Duration Of Hyperbilirubinemia Research Articles

Early prediction of urinary tract infection in neonates with hyperbilirubinemia.

Introduction: Hyperbilirubinemia is a common manifestation of infectious disorders during the neonatal period. Urinary tract infection (UTI) is one of the serious bacterial infections with hyperbilirubinemia among newborn infants. Objectives: The aim of this study was to identify the early predictive risk factors of UTI in neonates with hyperbilirubinemia, to prevent its long-term complications. Patients and Methods: A total of 95 neonatal hyperbilirubinemia were evaluated in 2 groups with (n = 40) and without UTI (n = 55). Results: Mean age at diagnosis of UTI was 16.37 ± 8.86 days. Hyperbilirubinemia was detected in 70% of patients during the first week of life. There was a significant difference regarding the age at admission, duration of hyperbilirubinemia, serum bilirubin and creatinine, white blood cells (WBC) , and also Hgb levels between the 2 groups in univariate analysis. However, prolonged jaundice (OR = 10.3, P = 0.001) and serum bilirubin concentration (OR = 5.15, P = 0.001) were statistically associated with a positive urine culture in multivariate analysis. Conclusion: Screening of UTI is recommended in neonates with prolonged unexplained jaundice, leukocytosis, and increased serum creatinine.

ДО ПИТАННЯ ПРОЛОНГОВАНОЇ ЖОВТЯНИЦІ У НОВОНАРОДЖЕНИХ.

<p> Стаття присвячена актуальній проблемі затяжної неонатальної жовтяниці, висвітлені особливості обміну білірубіну у новонароджених. Розглянуті фактори ризику виникнення кон'югаційної жовтяниці та їХ діагностичне значення щодо розвитку затяжного перебігу гіпербілірубінеміїу новонароджених.<br /><br /></p>

Time-dependent dual effects of high levels of unconjugated bilirubin on the human blood-brain barrier lining

In neonatal jaundice, high levels of unconjugated bilirubin (UCB) may induce neurological dysfunction (BIND). Recently, it was observed that UCB induces alterations on brain microvasculature, which may facilitate its entrance into the brain, but little is known about the steps involved. To evaluate if UCB damages the integrity of human brain microvascular endothelial cells (HBMECs), we used 50 or 100 μM UCB plus human serum albumin, to mimic the neuropathological conditions where levels of UCB free species correspond to moderate and severe neonatal jaundice, respectively. Our results point to a biphasic response of HBMEC to UCB depending on time of exposure. The early response includes increased number of caveolae and caveolin-1 expression, as well as upregulation of vascular endothelial growth factor (VEGF) and its receptor 2 (VEGFR-2) with no alterations of the paracellular permeability. In contrast, effects by sustained hyperbilirubinemia are the reduction in zonula occludens (ZO)-1 and β-catenin levels and thus of tight junctions (TJ) strands and cell-to-cell contacts. In addition, reduction of the transendothelial electrical resistance (TEER) and increased paracellular permeability are observed, revealing loss of the barrier properties. The 72 h of HBMEC exposure to UCB triggers a cell response to the stressful stimulus evidenced by increased autophagy. In this later condition, the UCB intracellular content and the detachment of both viable and non-viable cells are increased. These findings contribute to understand why the duration of hyperbilirubinemia is considered one of the risk factors of BIND. Indeed, facilitated brain entrance of the free UCB species will favor its parenchymal accumulation and neurological dysfunction.

Neurodevelopmental and audiological outcome of healthy term newborns with moderately severe non‐haemolytic hyperbilirubinemia

Our objective was to examine the outcome of term infants who developed moderate non-haemolytic jaundice as information regarding the neurodevelopmental outcome of term infants with moderately severe non-haemolytic hyperbilirubinemia remains controversial. Thirty-nine term infants rehospitalised with non-haemolytic hyperbilirubinemia (serum bilirubin levels: 20-30 mg/dL) during the first 2 weeks of life (study group), were assessed and compared to 36 children born at term who did not develop neonatal jaundice (control group). Assessment consisted of the Bailey 2 test, speech evaluation, behavioural hearing test and a neurological examination. The subjects were assessed at a mean age of 3 years. There was no difference between the groups with regard to background data, except for the mean gestational age (38 + 1.3 weeks (study group) vs. 39.5 + 1.4 weeks (control group), P= 0.01). There were no significant differences between the groups in outcome parameters initially, and after correcting for possible confounding factors. None of the children in either of the groups had a neurosensory hearing deficit or any significant neurological deficiency. There was no correlation of outcome parameters with the admission serum Bilirubin levels or with the duration of hyperbilirubinemia. No untoward outcome was found in term healthy infants with moderately severe non-haemolytic hyperbilirubinemia. Moreover, we did not find a correlation of outcome with serum bilirubin levels or with the duration of the hyperbilirubinemia in the study group.

