Might Bilirubin Serve as a Natural Antioxidant in Response to Neonatal Encephalopathy?

BACKGROUND: Neonatal asphyxia is often associated with hepatic injury. We hypothesized that this might lead to increased bilirubin concentrations. STUDY DESIGN: Term neonates admitted between January 2015 and April 2017 who remained hospitalized for ≥ 4 days and who had serial serum bilirubin concentrations recorded were divided into those with neonatal encephalopathy (NE) and controls. Serial serum bilirubin concentrations during the first days of life were compared between groups. RESULTS: Twenty-nine neonates with NE and 84 age-matched controls were identified. Mean total serum bilirubin concentrations of NE babies were significantly lower than those controls throughout the first days of life. At 96 hours of age, NE serum bilirubin concentrations were 4.5 (3.2, 5.8) versus controls of 10.5 (9.4, 11.5) mg/dL (p < 0.0001). The mean area under the curve (AUC) for the NE group was 268 (215, 321) versus 663 (608, 718), p < 0.0001, for the control group. All of the NE babies remained below the 40th percentile of the Bhutani curve and none required phototherapy. CONCLUSION: Contrary to our hypothesis, bilirubin concentrations in NE infants are significantly lower than expected during the first 4 days postnatally. We speculate that, under conditions of severe oxidative stress, bilirubin is consumed as an antioxidant.

Glucose-6-Phosphate Dehydrogenase Screening in Israel-Arab and Palestinian-Arab Neonates.

OBJECTIVE: To evaluate the frequency of glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, the incidence of clinically significant jaundice (any serum total bilirubin value >75th percentile on the hour-specific bilirubin nomogram), and the need for phototherapy in the pooled male Israeli-Arab and Palestinian-Arab population born at the Shaare Zedek Medical Center in Jerusalem, Israel. STUDY DESIGN: Quantitative G-6-PD enzyme testing of umbilical cord blood was performed during birth hospitalization. G-6-PD deficiency was defined as any G-6-PD value <7.0 U/gHb. Transcutaneous bilirubin was performed daily during birth hospitalization, with serum total bilirubin testing in those with a transcutaneous bilirubin value >75th percentile. RESULTS: Ten of 286 (3.5%) consecutively delivered male Arab newborns had G-6-PD deficiency. Clinically significant jaundice was higher in the population with G-6-PD deficiency compared with normal controls (relative risk, 3.45; 95% CI, 1.24-9.58). Thirty percent of the newborns with G-6-PD deficiency met American Academy of Pediatrics indications for phototherapy according to the high-risk (middle) curve on the phototherapy graph. CONCLUSION: The frequency of G-6-PD deficiency in the Arab neonatal population delivering at this medical center meets World Health Organization criteria for neonatal G-6-PD screening (3%-5%). As in other ethnic groups, clinically significant jaundice is more frequent in newborns of this ethnic group with G-6-PD deficiency compared with G-6-PD-normal controls. Neonatal G-6-PD screening for both males and females of this population subgroup, in conjunction with parental education regarding the dangers of the condition and its prophylaxis, has now been incorporated into our institution's routine G-6-PD screening program.

Neonatal hyperbilirubinemia in the low-intermediate-risk category on the bilirubin nomogram.

OBJECTIVE: Predischarge bilirubin screening predicts neonatal hyperbilirubinemia. We evaluated the incidence of false-negative bilirubin screening among readmissions for hyperbilirubinemia. METHODS: In healthy term and late preterm, predominantly breastfeeding newborns, predischarge transcutaneous bilirubin values were plotted on the hour of life-specific bilirubin nomogram and confirmed with plasma total bilirubin in those with a transcutaneous reading ≥ 75th percentile, or between the 41st and 75th percentiles in the presence of predictive icterogenic risk factors. False-negative bilirubin screen was defined as a predischarge bilirubin value ≤ 75th percentile in a newborn who was subsequently readmitted for phototherapy. RESULTS: Of a total of 25439 neonates born between 2008 and 2009, 143 (0.56%) were readmitted with a mean plasma total bilirubin of 18.7 ± 1.7 mg/dL at 125 ± 54 hours. False-negative predischarge bilirubin screen was identified in 46 (32.2%). Of these, 6 (4.2%) were in the low-risk zone (≤ 40th percentile, relative risk [RR] = 1) and 40 (28%) in the intermediate-low-risk zone (41st-75th percentile, RR 7.62 [95% confidence interval 3.23-17.96]). Of those in the high-risk zones, 76 (53.1%) were in the intermediate-high-risk zone (76th-95th percentile, RR 25.32 [11.03-58.10]) and 21 (14.7%) in the high-risk zone (>95th percentile, RR 27.78 [11.23-68.70]). CONCLUSIONS: Predischarge bilirubin levels in newborns classified as low risk did not eliminate the risk of readmission for hyperbilirubinemia. All newborns including those at low risk must be vigilantly observed for subsequent hyperbilirubinemia.

