Antioxidant defense systems in newborns undergoing phototherapy

This paper was designed to investigate whether phototherapy is an oxidative stress in newborn infants undergoing phototherapy. A day-light continuous phototherapy was given to jaundiced 20 term and 16 preterm newborns for 72 hours. We measured serum vitamin E and the activities of red blood cell anti-oxidation enzymes (superoxide dismutase, catalase and glutathione peroxidase) before and after 72 h of phototherapy. Serum vitamin E levels were not different before and after 72 h of phototherapy in both preterm and term infants. In several studies, antioxidant enzyme activities have been shown to increase in response to oxidative stresses. In this study, however, the antioxidant enzyme activities in the hemolysate were similar before and at the end of the phototherapy in both preterm and full term. In conclusion, the results of ourin vivo study do not confirm the thesis that phototherapy is an oxidative stress in newborn infants. Therefore, phototherapy would preferably seem to be safe and efficient method of treatment for all neonates presenting with hyperbilirubinemia.     

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.     

Correlation between fetal and maternal serum bile acid concentrations

Serum concentrations of different bile acids (BA) were determined by radioimmunoassay in 56 human fetuses and mothers. Serum was obtained immediately after legal abortion, performed between the 14th and the 21st wk of gestation. Conjugated cholic (CCA) and chenodeoxycholic acid (CCDCA) concentrations were determined in 33 cases, conjugated lithocholic (CLCA) and deoxycholic acid (CDCA) in 20, and sulfolithocholyglycine (SLCG) in 15. In fetal blood, mean concentrations of CCA (0.80 +/- 0.40 mumol/liter), CCDCA (4.50 +/- 2.70 mumol/liter), and CLCA (1.70 +/- 1.04 mumol/liter) were significantly higher than those in the mother (CCA 0.34 +/- 0.17 mumol/liter; CCDCA 0.79 +/- 0.34 mumol/liter; CLCA: 0.70 +/- 0.30 mumol/liter; p less than 0.001); fetal serum levels of CDCA (0.46 +/- 0.32 mumol/liter) and SLCG (0.15 +/- 0.09 mumol/liter) were lower than in the mothers (CDCA 1.20 +/- 0.80 mumol/liter, p less than 0.001; SLCG 0.40 +/- 0.30 mumol/liter, p less than 0.01). There was no correlation between levels of BA and gestational age. Serum total protein and albumin concentrations were both reduced in 10 fetuses as compared with the mothers. These data support the concept of a state of physiologic cholestasis during development and suggest that placental transfer of primary BA occurs mostly in the fetal to maternal direction. This transfer could be facilitated by the reduced fetal plasma albumin concentration, since BA in free solution diffuse more easily through the placenta. There is evidence of lithocholic acid synthesis in the fetal liver, while deoxycholic acid appears to be mostly of maternal origin. Finally, sulfation of BA is poorly developed at this age of gestation.     

Serum Bile Acid Levels in Preoperative and Postoperative Patients with Congenital Biliary Atresia

To elucidate the bile acid metabolism in the preoperative and postoperative stages of congenital biliary atresia (CBA), the unconjugated and conjugated bile acid levels in sera were measured by high performance liquid chromatography (HPLC). The results showed that the mean total serum bile acid (TSBA) level in the preoperative cases of CBA was higher, 122.1±39.0 n?mol/1 (1SD), and was about 12 times higher than the level in the age-matched normal controls (9.9±6.0). Even in the non-icteric patients several years after operation, the mean TSBA level was still much higher (15.2±9.6) than that of normal controls (5.7±3.1). The mean ratio of cholic acid to chenodeoxycholic acid (CA/CDCA) in the preoperative and postoperative cases of CBA was less than 1.0. The mean ratio of glycine-conjugated bile acids to taurine-conjugated bile acids (G/T) in the preoperative cases of CBA was the lowest (1.9±1.1). In the clinically good cases with sufficient bile flow after operation, G/T ratio was the highest (9.3±6.5). In the normal controls and the patients with preoperative and postoperative CBA, the main bile acids were glycocholic acid, taurocholic acid, glycochenodeoxycholic acid and taurochenodeoxycholic acid. These conjugated bile acids comprised more than 85% of the total in amount.     

