Prevention of bilirubin encephalopathy

Prevention of bilirubin encephalopathy is based on the detection of infants at risk of developing a significant hyperbilirubinemia. This task can be accomplished by performing a simple umbilical cord blood test, such as blood group, Rh, Coombs' test and glucose-6-phosphate dehydrogenase, in order to detect hemolytic diseases. In preterm infants, the prevention of hyperbilirubinemia with phototherapy is a relatively simple task, since these infants are cared for in hospital. Early hospital discharge of full-term neonates represents a major concern. The management of neonatal jaundice requires that therapy begins when total serum bilirubin levels are significantly below the levels at which kernicterus is considered an immediate threat. Unfortunately, determination of serum bilirubin is a painful procedure, and is not very accurate since there is a high variability in laboratory measurements. The accuracy and precision of a new transcutaneous bilirubin measurement, comparable to the standard of care laboratory test, makes the daily evaluation of transcutaneous bilirubin measurement a useful tool in distinguishing physiological from nonphysiological hyperbilirubinemia, and determining the bilirubin increment in the first days of life. Full-term neonates who lose a significant amount of weight are especially at risk of significant hyperbilirubinemia and must be treated with ad libitum feeding and intensive phototherapy.     

Carboxyhemoglobin concentration as an index of bilirubin production in neonates with birth weights less than 1,500 grams: a randomized double-blind comparison of supplemental oral vitamin E and placebo

A randomized double-blind study of the efficacy of oral vitamin E supplementation as a prophylactic treatment for hyperbilirubinemia was undertaken in preterm infants weighing less than 1,500 g. Hemoglobin (Hb) levels, blood carboxyhemoglobin saturation (HbCOc), end-tidal carbon monoxide concentration (ETCO), and serum total bilirubin levels were determined in each subject on the first and third days of the study. We found no differences between the vitamin E-treated and placebo-treated groups with respect to Hb, HbCOc, ETCO, or serum bilirubin levels on day 1 or 3. In addition, we reanalyzed our data to compare those infants who had low vitamin E levels at birth with those who had vitamin E levels greater than 0.4 mg/dl on day 1. We still observed no differences in Hb, HbCOc, ETCO, or serum bilirubin levels on day 1 or 3. The results of our study suggest that supplemental oral vitamin E therapy has no major effect on bilirubin production during the first 3 days of life in premature infants weighing less than 1,500 g at birth.     

Normal serum bilirubin levels in the newborn and the effect of breast-feeding

We measured the serum bilirubin concentrations in 2,416 consecutive infants admitted to our well-baby nursery. The maximum serum bilirubin concentration exceeded 12.9 mg/dL (221 mumol/L) in 147 infants (6.1%), and these infants were compared with 147 randomly selected control infants with maximum serum bilirubin levels less than or equal to 12.9 mg/dL. In 66 infants (44.9%), we identified an apparent cause for the jaundice, but in 81 (55%), no cause was found. Of infants for whom no cause for hyperbilirubinemia was found, 82.7% were breast-fed v 46.9% in the control group (P less than .0001). Breast-feeding was significantly associated with hyperbilirubinemia, even in the first three days of life. The 95th percentile for bottle-fed infants is a serum bilirubin level of 11.4 mg/dL v 14.5 mg/dL for the breast-fed population, and the 97th percentiles are 12.4 and 14.8 mg/dL, respectively. Of the formula-fed infants, 2.24% had serum bilirubin levels greater than 12.9 mg/dL v 8.97% of breast-fed infants (P less than .000001). When compared with previous large studies, the incidence of "readily visible" jaundice (serum bilirubin level greater than 8 mg/dL) appears to be increasing. The dramatic increase in breast-feeding in the United States in the last 25 years may explain this observation. There is a strong association between breast-feeding and jaundice in the healthy newborn infant. Investigations for the cause of hyperbilirubinemia in healthy breast-fed infants may not be indicated unless the serum bilirubin level exceeds approximately 15 mg/dL, whereas in the bottle-fed infant, such investigations may be indicated if the serum bilirubin exceeds approximately 12 mg/dL.(ABSTRACT TRUNCATED AT 250 WORDS)     

