +5 2ther important ris( factors for (ernicterus relate to neuronal susceptibility, including gestational age, infection or sepsis, and hemolysis, especially 6h disease. Sepsis or other neonatal inflammatory conditions and prematurity may decrease the bilirubin binding affinity of albumin. 4ven though a LsafeL level of bilirubin has not yet been determined, most of the circulatory bilirubin is bound to albumin which acts as a Hneuro-protectiveI. 'he bloodbrain-barrier has long been considered to play a role in protection of the brain from bilirubin to7icity, and its disruption produces diffuse yellow staining but not the specific pattern of (ernicterus.+B >hether the blood brain barrier acts as a pump through .'!-dependent e7port by transporter molecules to remove $f from the brain and maintain the concentration gradient of bilirubin from plasma to S* has yet to be determined, though .'!dependent e7port by transporter molecules has been suggested.+=-+, .nother important determinant of to7icity is neuronal susceptibility. Shapiro et al e7amined cerebella of jaundiced Kunn rats made to7ic at various developmental ages and found that neurons undergoing differentiation at the time of e7posure were the most susceptible to cell death, while those that were slightly more or less mature showed only transient changes or seemed to be much less sensitive.+, 'his supported the presence of a critical or sensitive period when elevated bilirubin could be most to7ic to neuronal development. $ilirubin can cause neuronal necrosis, and there is now good evidence in vitro that it induces apoptosis, which supports in vivo observations in older literature showing neuroanatomical changes consistent with apoptosis. 4vidence also suggests that bilirubin interferes with intracellular calcium homeostasis by altering function and e7pression of calcium:calmodulin (inase ##, by selectively decreasing calcium binding proteins in susceptible brainstem areas and increasing intracellular calcium in cultured neurons, and by sensitizing the cell to other injuries or triggering apoptosis. $ilirubin may also (ill cells by causing neuronal hypere7citability perhaps via e7citatory amino acid neuroto7icity, or it may have other membrane of neurotransmitter effects. *inally, it may act by interfering with mitochondrial respiration and energy production, perhaps as an o7idant injury.-/--9 2verall, it is hypothesized that bilirubin damages brain tissue cells via necrosis and apoptosis, either alone or in combination, in a neuro-anatomical distribution dependant on the amount, duration, and the developmental timing of e7posure of sensitive brain tissue to free bilirubin. >ith this perspective, the neuroanatomical and clinical e7pression of injury is li(ely to be comple7 with different patterns of damage and a range of clinical e7pression. &ifferent patterns of e7pression may relate to +" the amount of, and duration of e7posure to free bilirubin (high level, short duration e7posure not necessarily the same as lower level, long duration e7posure", -" the susceptibility of the developing %S, 9" the relative amount of necrosis vs. apoptosis produced, and @" whether surviving neurons will be functionally normal or more susceptible to other stressors either at the time of hyperbilirubinemia or afterwards. 2. Neuro)at%olo3" o* Kernicterus Kernicterus causes selective yellow staining in the basal

+9

J. Arab Neonatal Forum 2005; 2: 12-24 ganglia, especially the globus pallidus and subthalamic nucleus. $rainstem nuclei, especially the auditory (cochlear nucleus, inferior colliculus, superior olivary comple7", oculomotor and vestibular nuclei are especially vulnerable. 2ther vulnerable areas include the cerebellum, !ur(inje cells, and the hippocampus (especially the .sector". 'he basal ganglia are associated with the movement disorders of dystonia, athetosis and choreoathetosis. .bnormalities of the auditory brainstem nuclei are associated with deafness, hearing loss, and a recently described entity (nown as auditory neuropathy. .bnormalities of the brainstem oculomotor nuclei are associated with strabismus and gaze palsies, especially paresis of upgaze.+-9 #n the auditory system, bilirubin does not appear to affect either inner or outer hair cells, but appears to be to7ic to cell bodies of the auditory nerve in the spiral ganglia. $rainstem auditory nuclei and not the pathways are particularly susceptible. -@,-5 'he optimum means of assessment is neuro-physiological since this component of the auditory system cannot be imaged. %euro-physiological assessment involves the evaluation of the mechanical structure of the inner ear by otoacoustic emissions (2.4", and the outer hair cells (inner ear" by cochlear microphonic responses ( <". #n infants with (ernicterus, these are both normal. Sensori-neural assessment re3uires the testing of auditory brainstem response (.$6" or brainstem auditory evo(ed potential ($.4!". #n bilirubin-related injury, it is absent or abnormal and reflects damage to the auditory nerve (wave #" as well as the auditory brainstem nuclei (waves ### and ;". 'he basal ganglia lesions can be imaged with magnetic resonance imaging (<6#", the signature of which is bilateral damage of the globus pallidus. 'he subthalamic nuclei can sometimes be seen and are characteristically affected. &isordered outputs from the basal ganglia are possibly responsible for the dys(inetic movements. 'he <6# evidence of (ernicterus is distinct from that of hypo7ia-ischemia8 in the latter, the thalamus, corte7 and peri-ventricular white matter are involved8 while, the caudate nuclei and putamen are not affected in (ernicterus.-B 6. -linical (e*initions o* Bilirubin Neurolo3ic ("s*unction n$uce$
7able : 6oot auses for 6eemergence of Kernicterus 8a$a)te$ *rom J-A/9 0entinel Alert :11; an$ Jo%nson et al :5;< System *ailure #nstitutional <ajor 6oot auses for 6eemergence of Kernicterus 4arly hospital discharge (before e7tent of jaundice is (nown and signs of impending brain damage have appeared" Structural limitations within the healthcare systems to deal with continuity of mother-infant care after birthing. Eac( of ade3uate concern for the ris(s of severe jaundice in healthy term and near term newborns <edical care cost constraints with early discharge and limited access to healthcare during the first wee( after birth . lauded increase in breast feeding but unsupported by optimal lactation counseling to instruct, monitor and guide. !aucity of educational materials to enable parents to participate in safeguarding their newborns

!roviders

*amily and Societal

7able : $ilirubin-induced neurological dysfunction ($#%&" Score (adapted from 0ohnson et al (9+" +ental &ate: 0tatus 'ime %one / %ormal <ild + Sleepy, poor feeding <oderate Eethargic, #rritable Severe 9 Semicoma, Seizures oma Severity Score +uscle 7one %one / %ormal <ild + %ec( Stiffness, <ild hyper:hypotonia <oderate .rching nec(, retrocolis, .rching trun( Severe 9 $owing of trun( 2pisthotonus 0everit" 0core -r" )attern %one / %ormal <ild + 1igh pitched <oderate Shrill Severe 9 #nconsolable 'otal $ind Score %urse:<& signature Severity Score &ate: 'ime &ate: 'ime