Hyperbilirubinemia and Language Delay in Premature Infants

Our goal was to evaluate whether language delay at 3 years in premature infants is associated with previous exposure to hyperbilirubinemia during the first 2 weeks after birth. We performed a retrospective case-control study of infants admitted to the NICU between January and October 2003. Inclusion criteria included a birth weight of < or =1500 g and follow-up to age 3 years. Exclusion criteria included genetic disorders and hearing loss or recurrent ear infections. Peak total serum bilirubin levels during the first 2 weeks and duration of hyperbilirubinemia (days with total serum bilirubin level at >8 mg/dL) were determined. Infants with language delay and who were receiving speech therapy by 3 years were identified through developmental clinic charts and a tracking program and compared with infants who had normal language development. A total of 125 infants with birth weight of < or =1500 g were admitted to the NICU between January and October 2003. Fifteen infants died, and 110 were discharged from the hospital. A total of 102 (93%) of 110 infants had follow-up to the age of 3 years. Four infants were excluded (1 genetic disorder, 3 delayed hearing loss or recurrent ear infections). Twenty-four infants had a language delay and received speech therapy, whereas 74 infants had normal language development. There was no significant difference in peak total serum bilirubin level and duration of hyperbilirubinemia between the 2 groups. On logistic regression, only bronchopulmonary dysplasia was associated with language delay. Hyperbilirubinemia, defined as peak total serum bilirubin level or duration of elevated bilirubin in days, is not associated with language delay in premature infants. However, this issue deserves investigation, because other measures of bilirubin, such as unbound bilirubin, may be associated with language delay.

Profound Hyperbilirubinemia during Induction of Adult Acute Lymphoblastic Leukemia: Capping L-Asparaginase Dose to 10,000 Units Attenuates It without Compromising Remission Rate.

Introduction: Hyperbilirubinemia is a well known side-effect of L-asparaginase. Grade 4 hyperbilirubinemia (bilirubin > 3) results in delayed chemotherapy; compromising dose intensity. Hence a strategy to prevent this is important.Materials & Methods: At our center, we see around 125 cases of newly diagnosed adult acute lymphoblastic leukemia (age>24 years) every year. Since 2005, we have started treating these adult patients on modified BFM 90 protocol. This protocol includes 8 doses of L-asparaginase at 10,000 units/m2 during induction. Hyperbilirubinemia of grade 4 (median bilirubin upto 20) was encountered in the first few patients. To avoid delay in chemotherapy, we modified the protocol to cap L-asparaginase dose at 10,000 u for all patients.Results: A total of 64 patients with ALL was treated on this modified protocol in 18 months. We compared the degree of hyperbilirubinemia in this group of patients with the first 20 patients who were treated with the standard dose of L-asparaginase. Median age of the full cohort (All 84 patients) was 34 years (24–60). Fifty four patients had precursor B-cell ALL while 30 patients had T-cell ALL. Male: Female ratio was 4.1:1. All the analysed patients have completed induction. In first group of 20 patients who had received standard dose of L-asparaginase, 6 patients developed grade 4 hyperbilirubinemia (median bilirubin 23). SGPT, SGOT and SAP were either normal or borderline elevated. Viral markers at diagnosis and at the onset of hyperbilirubinemia were negative. No significant hepatic abnormality was seen on USG abdomen. In four out of 6 patients' bilirubin returned to normal after conservative management, over a period of 3 weeks. The two remaining patients developed sepsis, had deranged coagulation parameters and succumbed to sepsis. Of the second group of 64 patients ( L-asparaginase at 10,000 fixed dose), 5 patients developed hyperbilirubinemia (highest value of bilirubin 4). All other investigations (listed above) were normal.All patients' bilirubin came back to normal within 1 week of interruption of chemotherapy. Complete remission rates were 90% in the first group of 20 patients and 92% in the second group of 64 patients.Conclusion: In the cohort of 64 patients (second group), capping of L-asparaginase resulted in significant reduction in intensity, incidence and duration of hyperbilirubinemia. This modification did not affect CR rate, though we are currently evaluating long term survival to confirm sustained efficacy.