Evaluation of discharge management in the prediction of hyperbilirubinemia: the Jerusalem experience.

OBJECTIVE: We evaluated our program for prediction and follow-up of hyperbilirubinemia in preventing plasma total bilirubin (PTB) > or = 25 mg/dL and in limiting readmission for hyperbilirubinemia. STUDY DESIGN: Term and near-term neonates were screened before discharge for risk factors for hyperbilirubinemia. A PTB test was performed when visible jaundice was apparent. Formal postdischarge follow-up was integrated with a possibly unique religious/cultural support system complemented by ritual circumciser (mohel) home visits and a high rate of jaundice awareness in the community. RESULTS: During 2001-2002, 18,079 term and near-term healthy neonates were cared for in our well baby nurseries. Three hundred forty-two (1.9%) were treated with phototherapy, and 4 with exchange transfusion. Seventy-four (21.6%) of these (0.41% of total) were readmitted for hyperbilirubinemia. Forty-two percent of those readmitted had not been regarded as sufficiently jaundiced to warrant a predischarge bilirubin determination. In only 1 neonate did the PTB exceed > or = 25.0 mg/dL (0.006%). No infant had signs of bilirubin encephalopathy. CONCLUSIONS: Our practice was successful in keeping the number of readmitted neonates low and limiting those with extreme hyperbilirubinemia to the minimum. Local customs, rituals, and practices may be successfully adapted as adjuncts in the detection and prevention of hyperbilirubinemia.

Phototherapy and photo-oxidation in premature neonates.

OBJECTIVE: The potential for photo-oxidation during phototherapy in premature neonates was assessed by measuring parameters reflective of photo-oxidation. METHODS: Blood was sampled from premature neonates prior to, and after 4 and 24 h of phototherapy, respectively. Total plasma bilirubin (TPB), blood carboxyhemoglobin corrected for inspired carbon monoxide (COHbc) (a sensitive index of heme catabolism), blood thiobarbituric acid reacting substances (TBARS) (a measure of lipid peroxidation), and plasma protein carbonyls (representative of protein oxidation) were determined. Study measurements were compared with baseline values both for the entire study group, and also individually for subgroups < and > or = 1.5 kg birthweight, respectively. The percentage difference (%delta) between baseline and the 24-hour measurement was calculated for each parameter. RESULTS: Forty-one premature neonates (mean [+/- SD] gestational age 30.5 +/- 2.7 weeks and birthweight 1,499 +/- 448 g) were studied. Mean TPB values decreased from a baseline of 9.1 +/- 2.3 to one of 7.2 +/- 2.8 mg/dl, p < 0.01, during the first 24 h of phototherapy. For the entire patient sample, neither COHbc, TBARS or protein carbonyl values increased significantly over baseline measurements: COHbc: 0.90 +/- 0.26% vs. 0.92 +/- 0.32%; TBARS: 19.0 +/- 5.6 vs. 18.0 +/- 4.5 nmol/ml, and protein carbonyls 7.73 +/- 3.78 vs. 7.63 +/- 3.56 U/ml (baseline and 24-hour samples only are shown in the abstract). Similarly, for the entire group, %delta (mean, interquartile range) were not significantly different between COHbc [-3.77 (-15.89-17.65)%], TBARS [-7.47 (-17.37-7.38)%], and protein carbonyls [-1.47 (-28.51-43.48)%], respectively. For subgroup analysis of neonates < or > or = 1.5 kg birthweight, respectively, no significant increases in COHbc, TBARS or protein carbonyls were documented. A significant increase in %delta for COHbc in the <1.5 kg birthweight subgroup compared with those > or =1.5 kg, possibly indicative of hemolysis, was not matched by similar changes in %delta for TBARS or protein carbonyls, and may therefore not be a result of photo-oxidation. CONCLUSIONS: Except for changes in %delta in COHbc alone and in the smallest babies only, overall, short term phototherapy in premature infants was effective in reducing TPB concentrations without associated evidence reflective of photo-oxidation.

Hyperbilirubinemia among African American, glucose-6-phosphate dehydrogenase-deficient neonates.