Kernicterus has usually referred to the post-mortem evidence of icteric (yellow" staining of the basal ganglia and lesions of the e7tra-pyramidal nervous system. 'he !ilot 6egistry has offered formal clinical definitions of $#%& and Kernicterus ('able #". 'he spectrum of acute and chronic manifestations of $#%& varies from the acute stage bilirubin encephalopathy to those of chronic se3uelae such as isolated auditory neuropathy ( a form of

0core o* = to >: represent severe acute bilirubin encephalopathy8 urgent interventions are recommended to possibly minimize further brain injury. 0cores o* 4 to ?: 6epresent moderate acute bilirubin encephalopathy and is li(ely to be reversible with urgent bilirubin reduction. 0cores o* 1 to 6: 6epresent mild acute bilirubin encephalopathy and are usually reversible with urgent bilirubin reduction strategies. .n abnormal .$6 or HreferredI automated .$6 would indicative of $#%& would be suggestive of moderate to severe .$4

+@

Kernicterus: A Preventable Neonatal Brain n!ur"

7able : linical classification of Kernicterus (as proposed by Shapiro S<95" linical 1ave M 9 classic signs of (ernicterus including A +" .uditory (.%, hearing loss", -"<otor (hyper(inetic dystonia or athetosis, choreoathetosis, HathetoidI !, 9" oculomotor disorder esp. impairment of upgaze, @" dental enamel dysplasia. .uditory predominantA moderate of severe .% N hearing loss with mild motor symptoms (hypotonia, mildly delayed wal(ing, slightly abnormal muscle tone", normal or slightly abnormal K! (Signals" or <6# 1as signs and symptoms limited to only one system, either the auditory or motor system. <ost cases of isolated (ernicterus have turned out to be not strictly isolated, but have findings in another system on close e7amination .uditory Symptoms <ild .% (.$6 abnormal but present, may normalize" .% with absent or persistent abnormal .$6, <ild:moderate hearing loss, may fluctuate8 speech delayed or absent .% with absent .$6, severe-to-profound hearing loss: deafness 'iming *irst few days or wee(s of life, at the time of unconjugated bilirubin neuroto7icity, usually with e7cessive hyperbilirubinaemia but may have low bilirubin with displacers. 6arely may occur in older children and adults, eg with rigler-%ajjar syndrome or severe hepatic failure, but always with acute unconjugated bilirubin neuroto7icity. #n the days or wee(s after bilirubin neuroto7icity, eg after treatment with e7change transfusion or phototherapy the natural decline in bilirubin <onths, years, decades <otor Symptoms <ild dystonia N athetosis8 mild gross motor delays eg. >al(ing8 ambulates well, speech intelligible <oderate hyper(inetic dystonia: HathetoidI !8 ambulates with or without assistance with athetoid: choreoathetoid gait Severe dystonia:hyper(inetic !8 unable to ambulate, feed self, sign, spea(8 often with episodic severe hyper-tonial:spasticity, cramps Symptoms #n infantsA lethargy, variable hypotonia N hypertonia, high pitched cry, arching, retrocollis- opisthotonus, impaired upgaze, fever, seizures, death

lassification lassic Kernicterus <i7ed (ernicterus or $#%& #solated Kernicterus or $#%&

Eocation

<ild <oderate Severe

Severity

.cute 'ime

Subacute

Similar to acute, but also may have feeding and sleep disorders lassical clinical (ernicterus (movement &isorder, auditory, oculomotor, dental" or Subtle (ernicterus:$#%&

hronic

7able #: Signs Severe

linical definitions of Kernicterus severity %euromotor .bnormal 2culomotor .bnormal &ental .bnormal Owith onset of dentitionP .$6 Sensori-neural hearing loss <6# .bnormal Oif availableP

.ll four abnormal signs are present and :or abnormal <6# <oderate <ild .bnormal .ny two of three of these abnormal are present .ny two of these four signs are abnormal #f unavailable #f unavailable

sensorineural hearing loss", and chronic bilirubin encephalopathy of both neuromotor and auditory damage ((ernicterus". 'hough not yet proven, some e7perts believe that there may be more neurological manifestations of $#%& including subtle basal ganglia and central processing disorders. -=--, 'he effect of even moderate increases in 'S$ levels on early development remains a source of controversy, especially because some clinical manifestations are reversible upon reduction of the 'S$ concentration. a. Acute Bilirubin @nce)%alo)at%" :AB@;

'he actual incidence of .$4 is not (nown because (a" there have been no longitudinal surveillance studies of the condition, (b" there is limited awareness and recognition of this diagnosis in healthy babies and (c" the diagnosis is usually not coded on discharge summaries ('able ##". 1owever, recent case reports and registries suggest that (ernicterus has re-emerged as a public health problem after years of near e7tinction.B,++-+@ 'he introduction in the +,B/)s of 6hogam to prevent 6h sensitization and
Fi3ure 1: 7%e +a3netic resonance ima3e s%o4s )ost-icteric bilateral an$ increase$ 7-2 4ei3%te$ si3nals *rom t%e 3lobus

+5

J. Arab Neonatal Forum 2005; 2: 12-24

)alli$us in an "ear ol$ in*ant 4%o mani*este$ acute bilirubin ence)%alo)at%" )reviousl"

hypertonia and retrocolis, which increase in severity and are usually accompanied by a shrill cry, an une7plained irritability alternate with increasing lethargy. .dvanced signs are mar(ed by cessation of feeding, bicycling movements, inconsolable irritability and crying, possible seizures, fever and coma. 'hese are late findings and ominous predictors of the li(elihood of severe (ernicteric se3uelae, even with intensive treatment. .cute stage mortality is due to respiratory failure and progressive coma or intractable seizures. 6ate of progression of clinical signs depends on the rate of bilirubin rise, duration of hyperbilirubinemia, host-susceptibility and presence of co-morbidities. b. Post- cteric 0eAuelae: -%ronic Bilirubin @nce)%alo)at%" hronic, irreversible bilirubin encephalopathy has variable presentations and may include e7tra-pyramidal movement disorders (dystonia and athetosis", gaze abnormalities (especially upward gaze-figure +", auditory disturbances (especially sensori-neural hearing loss with central processing disorders and : or auditory neuropathy", and enamel dysplasia of the deciduous teeth. +-9 ognitive deficits are unusual but described as being occasionally present and in the retarded range in earlier reports. Such estimates probably reflected, for the most part, an inability to accurately assess intelligence in children with hearing, communication and coordination problems. 'he neuromotor manifestations of e7tra-pyramidal damage are present in almost all cases, but occasionally are apparent only with repeated attempts at s(illed movements. B. Belations%i) o* 7otal 0erum Bilirubin 'evel to 9ccurrence o* AB@ 'here are no randomized clinical trials that demonstrate a specific bilirubin level will or will not cause neuro-to7ic damage. 'he critical 'S$ level in any healthy baby is li(ely to be influenced by postnatal age, maturity within the range of term gestational age, duration of hyperbilirubinemia and rate-of-'S$ rise. !resence of comorbidities such as near-term gestation (95 to Q9C wee(s gestation", hypoalbuminemia, disruption of the bloodbrain barrier (asphy7ia or trauma", hemolysis (intravascular or e7travascular", factors that interfere with albumin binding of bilirubin, infection, and hypoglycemia predispose a newborn to $#%& at lower 'S$ values. . number of investigators, as noted by !oland, have presented evidence that unbound or Hfree bilirubinI is an appropriate predictor of neuroto7icity.99 .t present there are no commercial assays for albumin binding reserve or unbound bilirubin in the US. !reliminary US and 0apanese studies have suggested that levels J/.CB microg:dE of unbound bilirubin are associated with an increasing ris( of $#%&.9@-9B