Significance of low or normal serum gamma glutamyl transferase level in infants with idiopathic neonatal hepatitis

INTRODUCTION: We evaluated the significance of low/normal serum gamma glutamyl transferase (GGT) level in infants with idiopathic neonatal hepatitis (INH). MATERIALS AND METHODS: A retrospective review of the hospital records of 103 infants less than 3 months of age who were diagnosed with INH between August 1991 and November 2000 was performed. Variables including age at which jaundice was noticed, age at presentation, perinatal risk factors, family history of liver disease, parental consanguinity, initial ultrasound scan, liver biopsy, laboratory values at the first visit, the peak levels of total bilirubin, aspartate aminotransferase (AST), GGT and alkaline phosphatase (ALP) in the first 3 months of follow-up and interval for normalisation of serum bilirubin and AST were compared between infants presenting with low/normal GGT (100 U/L). RESULTS AND DISCUSSION: Infants with low/normal GGT levels presented earlier (median 36.5 days versus 44 days; p=0.016) and had significantly higher bilirubin and AST levels at presentation (bilirubin 167.5 micromol/L versus 133 micromol/L; p<0.005 and AST 187.5 U/L versus 106 U/L; p<0.001) and at peak levels (bilirubin 170 micromol/L versus 146 micromol/L; p=0.024 and AST 210.5 U/L versus 129 U/L; p=0.001). A significant correlation was also found between GGT levels and serum albumin levels (p=0.004). Patients with low/normal GGT levels were more likely to have giant cell hepatitis on histology (p=0.015). There was no difference in time taken to recovery. CONCLUSION: Low/normal levels of GGT in INH infants may be a predictor of more severe but recoverable disease.     

Screening for neonatal hyperbilirubinaemia and ABO alloimmunization at the time of testing for phenylketonuria and congenital hypothyreosis

In a population-based study including 2463 infants, serum bilirubin measurements were added to the neonatal screening programme for phenylketonuria and congenital hypothyreosis. This screening programme detected 11/17 (65%) of infants with serum bilirubin levels > 350/μmol l⁻¹, of whom 7 (3 per 1000) were readmitted from home (6 treated with phototherapy). A total of 139 infants (5.6%) received phototherapy. Maternal blood type O occurred significantly more often in term infants treated (30/54; 55.6%) compared with preterm infants treated (32/85; 37.6%) and with blood type O occurrence in the total population of mothers (906/2426; 37.3%) ( p < 0:05). The blood type constellations mother O/infant A or B showed a sensitivity of 64%, specificity 65%, positive predictive value 12% and a negative predictive value of 96% for the requirement of phototherapy for the whole material. Exchange transfusion was not required in any of the infants. No infant developed bilirubin encephalopathy (kernicterus). Adding bilirubin to a neonatal screening programme detects some cases with unexpectedly high bilirubin levels in need of intervention. Routine ABO blood typing of pregnant women, ABO cord blood typing and Coombs' test in infants of mothers with blood type O cannot be recommended because of low positive predictive value for the requirement of intervention (phototherapy) by these tests.     

The effect of shielding the hepatic area on the clinical response to phototherapy

The changes in serum bilirubin concentration in response to phototherapy were studied in 26 infants with and without an opaque patch on the liver area. Fifteen infants in the patched group were treated at a mean age of 50.7 h, and 11 control infants at 49.1 h. No significant differences were demonstrated between the two groups in duration of phototherapy, peak bilirubin concentration and rates of bilirubin decrement.Shielding the hepatic area during illumination does not alter the clinical response to phototherapy which suggests that the main site of action of phototherapy is in the skin.     