BACKGROUND: Although glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is prevalent in African Americans, their risk of associated neonatal hyperbilirubinemia has not been prospectively studied. OBJECTIVE: To compare hemolysis and the risk of hyperbilirubinemia among African American, G-6-PD-deficient neonates (study group) and G-6-PD-normal control subjects. METHODS: Consecutive, healthy, term and near-term, male neonates born to African American mothers comprised the patient cohort. G-6-PD testing was performed with umbilical cord blood samples. Routine management included measurement of the end tidal carbon monoxide level corrected for ambient carbon monoxide level (ETCOc) within 4 hours after delivery (assessment of hemolysis), > or =1 predischarge bilirubin determination, and additional bilirubin testing as clinically indicated. Indications for phototherapy were identical for study patients and control subjects. Neonates were monitored for the first 1 week of life. ETCOc results, the incidence of hyperbilirubinemia (defined as a transcutaneous or plasma total bilirubin concentration of > or =95th percentile for the hour of life), and the need for phototherapy were compared between the G-6-PD-deficient and G-6-PD-normal groups. RESULTS: Five hundred male patients were enrolled, of whom 64 (12.8%) were G-6-PD-deficient. ETCOc values (median and interquartile range) were higher among G-6-PD-deficient neonates than among control neonates (2.4 ppm [2.0-2.9 ppm] vs 2.1 ppm [1.7-2.5 ppm]). More G-6-PD-deficient neonates developed hyperbilirubinemia than did control subjects (14 of 64, 21.9%, vs 29 of 436, 6.7%; relative risk: 3.27; 95% confidence interval: 1.83-5.86), whereas 13 (20.3%) met the criteria for phototherapy, compared with 25 control subjects (5.7%) (relative risk: 3.53; 95% confidence interval: 1.91-6.56). No cases of kernicterus were observed. CONCLUSIONS: Within the African American neonatal population, there is a subgroup of G-6-PD-deficient infants with elevated rates of hemolysis, a higher incidence of hyperbilirubinemia, and a greater requirement for phototherapy, compared with G-6-PD-normal control subjects. These newborns should be monitored vigilantly for the development of hyperbilirubinemia.

Comparative effects of two phototherapy delivery systems on cerebral blood flow velocity in term neonates.

BACKGROUND: Phototherapy is an effective and generally safe method of treating neonatal hyperbilirubinemia. However, there is some concern that it may affect cerebral blood flow velocity (CBFV) in newborns with fragile cerebral vasculature. OBJECTIVES: To measure and compare the effects of two different phototherapy units, delivering similar irradiance, on CBFVs. METHODS: Doppler flow velocities were measured in term infants under fluorescent overhead and fluorescent BiliBed phototherapy units, respectively, at baseline, 4 and 24 h of therapy. RESULTS: Peak systolic CBFV increased during treatment in infants treated under overhead phototherapy (n = 18) but not in those treated in BiliBeds (n = 12). CONCLUSIONS: Different phototherapy delivery modalities can have differential effects on CBFV in term neonates.

Glucose-6-phosphate dehydrogenase deficiency: a hidden risk for kernicterus.

Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, a commonly occurring enzymatic defect, is an important risk factor in the pathogenesis of severe neonatal hyperbilirubinemia. Many of the recently reported cases of kernicterus, even in countries with a low overall incidence of the G-6-PD deficiency such as the United States and Canada, have been found to be enzyme deficient. In many cases the hyperbilirubinemia may be due to acute hemolysis precipitated by exposure to an identifiable chemical trigger, or to infection. In other cases the hemolysis may be mild, the hyperbilirubinemia being due to diminished bilirubin conjugation. An interaction between G-6-PD deficiency and promoter polymorphism for the gene encoding the bilirubin conjugating enzyme, UDP-glucuronosyltranferase 1A1, associated with Gilbert syndrome, has been implicated in the pathogenesis of hyperbilirubinemia. Neonates whose families originated in areas at high risk for G-6-PD deficiency should be vigilantly observed for jaundice. Phototherapy is the mainstay of treatment, with exchange transfusion being performed in those unresponsive to phototherapy. A high degree of physician awareness is essential in the identification and follow-up of these high-risk neonates.

Glucose-6-phosphate dehydrogenase deficiency: a potential source of severe neonatal hyperbilirubinaemia and kernicterus.

Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is a commonly occurring enzyme defect that can lead to severe neonatal hyperbilirubinaemia and kernicterus. Both increased haemolysis, sometimes due to an identifiable chemical trigger or to infection, and diminished bilirubin conjugation, the result of an interaction between G-6-PD deficiency and Gilbert's syndrome, contribute to the pathogenesis of the jaundice. Phototherapy is the mainstay of treatment, with exchange transfusion held in reserve for those neonates who do not respond to phototherapy. Pharmacological agents such as Sn-mesoporphyrins, which prevent bilirubin production by inhibiting the enzyme heme oxygenase, can limit hyperbilirubinaemia and possibly prevent the need for exchange transfusion. Predischarge serum total bilirubin screening is useful in predicting which neonates are at high risk for developing hyperbilirubinaemia. Migration patterns make G-6-PD deficiency a condition which may nowadays be encountered in virtually any corner of the globe and a high degree of physician awareness is essential.