erythroblastosis, and e7change transfusion and phototherapy to treat hyperbilirubinemia, virtually eradicated (ernicterus, which had accounted for BF of all cases of cerebral palsy seen in large clinics in the early +,5/)s. 'hus, for the -/ years prior to +,,+, there were no published reports of (ernicterus in healthy full term infants. 'he recent cases, during the early and mid +,,/s, coincided with trends towards earlier post-partum discharge (before jaundice is clinically evident or reaches its pea(" and decreased concern about the to7ic potential of bilirubin. 'he most troubling feature of these reports was that, contrary to popular belief, many of the affected infants had been otherwise well, term newborns without evidence of hemolytic disease.B,9/ -linical 0i3ns 'he classic signs of acute bilirubin encephalopathy in the severely hyperbilirubinemic term infants include increasing hypertonia, especially of e7tensor muscles, with retrocolis, opisthotonus, in association with varying degrees of drowsiness, poor feeding, hypotonia, and alternating tone. 'he early presenting signs and symptoms of .$4 can be described in terms of the infant)s mental status, muscle tone, and cry8 these progress as the injury worsens ('able ###". $ecause an accurate and reliable scoring system is needed to characterize the phases and progression of .$4 and to determine prognosis, this schema for grading the severity of .$4 has been developed as a clinical tool ('able #;".9+ 'he presenting signs of .$4 are subtle, non-specific and should be elicited by direct 3uestioning from parent of a severely hyperbilirubinemic neonate. &uring this phase early and prompt interventions can prevent chronic (ernicteric se3uelae.9- $#%& abnormalities with progression to scores between @ and B are often reversible with timely interventions. 'hese signs include early

+B

Kernicterus: A Preventable Neonatal Brain n!ur" 'he only prospective study that has shown an association between 'S$ levels and occurrence of .$4 is that reported by <ollison and utbush in a +,5@ follow-up report of babies with hyperbilirubinemia and hypoalbuminemia due to 6h hemolytic disease. 9= 'hese data are from over four decades ago and the sample size is small (nRB/" and applicable to babies with severe hemolytic disease. 1owever, an incremental relationship of (ernicterus to increasing levels of 'S$ J+, mg:dl is apparent. urrently most US nurseries discharge babies without screening for hemolysis other than 6h disease. 'hough hemolysis screening could be helpful, babies with pre-discharge high-ris( hyperbilirubinemia (J=5th percentile for age in hours" are as li(ely to have impaired bilirubin clearance due to confounding genetic polymorphisms in the glucuronyl transferase gene and : or delayed maturation of the otherwise normal glucuronyl transferase enzyme system. #n the !ilot Kernicterus 6egistry, 5 the causes for (ernicterus were attributed to three e3uivalent categories (one-third each"A hemolytic disorders (mostly .$2 isoimmunization", KB!& deficiency (associated with both hemolysis and impaired bilirubin conjugation" and idiopathic causes (presumably due to delayed or impaired function of the glucuronyl transferase enzyme system" coupled with breast-feeding and inade3uate nutritional inta(e. #n such newborns with 'S$ levels J=5th percentile a rate of 'S$ rise J/.-/ mg:dl:hr will e7ceed the pea( rate of rise observed at the ,5th percentile trac( on the bilirubin nomogram and increase the bilirubin load.9C .t these rates of rise, the bilirubin load will increase to severe hyperbilirubinemia and ris( for $#%&. -. Belations%i) o* Bilirubin to Albumin an$ Bis, o* AB@ .lbumin concentration is a powerful neuro-protective agent as well as a major determinant of both bilirubin to7icity and level of unbound bilirubin in e7cessively jaundiced babies. 'he integrity of binding (below the +A+ molar ratio" is compromised in a newborn because newborn albumin has a poor binding ability compared to adult albumin. #t is further compromised if a" albumin binding affinity is mar(edly decreased with concurrent prematurity, sic(ness or acidosis8 b" protein bound drugs compete for albumin binding sites. #t is further compromised for postnatal age Q =- hours, and if the serum albumin level is lower than e7pected. #n severely hyperbilirubinemic but otherwise healthy newborns ('S$ levels J,5th percentile and over =hours age" the bilirubin to albumin ratio is a useful tool to define one)s HworryI and potential ris( for $#%&.9,,@/ *or practical purposes, the $A . ratio can be e7pressed in terms of mg of bilirubin to grams of albumin. . bilirubin to albumin ratio of =./ in mg to grams corresponds to a bilirubin to albumin molar ratio of /.C/. 47posure to bilirubin:albumin ratios of J=./ (mg to gram" carry a clear ris( of irreversible neuroto7icity, especially if such e7posure is prolonged. .vailable clinical and e7perimental data suggests that $A . ratios of J5.9 and Q=./ mg:g (molar ratios of bilirubin to albumin J/.B9 and Q/.C/" are generally associated with reversible abnormalities of auditory brainstem responses.@+-@5 #n a term newborn with subtle signs of $#%& these $A . ratio values can be reassuring as long as the bilirubin load is vigorously reduced and signs of progression are closely monitored. (. D-?-P( $e*icienc"& Neonatal /")erbilirubinemia an$ Kernicterus K-B-!& deficiency is one of the commonest enzyme deficiencies in humans and can present with hemolytic crises in children and adults (favism" who ingest fava beans or have e7posure to stress of o7idants, drugs,