Indications for early exchange transfusion in patients with erythroblastosis fetalis

The postnatal rate of rise of the undirect bilirubin concentration was compared with cord hematocrit and bilirubin values in 44 newborn infants with Rh isoimmune hemolytic disease. Cord blood values failed to predict the severity of hyperbilirubinemia with sufficient accuracy to warrant their use as therapeutic guidelines. A statistically significant positive correlation was found between the cord serum indirect bilirubin concentration and its subsequent rise in 19 infants who had received antenatal phenobarbital therapy, but this relationship was not observed in untreated infants. The phenobarbital-treated infants had a slower postnatal rise of indirect bilirubin than did nontreated controls. There was no reliable indicator of the severity of hyperbilirubinemia other than careful monitoring of the serum bilirubin concentration during the early hours of life.     

Acute management of extreme neonatal jaundice–––the potential benefits of intensified phototherapy and interruption of enterohepatic bilirubin circulation

Abstract Increasing numbers of neonates are being admitted to hospital because of extreme jaundice. Phototherapy should be very effective in such infants, because the efficacy of phototherapy is proportional to the concentration of bilirubin in the skin. Here, I report on four infants who were admitted for indirect serum bilirubin levels of >500 µmol/1 (>>30mg/dl). In one of them, unrecognized Rhesus immunization was the main cause of hyperbilirubinemia, while in the other three increased enterohepatic circulation of bilirubin was thought to be an important contributory factor. In all four infants phototherapy (11–14 µW/cm²/nm) with whole body exposure plus ad lib feeding with milk were initiated immediately upon admission to the nursery. After 2h serum bilirubin values were reduced by 170–185 µmol/1 (10-11mg/dl) in the first three infants, while in the fourth infant a reduction of 195 µmol/1 (11.3mg/dl) was seen in the 5h interval between the first and second bilirubin measurement. This experience suggests that in some infants with extreme jaundice, intensified phototherapy plus feeding with milk may be very effective in reducing serum bilirubin levels. Even if an exchange transfusion is performed, using this strategy in the waiting period may be beneficial, as both the rapid reduction in serum bilirubin levels as well as the conversion of significant amounts of bilirubin into water-soluble isomers may reduce the risk of neurotoxicity.     

Excessively high bilirubin and exchange transfusion in very low birth weight infants

Aim: To evaluate the performance of exchange transfusion in very low birth weight (VLBW) infants with excessively high serum bilirubin levels. Methods: A population‐based observational study using data collected by the Israel National VLBW Infant Database. The study sample comprised 13 499 infants. Two definitions of excessively high‐peak bilirubin levels that might be considered as threshold levels for performance of exchange transfusion were used. First, a bilirubin level of ≥15 mg/dL for all infants (PSB‐15), and second, incremental bilirubin levels ranging from 12 to 17 mg/dL according to gestational age (PSB‐GA). Results: Four hundreds sixty‐eight (3.5%) and 1035 infants (7.7%) infants in the PSB‐15 and in the PSB‐GA groups respectively had peak serum bilirubin levels above thresholds for exchange transfusion. Exchange transfusions were performed in 66 (14.1%) of these infants in the PSB‐15 group and 91 (8.8%) in the PSB‐GA group. Using logistic regression analysis, peak serum bilirubin was found as an independent factor for performing exchange transfusion. Conclusion: Exchange transfusion was performed in only 9–14% of VLBW infants with excessively high bilirubin levels. We speculate that this may be a result of an absence of definitive guidelines or the possible belief that the risks of exchange transfusion outweigh the potential risk of bilirubin‐induced neurological injuries.     