The Frequency of UDP-Glucuronosyltransferase 1A1 Promoter Region (TA)7 Polymorphism in Newborns and it's Relation with Jaundice

Increased bilirubin formation and decreased bilirubin conjugation play an important role in the pathogenesis of the newborn jaundice. Although physiologic jaundice is seen in most of the newborns, there are many risk factors that affect the severity and duration of hyperbilirubinemia. The latest studies showed that the frequency and severity of neonatal jaundice have been increased when mutations of the gene coding UDP-glucuronosyltransferase(UGT)1A1 coexist with other risk factors. Healthy term newborns weighing over 2500 g. were included in this study. The patient group consisted of 107 newborns either with total bilirubin level over 15 mg dl(-1) within 7 days or 5 mg dl(-1) after 15 days of age. The control group consisted of 55 newborns with bilirubin levels in physiological ranges. We investigated the frequency of promoter region [thymine-adenine(TA)]7 polymorphism in UGT1A1 gene. Factors which might cause pathologic and prolonged jaundice with coexisting polymorphism were also investigated. UGT1A1 6/7 genotype was found to be 11% in patient group and 13% in the control group. The difference between patient and control groups was not statistically significant. (TA)7 allele frequency was 0.069 and it is concluded that UGT1A1 promoter region polymorphism was not a risk factor for neonatal jaundice.

Neurodevelopmental Outcomes of Newborns with Severe Neonatal Jaundice

Source: Newman TB, Lijestrand P, Jeremy RJ, et al. Outcomes among newborns with total serum bilirubin levels of 25 mg per deciliter or more. N Engl J Med. 2006;354:1889–1900; doi:10.1056/NEJMoa054244Although newborns with severe hyperbilirubinemia (those whose serum bilirubin levels reach 25 mg per deciliter or more) are aggressively treated, long-term outcomes are poorly defined. A prospective study was performed by investigators from the University of California, San Francisco and the Division of Research at Kaiser Permanente Medical Care Program in Oakland, Calif. to determine whether neurodevelopmental outcomes were affected in term and near term newborns whose total serum bilirubin reached 25 mg per deciliter or greater. A total of 140 infants with severe hyperbilirubinemia were compared to 419 randomly selected controls. Perinatal data were collected from paper and electronic records. Formal evaluation of neurologic development at approximately 5 years of age was performed per parental consent by an examiner masked to the group. Fifty-nine percent of parents of children in the hyperbilirubinemia group agreed to formal evaluation versus 40% for the control group. For infants who did not have a formal neurological assessment, outcome was assessed using parental questionnaires and a search of electronic medical records for neurological diagnosis codes.A formal evaluation, completed parental questionnaire, or record of an outpatient visit at the age of 5 years or more was available for 94% of the subjects in the hyperbilirubinemia group, and 89% of those in the control group (P=.06). Very few infants (10) had serum bilirubin measurements of greater than 30 mg per deciliter, and only 5 were treated with an exchange transfusion. The study identified no significant differences between the hyperbilirubinemia and control groups with regard to intelligence testing, verbal-motor skills, or parental report of behavioral problems at ~5 years of age. However, lower IQs were observed in the very small number of children (9) who had positive direct antiglobulin tests. Neither the degree nor duration of hyperbilirubinemia or gestational age at birth had a significant effect on outcome.Dr. Eichenwald has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of a commercial product/device. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.This study is 1 of only 2 available that has prospectively followed a group of term and near term newborns with severe hyperbilirubinemia and compared them to a control group without elevated bilirubin levels.1 Recent identification of the re-emergence of kernicterus makes this study timely and important in understanding treatment recommendations for neonatal jaundice.2 Although limited by the inability to perform formal neurological assessments on all the enrolled infants, the study was able to accomplish some assessment of outcome beyond 2 years of age, when cerebral palsy should be evident, in the majority of infants. Very few of the subjects with hyperbilirubinemia had bilirubin levels that exceeded 30 mg per deciliter, and most had short periods with a documented bilirubin level over 25 mg per deciliter. Despite these limitations, the results of this study should provide reassurance to pediatricians and families that total serum bilirubin values between 20 and 25 mg per deciliter are unlikely to cause long-term sequelae with adequate treatment. The lower IQs in the small sample of infants with positive direct antiglobulin tests, while too limited to draw firm conclusions, do suggest that more aggressive treatment of newborns with jaundice and evidence of hemolysis is warranted.2