Fi3ure 2: An in*ant 4it% earl" onset %")erbilirubinemia t%at 4as )ro3ressive& unres)onsive to intensive )%otot%era)". Follo4in3 an eEc%an3e trans*usion& t%e in*ant %as %a$ a normal neurolo3ic outcome. 0erial 70B levels are )lotte$ on an %our-s)eci*ic bilirubin nomo3ram :6F;

-ase: +ale n*ant 4it% D-?-P( (e*icienc"

@Ec%an3e 7rans*usion
60

0erum Bilirubin :m3C$l;

Jaun$ice note$
20

>5t% )ercentile =5t% )ercentile 40t% )ercentile

10

n te nsive )%otot%era)"

+=

J. Arab Neonatal Forum 2005; 2: 12-24 infections and other chemical triggers. @B K-B-!& deficiency is also associated with neonatal hyperbilirubinemia though favism is unusual in infants. 'he association with severe neonatal hyperbilirubinemia with its potentially devastating complication of (ernicterus was made in Kreece soon after recognition of K-B-!& deficiency as an entity and has subse3uently been reported from many geographic areas in which K-B-!& deficiency is found. @= 'he incidence of neonatal hyperbilirubinemia has repeatedly been shown to be several-fold greater in K-B-!& deficient populations than in the K-B-!& normal population.@C,@, 1owever, this incidence is not constant and varies in different communities and geographic areas and is related to numerous mutations. *unctional severe mutations may cause hemolysis in the absence of stress. &ifferent mutations are characteristic of .sian, .frican, Southern 4urope populations. Kourley lin(ed neonatal jaundice with Kilbert syndrome. %eonates with the KS polymorphism have an increased rate of 'S$ rise in the first two days after birth and a predisposition to prolonged or severe neonatal hyperbilirubinemia in infants with K-B-!& deficiency or co-inherited with hematological abnormalitiesA a" beta-thalassemia, b" hereditary spherocytosis and certain forms of .$2 incompatibility. 5/,5+ Kaplan et al have observed that infants with K-B-!& deficiency do not have an increased incidence of hyperbilirubinemia (compared to K-B-!& normals" unless they also carry the UK'+.+ promoter polymorphism. 1omozygotes have significantly higher 'S$ levels than hemizygotes.5'wo clinical manifestations of K-B-!& deficiency and neonatal hyperbilirubinemia are described in clinical practiceA +" severe jaundice resulting from acute hemolysis, similar to favism8 -" jaundice and hyperbilirubinemia of more gradual but progressive onset. 'he fre3uency of either manifestation is not well documented. +. Acute an$ severe !aun$ice accompanied by suddenonset of hemolysis is unusual in neonates. #n some cases a (nown trigger of hemolysis can be identified and results in rapidly rising serum total bilirubin ('S$" levels. <aternal ingestion of fava beans can cause severe intrauterine hemolysis presumably by transplacental transmission of the fava metabolites. #n other cases transmission of metabolites to the nursing infant via breast mil( has been suggested. 1owever, severe hemolytic episodes can occur even when all (nown offenders are scrupulously avoided. #t is possible that as yet unidentifiable chemical offenders may be included in the vast array of cleaning or other household materials available. $eutler has emphasized infection as a possible inducer of hemolysis. 'hese severe hemolytic episodes Owith clinical evidence of hemolysisP can be unpredictable and there is fre3uently no warning that acute hemolysis is about to occur. 'his form of K-B-!& deficiency associated neonatal hyperbilirubinemia may not be completely amenable to prediction of hyperbilirubinemia or prevention of (ernicterus.59,5@ -. Dra$ual onset !aun$ice 4it% )ro3ressive neonatal %")erbilirubinaemia. #n contradistinction to the above, significantly more K-B-!& deficient neonates develop hyperbilirubinemia compared with controls. Kradual onset jaundice with progressive neonatal hyperbilirubinemia can be severe and is associated with a slower increase in 'S$ concentrations than in those with acute hemolysis. >ith intensive, modern day phototherapy e7change transfusion is rarely necessary with this variant of the hyperbilirubinemia. .s these babies are usually treated aggressively, the natural history of the hyperbilirubinemia and conse3uently the potential of e7treme hyperbilirubinemia and the ris( of (ernicterus are un(nown in this subgroup. 'here is some evidence that this form of jaundice has its origins in uteroA 'S$ values sampled immediately after birth were higher than in controls and correlated with both third day 'S$ values as well as with those who subse3uently developed hyperbilirubinemia, defined as 'S$ value J+5./ mg:dE. .lso, blood carbo7yhemoglobin and end tidal carbon mono7ide and representative of hemolysis, were higher in K-B-!& deficient neonates than in controls shortly after birth. 'he pathogenesis of hyperbilirubinemia in K-B-!& deficient neonates appears to be different from K-B-!& normal counterparts, greater emphasis being laid on the role of bilirubin conjugation defects. .lso important in understanding of the pathogenesis hyperbilirubinemia is the concept that the 'S$ at any point in time represents bilirubin production on the one hand, and its elimination from the body, on the other. .s long as e3uilibrium between these processes is maintained, 'S$ concentrations should not e7ceed the physiologic range. 1owever, should bilirubin production e7ceed the body)s capacity to eliminate it, hyperbilirubinemia may develop. Severe hemolysis is not essential to the mechanism of hyperbilirubinemiaA moderately increased heme catabolism in the face of diminished bilirubin conjugation may be sufficient to tip the balance. $ecause increased hemolysis does not appear to play a major role in the patho-physiology of hyperbilirubinemia, diminished bilirubin conjugation has been emphasized by some as an important factor Osee *igure -P. 'he current literature suggests that insufficiency of bilirubin conjugation is the mechanism of neonatal hyperbilirubinemia in infants with K-B-!& deficiency.55-5= !re-discharge hour-specific bilirubin screening can identify many K-B-!& deficient neonates at high ris( for developing hyperbilirubinemia and facilitate discharge and follow-up planning. 2f those K-B-!& deficient neonates with pre-discharge 'S$ value Q5/ th percentile on the hour-specific nomogram, the incidence of developing a 'S$ J+5./ mg:dE was very