Hyperbilirubinemia in preterm infants in Japan: New treatment criteria

In 1992, Kobe University proposed treatment criteria for hyperbilirubinemia in newborns using total serum bilirubin and serum unbound bilirubin reference values. In the last decade, chronic bilirubin encephalopathy has been found to develop in preterm infants in Japan because it can now be clinically diagnosed based on an abnormal signal of the globus pallidus on T2‐weighted magnetic resonance imaging and abnormal auditory brainstem response with or without apparent hearing loss, along with physical findings of kinetic disorders with athetosis. We therefore revised the Kobe University treatment criteria for preterm hyperbilirubinemic infants in 2017. The three revised points are as follows: (i) newborns are classified under gestational age at birth or corrected gestational age, not birthweight; (ii) three treatment options were created: standard phototherapy, intensive phototherapy, and albumin therapy and/or exchange blood transfusion; and (iii) initiation of standard phototherapy, intensive phototherapy, and albumin therapy and/or exchange blood transfusion is decided based on the total serum bilirubin and serum unbound bilirubin reference values for gestational weeks at birth at <7 days of age, and on the reference values for corrected gestational age at ≥7 days of age. Studies are needed to establish whether chronic bilirubin encephalopathy can be prevented using the 2017 revised Kobe University treatment criteria for preterm infants in Japan.     

Spectrum of outcome in infants with extreme neonatal jaundice

The increasing number of case reports on neurologic sequelae related to hyperbilirubinaemia may represent a re-emergence of kernicterus in the industrialized world. However, not much has been written about infants who survived extreme levels of serum bilirubin without neurologic damage. We present three cases of extreme neonatal hyperbilirubinaemia, all with peak serum bilirubin levels > 600 µmol/L. Two of the infants developed neurologic sequelae, but the third infant did not. In contrast to the two with sequelae, the infant without sequelae was female, had a positive Coombs' test, less clinical signs compatible with bilirubin encephalopathy, and a shorter exposure to serum bilirubin values > 400 µmol/L. Conclusion: The basic mechanism of bilirubin neurotoxicity remains unknown, and it is not clear why some infants do not develop neurologic injury at serum bilirubin levels at which others do. We speculate that a comparison between patients with sequelae and those without may yield important information.     

Newborn screening for ABO hemolytic disease

Confusion still exists regarding the true incidence of ABO hemolytic disease and the significance of the various laboratory investigations commonly employed in its evaluation. With such imprecision in diagnosis, early hospital discharge of newborns can be a potential problem. To evaluate the usefulness of more extensive screening than commonly employed and to identify possible indicators of severity, a pilot study of cord blood screening was undertaken. In the study, 1391 cord blood specimens were tested for type, Rh, direct antiglobulin test (DAT), indirect Coombs, and total and indirect bilirubin. Of the specimens, 53.3 percent were type A, B, or AB, and 19.3 percent of both A and B infants and 7 percent of AB infants had immune antibodies in their sera. DAT was neither diagnostic nor predictive of severity. DAT was negative in 48 percent of infants with serum antibody and did not correlate with cord blood or peak serum bilirubin levels. The cord blood bilirubin also was not diagnostic of hemolytic disease but was moderately predictive of peak bilirubin levels. The data do not support the use of any routine screening tests in the management of ABO hemolytic disease.     

High-dose intravenous immune globulin therapy for hyperbilirubinemia caused by Rh hemolytic disease.

We conducted a multicenter controlled trial to test the hypothesis that high-dose intravenous immune globulin (HDivIG) therapy can modulate bilirubin production and reduce the frequency of exchange transfusions in newborn infants with Rh hemolytic disease. Thirty-four patients with Rh incompatibility proved by positive direct antiglobulin test (Coombs test) results were randomly assigned to receive conventional treatment including phototherapy, with or without additional HDivIG therapy at 500 mg/kg given for a 2-hour period as soon as the diagnosis was established. Exchange transfusions were performed if serum bilirubin concentrations exceeded the modified curves of Polácek by more than 2 mg/dl. Two patients were excluded because of protocol violations. The results in 32 infants were analyzed. In the HDivIG group, 2 (12.5%) of 16 children required exchange transfusions, whereas it became necessary in 11 (69%) of 16 children in the control group (p less than 0.005). Bilirubin levels in the HDivIG group were lower despite reduced frequency of exchange transfusions. No side effects of HDivIG treatment were observed. We conclude that HDivIG therapy by a yet unknown mechanism reduces serum bilirubin levels and the need for blood exchange transfusions in children with Rh hemolytic disease.     