The Effects of Hyperbilirubinemia on Sleep-Spindle Characteristics in Infants

The purpose of this study is to investigate the effect of hyperbilirubinemia on sleep-spindle characteristics. Rhythmic activities, such as sleep spindles, may be abolished by hyperbilirubinemia. Electroencephalogram records were taken from 15 infants with hyperbilirubinemia and 18 healthy infants at the 12th week after birth. Sleep spindles of the 2 groups were compared according to location, density, duration, amplitude, frequency, asynchrony, and asymmetry. In the study and control groups, the density of the spindles was found to be 76.9 +/- 23.7 and 105.2 +/- 33.9, respectively, in a 1-hour non-rapid eye movement sleep period. The mean durations of the sleep spindles in the study and control groups were found to be 4105 +/- 802 milliseconds and 5162 +/- 1075 milliseconds, respectively. There was not any difference between the groups according to the amplitude and asymmetry. However, there was a significant difference between the 2 groups in the frequency of spindles. The mean frequency was found to be 12.5 +/- 0.6 Hz in the study group and 13.2 +/- 0.9 in the control group. The percentage of asynchronous spindles was higher in the study group than in the control group. There was a significant negative correlation between the bilirubin levels during the newborn period and density, duration, and frequency of spindles. However, there was a significantly positive correlation between the bilirubin levels and percentage of asynchronous spindles. There was a significant negative correlation between the duration of hyperbilirubinemia and spindleamplitude. We suggest that studies on the critical maturation periods of sleep-spindle patterns might provide a sensitive tool for early diagnosis of neurophysiologic brain alterations during the first trimester of life in a population of at-risk children, such as jaundiced infants.

Reversible Hepatic Dysfunction Associated with Rhabdomyolysis

Hepatic dysfunction was observed in 34 patients with nontraumatic rhabdomyolysis. The serum levels of lactic dehydrogenase were markedly elevated in all patients. The peak values occurred within 72 h of hospitalization. There was no significant difference among patients with (9,044 +/- 1,154 U/l) and without acute renal failure (ARF; 9,125 +/- 3,067 U/l). Similarly, marked elevation in both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed within 72 h after admission to the hospital. They were significantly higher in patients with ARF (ALT: 4,718 +/- 785 vs. 2,496 +/- 927 U/l, p less than 0.01; AST: 3,635 +/- 820 vs. 1,352 +/- 624 U/l, p less than 0.01). Hyperbilirubinemia was noted in 13 of 22 (60%) patients with ARF and in 5 of the 12 (41%) of those without ARF. Serum levels of bilirubin ranged from 2.6 to 14.3 mg/dl. Prothrombin time was prolonged in 4 of 12 (33%) without ARF and in 14 of 22 (63%) of patients with ARF. This abnormality lasted from 1 to 13 days. The magnitude and duration of hyperbilirubinemia and abnormal prothrombin time were similar in patients with and without ARF. Hepatic dysfunction appears to occur in about 25% of patients with rhabdomyolysis. The pathogenesis of these abnormalities is not well defined and may be multifactorial. Hyperpyrexia, hypotension and proteases released from injured muscle may each or all be contributory. These hepatic derangements are reversible.

EFFECTIVENESS OF EARLY PHOTOTHERAPY IN VERY-LOW-BIRTH-WEIGHT (VLBW) INFANTS

Routine initiation of phototherapy (PT) within a few hours of birth in VLBW infants has been suggested as a means of modifying the severity and duration of hyperbilirubinemia (HB). The purpose of this study was to determine whether early PT alters the course of HB in VLBW infants. 16 preterm infants, (BW 878 ± 56 g; EGA 27.6 ± 0.4 weeks - mean ± SEM) were randomly assigned to receive PT either within 8 h of birth (E) or after BR reached 5 mg/dl (L). Irradiance at 450 nm was controlled at 12uw/cm2/nm with a Healthdyne Cavitron PT unit. BR values were measured B.I.D., and specimens for configurational (ZE) and structural (LUM) photoisomers were obtained once each day for analysis by HPLC. Age and BR at the onset of PT, peak BR, age at peak, rate of rise of BR, and total duration of PT were compared for both treatment groups. A significant rise in both ZE and LUM (p<.005) independent of BR concentration was seen following the onset of PT in all patients. This data suggests that the clinical course of HB is not altered in infants receiving early PT compared with infants whose PT was begun at 5 mg/dl. In addition, infants receiving early PT were exposed to PT for a significantly longer time. Since PT may be associated with serious side effects, its prophylactic use does not appear to be justified. (NIH Grant RR-00240)