+C

Kernicterus: A Preventable Neonatal Brain n!ur" low, but increased progressively as pre-discharge 'S$ values increased from the 5/th to J,/th percentile. .dditional population-based data are needed to better describe and understand the predictive role of predischarge hyperbilirubinemia as well as the natural history of hyperbilirubinemia in both homozygous and heterozygous neonates with K-B-!& deficiency.5C @. A s"stems-a))roac% *or a sa*er mana3ement o* ne4born !aun$ice 'he rationale to update Hbilirubin guidelinesI such as the +,,@ ..! guidelines5, are based on new data related to newborn safety, that jaundice is an unreliable indicator for severity of hyperbilirubinemia, the predictive abilities of pre-discharge screening for subse3uent severe hyperbilirubinemia is wea( and there is a need for lowered bilirubin level thresholds for interventions.B/-B- 'hese studies have provided an opportunity for restructuring to a more physician friendly instrument and enhancing its acceptance for wider implementation. 'he purpose of the guidelines is to ensure that clear criteria for patient safety, family centeredness, and precise, practical, user-friendly, preventive approaches and for timely interventions, are met.B9 $arriers to seamless transition from birth to home have been recognized to compound the ris( for hyperbilirubinemia.B@-BB *our clinical entities that add to inefficient continuity of care include +" early discharge (Q=- hours age" without timely follow-up, -" inade3uate lactation support, 9" undue reliance on the visual assessment of jaundice to initiate evaluation, and @" lac( of data to define persistence of jaundice, including the potential for unrecognized cholestatic jaundice. 1. @arl" $isc%ar3e an$ multi)le )rovi$ers at multi)le sites :)roblems 4it% G%an$-o**H;. 4arly discharge shifted the locus of care from the hospital to home and created a need for post discharge observation, a change in venue for patient and family education, and gaps in communication. *urthermore, follow-up appointments after hospital discharge are often scheduled after the anticipated pea( of serum bilirubin concentration. Systems are limited to facilitate sharing of clinical data among multiple clinical providers at multiple sites such as between the birth hospital and the paediatric office. %ew parents may have difficulty arranging for a clinician to chec( their child after discharge. *lawed interactions between many different parties perpetuate the problems. 'o ensure a safe first wee( after birth for all newborns re3uires broad changes in the processes of care. 2. ne**icient lactation counselin3. . clinical diagnosis of jaundice may lead to disruption of breastfeeding rather than implementation of steps that would enhance breast mil( inta(e. .lthough breast mil( is the most appropriate feeding for newborns, e7clusive breast feeding, especially if it is not going well, is a major ris( factor for hyperbilirubinemia. 1owever, no 3uantitative data are available to document either the incidence of lactation failure leading to adverse hyperbilirubinemia outcomes or the incidence of lactation disruption associated with management of hyperbilirubinemia. 6. 1n$ue reliance on visual assessment o* !aun$ice. 'he ..! guideline cautions on the reliance of visual estimation of jaundice. 1owever, the inaccuracy of visual assessment of jaundice may not be widely appreciated. 4. Persistent %")erbilirubinemia. 'he incidence of persistent indirect hyperbilirubinemia (age J- wee(s", especially in breastfed infants, and its possible se3uelae are not (nown. #n addition, clinical distinction of benign persistent jaundice from cholestasis is often difficult. holestasis, which occurs in appro7imately +A-5// live births, can be a manifestation of more than =/ different diseases, biliary atresia being the most common. B=,BC *actors contributing to delayed referral of infants with biliary atresia include lac( of follow-up of neonatal jaundice and misdiagnosis of breast mil( jaundice. 4arly diagnosis of biliary atresia is crucial for a successful surgical outcome but has no lin(age with (ernicterus. #t is to be noted the -//@ ..! guidelines strongly recommends that a clinician should not subtract the direct bilirubin value from the total serum bilirubin value for clinical decisions, especially for administration of phototherapy or e7change transfusion.B, Since clear evidence for a course of action has been absent, we have recommended an approach that guarantees patient safety pending the HgatheringI of evidence. Structural changes that would facilitate such a system-based approach should include a" pre-discharge bilirubin management8 b" follow-up bilirubin management8 and, c" lactational support and nutritional management. urrently there are two major predischarge screening strategies that are amenable to a system-based approachA i" pre-discharge total serum bilirubin screening and ii" a scoring system based on clinical ris( factors. >ith either approach there should be no room for error and a wide margin of safety to prevent the need for a Hcrash cartI approach for babies with e7cessive hyperbilirubinemia. 2n the basis of available evidence, we should screen all babies for hyperbilirubinemia for targeted follow-up that is based on an hour-specific 'S$ measured for ris( assessment. #n addition, we should provide focused universal education with an emphasis on supporting ade3uate lactational nutrition to decrease severe hyperbilirubinemia and thus prevent (ernicterus.=/ F. Bole o* -%emo)revention hemoprevention of hyperbilirubinemia by pharmacological agents to effectively reduce adverse bilirubin loads has been studied for several years and recently reviewed by &ennery.=+ 'he proven available options for pharmacotherapy include drug-induced acceleration of bilirubin e7cretion (such as use of