Sequential Trial of Effect of Phenobarbitone on Serum Bilirubin of Preterm Infants

(1) Phenobarbitone in a dose of 8 mg/kg per day was given in twice-daily intramuscular doses to preterm infants with a gestational age of 36 completed weeks or less. The phenobarbitone was started within the first 24 hours after birth. (2) The peak serum bilirubin levels of these infants and matched, randomly selected, control infants were compared sequentially. A significantly lower (P [unk]0·05) peak bilirubin level was found in the treated group. (3) This lower level of serum bilirubin may be less liable to produce neurological damage in preterm infants.     

An evidence-based review of important issues concerning neonatal hyperbilirubinemia

This article is adapted from a published evidence report concerning neonatal hyperbilirubinemia with an added section on the risk of blood exchange transfusion (BET). Based on a summary of multiple case reports that spanned more than 30 years, we conclude that kernicterus, although infrequent, has at least 10% mortality and at least 70% long-term morbidity. It is evident that the preponderance of kernicterus cases occurred in infants with a bilirubin level higher than 20 mg/dL. Given the diversity of conclusions on the relationship between peak bilirubin levels and behavioral and neurodevelopmental outcomes, it is apparent that the use of a single total serum bilirubin level to predict long-term outcomes is inadequate and will lead to conflicting results. Evidence for efficacy of treatments for neonatal hyperbilirubinemia was limited. Overall, the 4 qualifying studies showed that phototherapy had an absolute risk-reduction rate of 10% to 17% for prevention of serum bilirubin levels higher than 20 mg/dL in healthy infants with jaundice. There is no evidence to suggest that phototherapy for neonatal hyperbilirubinemia has any long-term adverse neurodevelopmental effects. Transcutaneous measurements of bilirubin have a linear correlation to total serum bilirubin and may be useful as screening devices to detect clinically significant jaundice and decrease the need for serum bilirubin determinations. Based on our review of the risks associated with BETs from 15 studies consisting mainly of infants born before 1970, we conclude that the mortality within 6 hours of BET ranged from 3 per 1000 to 4 per 1000 exchanged infants who were term and without serious hemolytic diseases. Regardless of the definitions and rates of BET-associated morbidity and the various pre-exchange clinical states of the exchanged infants, in many cases the morbidity was minor (eg, postexchange anemia). Based on the results from the most recent study to report BET morbidity, the overall risk of permanent sequelae in 25 sick infants who survived BET was from 5% to 10%.     

Formation of bilirubin conjugates in human newborns

Bilirubin conjugates in the serum of newborn human infants were investigated using the alkaline methanolysis-high-performance liquid chromatography method, a specific and sensitive method for measurement of unconjugated bilirubin and bilirubin mono- and diester conjugates. Serum samples were analyzed from 13 premature infants, 11 full term newborns, 22 healthy adults, seven pregnant women at term and their corresponding infants cord blood at delivery, 46 cord blood specimens obtained at unselected deliveries, three cord bloods from infants with maternal-fetal blood group incompatibility, and two cord bloods from infants with intrauterine hypoxia. Bilirubin conjugates were not detectable in the healthy adults, maternal blood, or in the cord blood specimens except from infants with blood group incompatibility or intrauterine hypoxia. The two isomeric monoconjugates of bilirubin appeared in serum during the first 24 to 48 postnatal h in both premature and full term infants, followed by the diconjugate on the 3rd day. Conjugated esters accounted for 2 to 5% of the total bilirubin, with the diconjugate constituting 21% of total conjugated pigment (day 3). In all instances, the unconjugated serum bilirubin concentration had increased to at least 2 mg/dl in the course of physiologic neonatal hyperbilirubinemia before bilirubin conjugates became detectable. Both premature and full term human infants displayed the identical pattern of bilirubin conjugation in serum.     