Light (phototherapy)-induced riboflavin deficiency in the neonate

Phototherapy with blue light decomposes riboflavin, which has a maximum absorption at 450 nm. A study was designed to determine whether riboflavin deficiency developed in neonates who received phototherapy for moderate hyperbilirubinemia. Twenty-one infants with normal erythrocyte glucose-6-phosphate dehydrogenase activity were investigated. Five infants with moderate hyperbilirubinemia who did not require phototherapy served as the controls. Riboflavin deficiency was determined from the degree of saturation of erythrocyte glutathione reductase, a method shown to reflect riboflavin nutritional status in the neonate. Sixteen of 21 infants who were exposed to phototherapy developed riboflavin deficiency; all who had phototherapy for 49 hours or more developed the deficiency. That the concentration of serum bilirubin or the duration of hyperbilirubinemia was not a factor is supported by the fact that none of the controls became deficient. This observation may have important metabolic and clinical consequences for the neonate.

"Physiologic" hyperbilirubinemia in the neonatal period.

THE degree and duration of hyperbilirubinemia during neonatal life result from many influences unique to the newborn period that serve either to increase the rate of formation of bilirubin or to retard its excretion. The present paper reviews recent concepts that elucidate several causes of hyperbilirubinemia that are unrelated to hemolytic disease.The overall hepatic excretion of bilirubin involves at least three separate processes1: Uptake. Bilirubin is transported in the serum attached to serum albumin and enters the sinusoidal circulation of the liver from either the hepatic artery or the portal vein, where it is taken up by . . .

Studies of prolonged neonatal jaundice in the breast-fed infant

The clinical course of 20 breast-fed infants with prolonged unconjugated hyperbilirubinemia is described. Severe jaundice began during the latter part of the first or beginning of the second week of life and maximum concentrations of unconjugated bilirubin in the serum ranged from 9.0 to 26.0 mg. per 100 ml. Milk from the mothers of the jaundiced infants markedly inhibited hepatic glucuronyl transferase activity in vitro. Pregnane-3(α),20(β)-diol was isolated from milk obtained from 4 mothers of infants with prolonged jaundice, but has not been isolated from normal human milk. The relationship between intensity and duration of inhibition by milk and intensity and duration of hyperbilirubinemia in the infants is illustrated. Two thirds of the breast-fed siblings of the infants studied had a history of prolonged jaundice, whereas none of the artificially fed siblings had a history of prolonged jaundice.

BREAST-MILK HYPERBILIRUBINEMIA: REPORT OF A CASE.

IT has become evident that several substances may interfere with the capacity of the newborn infant to conjugate bilirubin, thereby resulting in varying degrees and duration of hyperbilirubinemia in the neonatal period. Prolonged and unexplained acholuric jaundice has been observed in several breast-fed infants, but only recently has a biochemical basis for this clinical observation been described. An inhibitor substance occurring postnatally in the breast milk of some women that was clinically associated with prolonged neonatal icterus has been identified.1 This report presents an additional case of persistent indirect hyperbilirubinemia with a demonstrable inhibitor substance in the maternal breast milk, . . .

MECHANISM OF HYPERBILIRUBINEMIA IN THE NEWBORN INFANT

IT HAS been demonstrated that although only approximately 50 per cent of newborn infants become detectably jaundiced, cord blood and neonatal blood serum will, with rare exception, show hyperbilirubinemia when examined by chemical methods. After birth the serum bilirubin level rises for a few days, followed by a slow progressive fall to normal. In a series of 106 infants studied by Davidson and associates, 1 the median maximum serum bilirubin level was 5.7 mg. per hundred cubic centimeters, and only 2 infants from the group showed maximum levels of less than 1.0 mg. per hundred cubic centimeters. These workers demonstrated a high degree of correlation between the bilirubin level in the cord blood and the subsequent height and duration of hyperbilirubinemia in early postnatal life. They also showed a close association between the maximum level which the serum bilirubin attains and the duration of the hyperbilirubinemia. The fact that the