+,

J. Arab Neonatal Forum 2005; 2: 12-24 !henobarbital" and alteration of bilirubin production by synthetic heme analogues that act as competitive inhibitors for heme catabolism (such as tin mesoporphyrin". #n view of patient safety concerns from unmonitored adverse effects related to severe hyperbilirubinemia, the role of chemoprevention in infants at ris( for severe hyperbilirubinemia is being investigated. !henobarbital increases hepatic clearance and e7cretion, and may be administered prenatally. =+,=#t is effective when administered + wee( prior to delivery and when given to newborn infants. 1owever, this intervention has limited or no clinical effect when administered to infants Q9- wee(s of gestation and has now been shown to be ineffective when given prior to +- hours of age. 'he adverse effects of this therapy are of concern. 'hese are sedation, ris( of hemorrhagic disease, and potential for addiction. 'his drug has a slow onset of effect (usually several days" and a long duration of action (one to two wee(s" after its discontinuation. #n addition, its confounding effects on other hormones and concerns of drug safety have limited the clinical value of phenobarbital as a chemopreventive agent for newborn jaundice. %ewer chemopreventive strategies have included investigations of a number of synthetic heme analogues that are protoporphyrin derivatives of tin, zinc, manganese, chromium, and cobalt. =9 2verall, metalloporphyrins (<e!s" reduce bilirubin production, can be phototo7ic and may increase transcription of 12-+, the inducible 12 isozyme. 4ffective development of this class of compounds has been in the direction of products that are less phototo7ic and are stronger inhibitors of heme o7ygenase. . number of <e!s have been evaluated e7perimentally with variations of the pertinent metal (such as tin, zinc, chromium" and porphyrin (protoporphyrin, mesoporphyrin, bisglycol porphyrin, etc". 2ur understanding of the molecular basis of heme o7ygenase inhibition is evolving as new heme o7ygenase isoenzymes are characterized in different organs. 'he significance of prolonged and potent, longlasting inhibition of heme o7ygenase needs to be differentiated from a single, acute and transient inhibition. 'he inherent appeal of naturally occurring molecules, such as zinc, has been 3uestioned by the finding of deleterious effects on rabbit bone marrow erythroid and myeloid cells and by lethal conse3uences of chromium mesoporphyrin injection in animals. 'hus far, the stannic porphyrins, in particular tin protoporphyrin and tin mesoporphyrin have been e7tensively investigated and found to be safe and effective in preclinical studies. >ith the successful completion of nearly two decades of e7tensive clinical pharmacological and to7icological studies, as recently summarized by Kappas,=@ stannate, an effective <e!, has demonstrated its therapeutic ability to safely reduce bilirubin production through competitive inhibition of heme-o7ygenase, the rate-limiting enzyme in heme catabolic se3uence. #ts chemopreventive role is being investigated and evaluated in infants at ris( for severe hyperbilirubinemia. 2ther strategies that warrant further investigations and clinical trials are use of agents that interrupt the enterohepatic circulation and bilirubin accumulation from the continued action of beta-glucuronidase. hemoprevention with use of casein supplements=5 or other agents such as E-aspartic acid could decrease intestinal reabsorption of bilirubin and may have a potential clinical role.=B D. Dlobal Pers)ective o* Jaun$ice an$ Kernicterus. Kernicterus is still thought of by many as a condition that occurs primarily in underdeveloped countries. .s the 0 .12 root cause list suggests, the safety net protecting newborns has significant deficits. <ost families learn about potential problems related to newborn care during childbirth education classes. Unfortunately, the lac( of concern about jaundice among health care providers has led to a major lacuna in childbirth education curricula.== 'he teaching and discussion of jaundice, impact of early discharge, and breast-feeding have been minimal or non-e7istent. 'he role of family and community in prevention of $#%& and Kernicterus is an integral component of any public health strategy.=C Since this condition is not yet a HnotifiableI disease, there is an urgent need for a tightening of the Hsafety netI and reaching all families and health-care wor(ers to supplement e7isting information and e7pedite change in current practices for assessing and effectively treating hyperbilirubinemia. Kernicterus is fre3uent and less preventable in countries with poor access to healthcare (for e7ampleA South .sia, and .frica", those with high-ris( populations (<iddle-4ast, as well as %orth .frican and South .frican nations" and countries who are rapidly improving their healthcare systems to contemporary standards (4astern 4urope and Eatin .merica". #n conclusion, Kernicterus ran(s as a major cause for infant mortality and morbidity in developing countries but not considered as serious as birth asphy7ia, sepsis, malnutrition and prematurity. 1owever, it is the only neonatal condition for which safe, ine7pensive and effective clinical strategies are easily available. osteffective bilirubin reduction strategies such as promotion of breast feeding, universal availability of safe and effective phototherapy as well as chemoprevention need to be targeted to infants at ris( while ensuring patient safety and universal access. Klobal eradication of (ernicterus, through a national public health agenda, is feasible and practical. #t is essential to a society that aspires for every family and their newborn to have a safer e7perience with newborn jaundice. Ac,no4le$3ement: !reliminary paper presented at the H1ot 'opics in %ewborn areI, 0eddah, Saudi .rabia, *ebruary, -//5 ( onvenerA &r. <ai-Seoud".

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Kernicterus: A Preventable Neonatal Brain n!ur" Be*erences: +. van !ragh 6. &iagnosis of (ernicterus in the neonatal period. !ediatrics +,B+8-CA C=/-C=@. -. 0ones <1, Sands 6, 1yman $, Sturgeon !, Koch *!. Eongitudinal study of the incidence of central nervous system damage following erythroblastosis fetalis. !ediatrics +,5@8+@A9@B. 9. ;olpe 00. $ilirubin and brain injury. #nA %eurology of the %ewborn. @th 4dition, -//+. @. !erlstein <. %eurologic se3uelae of erythroblastosis fetalis. .m 0 &is hild +,5/8=,AB/5-B/B. 5. 0ohnson E1, $rown .K, $hutani ;K. Systembased approach to management of neonatal jaundice and prevention of Kernicterus. 0 !ediatr -//-8+@/A9,B-@/9. B. $hutani ;K, 0ohnson E1, <aisels <0, %ewman '$, !hibbs , Star( .6, Seargin-.llsopp <. KernicterusA 4pidemiological Strategies for its !revention through Systems-$ased .pproaches. 0 !erinatol -//@8-@ (+/"AB5/-BB-. =. %ewman '$, Tiong $, Konzales ;<, 4scobar K0. !rediction and prevention of e7treme neonatal hyperbilirubinemia in a mature health maintenance organization. .rch !ediatr .dolesc <ed -///8 +5@A++@/-++@=. C. %ewman '$, Eiljestrand !, 4scobar K0. #nfants with bilirubin levels of 9/ mg:dE or more in a large managed care organization. !ediatrics -//98+++(B !t +"A+9/9-+9++. ,. 4bbesen *. 6ecurrence of (ernicterus in term and near-term infants in &enmar(. .cta !aediatr -///8C,(+/"A+-+9-+-+=. +/. $hutani ;K, 6odriguez <, and 1 . !erinatal Safety #nitiative Kernicterus 'as(force. 6ecent 4pidemiologic #ndices of Severe 1yperbilirubinemia and Kernicterus for a &iverse <ulti-State %ewborn !opulation in US.. !ediatric 6esearch -//5. .bstract. ++. 0 .12A 6evised guidance to help prevent (ernicterus. Sentinel 4vent .lert -//@ 9+(9+"A+--. +-. *rom the enters for &isease ontrol and !revention. Kernicterus in full-term infantsU United States, +,,@-+,,C. 0.<. -//+8 -CBA -,,9//A httpA::www.cdc.gov:ncbddd:dd:(ernres.htm +9. Serious reportable events report. . onsensus 6eportA . %ational *ramewor( for 1ealthcare Vuality <easurement and 6eportingA. %ational Vuality *orum httpA::www.3ualityforum.org:activities:caWarchive. htm (available as a print copy" +@. Schyve !<. <icrosystems, macrosystems, and (ernicterus. 0t omm 0 Vual Saf -//@89/(++"A5,+5,-. +5. .hlfors 4, >ennberg 6!. $ilirubin-albumin binding and neonatal jaundice. Semin !erinatol -//@8-C(5"A99@-99,. +B. .hlfors 4. $ilirubin-albumin binding and free bilirubin. 0 !erinatol -//+8-+ (Suppl +"AS@/-S@-8 +=. 1ansen '>. <echanisms of bilirubin to7icityA clinical implications. lin !erinatol -//-8-,(@"A =B5-==C. +C. >atch(o 0*, &aood <0, $iniwale <. Understanding neonatal hyperbilirubinemia in the era of genomics. Semin %eonatol -//-8=(-"A+@9+5-. +,. Shapiro S<. $ilirubin to7icity in the developing nervous system. !ediatr %eurol -//98-,(5"A@+/@-+. -/. 1ansen '>, Sagvolden ', $ratlid &. 2pen-field behavior of rats previously subjected to short-term hyperbilirubinemia with or without blood-brain barrier manipulations. $rain 6es +,C=8@-@(+"A-B9B. -+. 1an(o 4, 1ansen '>, .lmaas 6, Eindstad 0, 6ootwelt '. $ilirubin induces apoptosis and necrosis in human %'--% neurons. !ediatr 6es -//585=(-"A+=,-+C@. --. $rito <., $rites &, $utterfield &.. . lin( between hyperbilirubinemia, o7idative stress and injury to neocortical synaptosomes. $rain 6es -//@8+/-B(+"A99-@9. -9. Shapiro S<. Somatosensory and brainstem auditory evo(ed potentials in the Kunn rat model of acute bilirubin neuroto7icity. !ediatr 6es -//-85-(B"AC@@-C@,. -@. Shapiro S<, %a(amura 1. $ilirubin and the auditory system. 0 !erinatol -//+8-+ (Suppl +"AS5--S558 discussion S5,-SB-. -5. Shapiro S<. &efinition of the clinical spectrum of (ernicterus and bilirubin-induced neurologic dysfunction ($#%&". 0 !erinatol -//58-5(+"A5@-5,. -B. <artich-Kriss ;, Kollias SS, $all >S 0r. <6 findings in (ernicterus. .0%6 .m 0 %euroradiol +,,58+B(@ Suppl"AC+,-C-+. -=. 0ohnson E. 'he hyperbilirubinemic term infantA >hen to worry, when to treat. %S State 0 <ed +,,+8++A @C9. -C. 2dell K$, Storey K%$, 6osenberg E.. Studies in (ernicterusA ###. 'he saturation of serum proteins with bilirubin during neonatal life and its relationship to brain damage at five years. 0 !ediatr +,=/8 =BA+---+. -,. 0ohnson E, $oggs '6. $ilirubin-dependent brain damageA incidence and indications for treatment. #nA 2dell K$, Schaffer 6, Simopoulos .!, editors. !hototherapy in the %ewbornA .n 2verview. >ashington, & , %ational .cademy of Sciences, +,=@A +---+@,. 9/. #p S, hung <, Kulig 0, 2)$rien 6, Sege 6, Klic(en S, <aisels <0, Eau 0, and the .merican .cademy of !ediatrics Subcommittee on 1yperbilirubinemia. .n evidence-based review of important issues concerning neonatal hyperbilirubinemia. !ediatrics -//@8++@Ae+9/e+59. 9+. 0ohnson E, $rown .K, $hutani ;K. $#%& - . clinical score for bilirubin induced neurologic