Abnormal results of biochemical liver function tests in breast-fed infants with prolonged indirect hyperbilirubinaemia

To clarify the relationship between hyperbilirubinaemia and abnormal results of biochemical liver function tests in infants with breast milk jaundice (BMJ), 58 breast-fed infants with indirect hyperbilirubinaemia were enrolled in this study. Sera obtained from the above infants were subjected to routine liver function tests. Although serum transaminases were within normal limits in all 58 patients, serum alkaline phosphatase levels were abnormally increased in 13, gamma-glutamyltranspeptidase in 8 and total bile acids in 11 out of all patients examined. A total of 18 (31%) patients had abnormal results in at least one item of the liver function tests. The intrinsic bile acid loading test showed postprandial increases in bile acids in 5 of 16 (31%) patients examined at either 60 or 120 min, while all 13 breast-fed, agematched controls had no abnormal results. The decrease in rate of serum bilirubin levels after the 3-day discontinuation of breast-feeding was significantly less in patients with increased fasting bile acids than in patients with normal fasting levels of serum bile acids. These results may suggest that mild hepatic dysfunction or cholestasis is associated with indirect hyperbilirubinaemia in some infants with BMJ.     

Investigation and outcome of neonatal hepatitis in infants with hypopituitarism

Congenital hypopituitarism is a recognized cause of neonatal hepatitis, but the diagnosis may be difficult to establish even if clinically suspected. In order to determine the natural history of this disorder, the outcome of 12 infants with neonatal hepatitis secondary to hypopituitarism is reviewed. The clinical diagnosis of hypopituitarism was established on a combination of features, which include dysmorphism (4 infants), optic nerve hypoplasia (8 infants), micropenis (5 male infants) and recurrent hypoglycaemia (blood glucose < 2.4 mmol/l (8 infants)). Endocrine investigation revealed low free thyroxine (T4) levels (< 10 pmol/l), with normal thyroid stimulating hormone (TSH) levels (0.4-4.5 mU/l) (11 infants), and serum cortisol levels which were inappropriately low (< 200 nmol/l). In 9 of 12 infants, liver disease resolved within 6 wk following treatment with thyroxine, hydrocortisone and, where appropriate, growth hormone, including Cases 9 and 1 in whom diagnosis and treatment were delayed until 3 mo and 3 y of age, respectively. Liver disease resolved spontaneously in two infants prior to starting hormone replacement therapy (Cases 11, 12), and one male infant (Case 10), in whom the diagnosis and hormone replacement therapy were delayed until 5 y of age, developed cirrhosis and portal hypertension and later underwent liver transplantation. CONCLUSION: The diagnosis of hypopituitarism should always be considered in infants with unexplained neonatal hepatitis. Delay in diagnosis and appropriate treatment was associated with persistently abnormal liver function tests and may lead to irreversible liver disease.     

Transcutaneous bilirubinometry: an evaluation.

The transcutaneous bilirubinometer was evaluated in 60 term and 10 preterm infants. A significant correlation was found between the transcutaneous index and the total serum bilirubin concentration for both term and preterm infants. The reliability of the transcutaneous bilirubinometer as a screening method was confirmed, and index criteria for serum bilirubin analysis have been suggested for term babies. The instrument was precise and accurate and the method both noninvasive and atraumatic. Since individual serum bilirubin levels and the transcutaneous index may correlate poorly the transcutaneous method cannot replace traditional serum bilirubin estimation.     

Jaundice in infancy

Jaundice in infancy may be physiologic or due to a pathologic cause. Fractionation of the serum bilirubin level is the first step in the evaluation. Unconjugated hyperbilirubinemia if left untreated may reach toxic levels. Primary hepatobiliary disorders, as well as infectious, toxic, genetic, and metabolic diseases, may manifest with conjugated hyperbilirubinemia. A carefully organized diagnostic evaluation in a timely fashion allows early identification of treatable disorders. Medical management of the complications of cholestatic liver disease remains a major challenge. Early surgical intervention for biliary atresia and significant advances in hepatic transplantation offer the opportunity for long-term survival for infants with previously fatal liver disorders.