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J. Arab Neonatal Forum 2005; 2: 12-24 dysfunction in newborns. !ediatrics Supplement +,,,8+/@A=@B. 1ansen '>6. .cute <anagement of e7treme neonatal jaundice- the potential benefits of intensified phototherapy and interruption of enterohepatic circulation. .cta !ediatr +,,=8 CBA C@9-C@B. !oland 6E. !reventing (ernicterusA almost there. 0 !ediatr -//-8+@/(@"A9C5-9CB. %a(amura 1, Sonetani <, Uetani S, *unato <, Eee S. &etermination of serum unbound bilirubin for prediction of (ernicterus in low birthweight infants. .cta !ediatrica 0aponica +,,-89@AB@--B@=. .hlfors 4. riteria for e7change transfusion in jaundiced newborns. 0 !ediatrics +,,@8,9A @CC-@,@. *unato <, 'erao(a S, 'amai 1, Shimada S, %a(amura 1. *ollow-up study of auditory brainstem evo(ed responses in hyperbilirubinemic newborns treated with e7change transfusion. .cta !ediatrica 0aponica +,,B89CA+=--+. <ollison !E, utbush <. . method of measuring the severity of a series of cases of hemolytic disease of the newborn. $lood +,5+8B(,"A===-=CC. $hutani ;K, 0ohnson E, Sivieri 4<. !redictive ability of a pre-discharge hour-specific serum bilirubin for subse3uent significant hyperbilirubinemia in healthy term and near-term newborns. !ediatrics +,,,8+/9(+"AB-+@. >ennberg 6!, 1ance .0A 47perimental bilirubin encephalopathyA importance of total bilirubin, protein binding, and blood-brain barrier. !ediatr 6es+,CB8 -/A=C,-=,-. 6obinson !0, 6apoport S#. $inding effect of albumin on upta(e of bilirubin by brain. !ediatrics +,C=8=,A559-55C. .hlfors 4, $ennett S1, Shoema(er ', 4llis >K, &avis SE, >ennberg 6!, Koetzman $>. hanges in the auditory brainstem response associated with intravenous infusion of unconjugated bilirubin into infant rhesus mon(eys. !ediatr 6es +,CB8-/A5++-5+5. .hlfors 4, 1erbsman 2. Unbound bilirubin in a term newborn with (ernicterus. !ediatrics -//98+++A+++/-+++-. 2dell K$. Studies in (ernicterus #A 'he protein binding of bilirubin. 0 lin #nvest +,5,89CA C-9C99. 6obertson .*, Karp >$, $rodersen 6. omparison of bilirubin concentration and bilirubin:albumin ratio with the bilirubin binding ability in neonatal serum. 0 !ediatr +,,C8+9-A9@99@@. .hlfors 4. Unbound bilirubin associated with (ernicterusA . historical approach. 0 !ediatr -///8+9=A5@/-5@@. $eutler 4. KB!& &eficiency. $lood +,,@8C@A9B+9-9B9B. ;alaes '. Severe neonatal jaundice associated with glucose-B-phosphate dehydrogenase deficiencyA pathogenesis and global epidemiology. .cta !aediatr +,,@8Suppl 9,@A5C-=B. @C. Kaplan <, 1ammerman . Severe neonatal hyperbilirubinemiaA a potential complication of glucose-B-phosphate dehydrogenase deficiency. lin !erinatol +,,C8-5A5=5-5,/. @,. Kaplan <, <uraca <, 1ammerman , et al. #mbalance between production and conjugation of bilirubinA a fundamental concept in the mechanism of neonatal jaundice. !ediatrics -//-8++/Ae@=. 5/. $ancroft 0&, Kreamer $, Kourley K6. Kilbert syndrome accelerates development of neonatal jaundice. 0.!ediatr +,,C8+9-AB5B-BB/. 5+. Kaplan <, $eutler 4, ;reman 10, et al. %eonatal hyperbilirubinemia in glucose-B-phosphate dehydrogenase-deficient heterozygotes. !ediatrics +,,,8+/@ABC-=@. 5-. ;alaes ', Kara(lis ., Stravra(a(is &, et al. #ncidence and mechanism of neonatal jaundice related to glucose-B-phosphate dehydrogenase deficiency. !ediatric 6esearch +,B,89A@@C-@5C. 59. Kaplan <, ;reman 10, 1ammerman , et al. *avism by pro7y in nursing glucose-B-phosphate dehydrogenase-deficient neonates. 0 !erinatol +,,C8+CA@==-@=,. 5@. Kaplan <, .lgur %, 1ammerman . 2nset of jaundice in glucose-B-phosphate dehydrogenasedeficient neonates. !ediatrics -//+8+/CA,5B-,5,. 55. Stevenson &K, ;reman 10, $enaron &.. 4valuation of neonatal jaundiceA monitoring the transition in bilirubin metabolism. 0 !erinatol +,,B8+BASB--B=. 5B. Kaplan <, ;reman 10, 1ammerman , Eeiter , .bramov ., Stevenson &K. ontribution of haemolysis to jaundice in Sephardic 0ewish glucoseB-phosphate dehydrogenase deficient neonates. $r 0 1aematol +,BB8,9AC---C-=. 5=. Kaplan <, 1ammerman , *eldman 6 et alA !redischarge bilirubin screening in glucose-Bphosphate dehydrogenase-deficient neonates. !ediatrics -///8+/5A599-59=. 5C. $eutler 4, Kelbart ', &emina .. 6acial variability in the U&!-glucuronosyltransferase + (UK'+.+" promoterA a balanced polymorphism for regulation of bilirubin metabolismM !roc %atl .cad Sci US. +,,C8,5AC+=/-C+=@. 5,. .cademy of !ediatrics, !rovisional ommittee for Vuality #mprovement, 6obertson >2, .lm3uist 06, Eight #0, <aisels <0, et al. !ractice parameterA management of hyperbilirubinemia in the healthy term newborn. !ediatrics +,,@8 ,@(@"A55C-5B5. B/. %ewman '$, Tiong $, Konzales ;<, 4scobar K0. !rediction and prevention of e7treme neonatal hyperbilirubinemia in a mature health maintenance organization. .rch !ediatr .dolesc <ed -///8+5@A++@/-++@=. B+. 0ohnson E1, $rown .K, $hutani ;K. Systembased approach to management of neonatal jaundice and prevention of Kernicterus. 0 !ediatr -//-8+@/A9,B-@/9.

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Kernicterus: A Preventable Neonatal Brain n!ur" B-. $rown .K, 0ohnson E. Eoss of concern about jaundice and the reemergence of (ernicterus in fullterm infants in the era of managed care. hapter #nA 'he Sear $oo( of %eonatal and !erinatal <edicine, *anaroff .., Klaus <1 (eds". <osby Searboo(, !hiladelphia, pp 7vii-77viii,+,,B. B9. .merican .cademy of !ediatrics. Subcommittee on 1yperbilirubinemia, <aisels <0, $altz 6&, $hutani ;K, %ewman '$, !almer 1, 6osenfeld >, et al. linical !ractice KuidelineA <anagement of 1yperbilirubinemia in the %ewborn #nfant G95 >ee(s of Kestation. !ediatrics (in press, 0uly -//@". httpA::www.aap.org:jaundice guidelines.htm B@. !almer 61, lanton <, 4zhuthachan S, %ewman , <aisels 0, !lse( !, Salem-Schatz S. .pplying the L+/ simple rulesL of the institute of medicine to management of hyperbilirubinemia in newborns. !ediatrics -//98++-A+9CC-+9,9. B5. Eannon , Star( .6. losing the gap between guidelines and practiceA ensuring safe and healthy beginnings. !ediatrics -//@8++@(-"A@,@-@,B. BB. Salem-Schatz S, !eterson E4, !almer 61, lanton S<, 4zhuthachan S, Euttrell 6 , %ewman , >estbury 6. $arriers to first-wee( follow-up of newbornsA findings from parent and clinician focus groups. 0t omm 0 Vual Saf -//@89/(++"A5,9-B/+. B=. >at(ins 0$. %eonatal holestasisA &evelopmental .spects and urrent oncepts. Semin Eiver &is +,,98+9(9"A-=B--CC. BC. Kourley K6. %eonatal 0aundice and &isorders of $ilirubin <etabolism. Suchy *0, So(ol, 60, and $alistreri >*. Eiver &isease in hildren. -nd ed. !hiladelphia, Eippincott >illiams X >il(ins, -///, pp.-=5-9+@. B,. 4sbjorner 4. .lbumin binding properties in relation to bilirubin and albumin concentrations during the first wee( of life. .cta !aediatr Scand +,,+8 C/A@//-@/5. =/. $hutani ;K, 0ohnson E1, Keren 6. &iagnosis and management of hyperbilirubinemia in the term neonateA for a safer first wee(. !ediatr lin %orth .m -//@85+(@"AC@9-CB+. =+. &ennery !., Seidman &, Stevenson &K. %eonatal 1yperbilirubinemia. % 4ngl 0 <ed -//+899@A5C+. =-. .rya ;$, .garwal 6, !aul ;K, &eorari .K. 4fficacy of 2ral !henobarbitone in 'erm H.t 6is(I %eonates in &ecreasing %eonatal 1yperbilirubinemiaA . 6andomized &oubleblinded, !lacebo ontrolled 'rial. #ndian !ediatr -//@8@+(@"A9-=-99-. =9. .le7ander &. . method for interdicting the development of severe jaundice in newborns by inhibiting the production of bilirubin. !ediatrics -//@8++9A+95. =@. Kappas .. . method for interdicting the development of severe jaundice in newborns by inhibiting the production of bilirubin. !ediatrics -//@8++9A++,-+-9. =5. Kourley K6, Kreamer $, ohnen <, Kosoro( <6. %eonatal jaundice and diet. .rch !ediatr .dolesc <ed +,,,8+59(-"A+C@-+CC. =B. Kreamer $E, Siegel *E, Kourley K6. . novel inhibitor of beta-glucuronidaseA E-aspartic acid. !ediatr 6es -//+8 5/A@B/-@BB. ==. $hutani ;K, 0ohnson E1. %ewborn jaundice and (ernicterus--health and societal perspectives. #ndian 0 !ediatr -//98=/A@/=-@+B. =C. Sheridan S4. !arents of #nfants and hildren with Kernicterus. 0 !erinatol -//58-5(@"A--=---C.

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