全自动同步换血治疗新生儿重症高胆红素血症的护理

目的 观察全自动外周动静脉同步换血法治疗重症新生儿高胆红素血症的效果及采取的护理措施.方法 对14例重症高胆红素血症患儿采用外周动静脉全自动同步换血疗法,外周静脉输血,外周动脉抽血,均用输液泵控制,速度200～240 ml/h.置辐射台上保暖,在换血的过程同时采用白光光疗.结果 14例患儿血清总胆红素在换血前为(523±104.3) μmol/L,换血后为(249.8±78.4)μmol/L,两者差异有显著统计学意义(P＜0.01).总胆红素换出率52.2%.结论 输液泵控制的外周动静脉同步换血法简单、实用、安全,是治疗重症新生儿高胆红素血症的有效方法.优良的护理对提高换血成功率,减少并发症起着重要的作用.     

Sister chromatid exchanges in peripheral lymphocytes in newborns treated with phototherapy and vitamin E

A study was undertaken to determine whether blue fluorescent light might affect the sister chromatid exchange (SCE) frequency of peripheral lymphocytes in icteric newborns undergoing continuous phototherapy treatment (72 h). Also, the potential preventive effect of vitamin E on SCE frequency was studied in a subgroup of 11 preterm and 9 fullterm newborns after daily administration of vitamin E (46.44 mumol/kg/d, im). The results revealed that only the preterm icteric newborns showed an increase in mean SCE frequency of peripheral lymphocytes after phototherapy (9%, p = 0.02), but in no case did the highest SCEs/cell ratio exceed the normal values. No correlation was found between the average SCE rate and birth weight, gestational age or bilirubin levels. Also, no difference in SCEs was observed between newborns treated or untreated with vitamin E.     

Maternal and fetal circulation of unusual bile acids: A pilot study

Background: Large amounts of unusual bile acids are synthesized by the fetal liver in late gestation. These compounds are mostly transferred from fetus to mother, although some are excreted into the amniotic fluid. We investigated the role of placental transfer of bile acids in fetal bile acid metabolism, particularly with respect to the unusual bile acids (1β‐hydroxylated and ketonic bile acids). Methods: We measured concentrations of bile acids in umbilical cord blood and urine of newborn infants, and in perinatal maternal serum and urine, using gas chromatography‐mass spectrometry. Serum and urine specimens from healthy non‐pregnant women were used as controls. Results: In newborn infants at delivery, cord blood and urine contained mostly primary and 1β‐hydroxylated bile acids, respectively. We also detected large amounts of ketonic bile acids in their urine, and the urinary concentration of total bile acids was elevated. Main maternal bile acids at 30 and 35 weeks of gestation and at delivery were 1β‐hydroxylated bile acids. After delivery, main bile acids changed from 1β‐hydroxylated bile acids to primary bile acids (P < 0.03), which also predominated in healthy non‐pregnant women. Conclusion: Fetally synthesized unusual bile acids were transported from fetus to mother. Pregnant women appear to excrete these bile acids into the urine, lowering both fetal and maternal serum bile acid concentrations.     

Riboflavin (vitamin B2) treatment of neonatal pathological jaundice

The effect of traditional blue-light and riboflavin combined with blue-light was compared in newborns affected by ABO incompatibility, admitted for exchange transfusion. During the period of preparation for the intervention 14 patients were treated with blue light alone and 14 patients with riboflavin combined with phototherapy. A single dose of 10 mg/kg riboflavin was administered intravenously. The duration of treatment was three hours in both groups. The effect of phototherapy was markedly enhanced by the additional riboflavin, by the end of the 3-hour period a significant fall of serum bilirubin was demonstrated in the 14 patients treated with blue light and riboflavin while in the patients treated with phototherapy alone the bilirubin level continued to rise. There was no difference in the activity of the antioxidant enzymes superoxide dismutase and catalase, and in lipid peroxidation between the groups.     

Simulation of bilirubin detoxification in the newborn using an extracorporeal bilirubin oxidase reactor

Jaundice, which is characterized by an excessive accumulation of bilirubin in the blood and tissues, occurs in 13% of newborns. The common treatments for neonatal jaundice are phototherapy and blood exchange transfusion. A novel approach using an extracorporeal blood filter containing immobilized bilirubin oxidase was recently proposed to detoxify jaundiced blood, and a prototype device markedly reduced serum bilirubin in genetically jaundiced Gunn rats. The primary toxicologic effect in that study was a 20% reduction in red blood cell count. Using a compartmental model for bilirubin metabolism, a mathematical simulation of the extracorporeal treatment's ability to reduce serum bilirubin levels in jaundiced infants is presented. Using a 10-mL reactor volume containing immobilized bilirubin oxidase, the simulation predicts a 32 to 65% decrease in plasma bilirubin concentration over a 4-h treatment for a 2 kg preterm hyperbilirubinemic newborn. In addition, a new approach to altering support material has essentially eliminated red blood cell lysis in vivo using Gunn rats and in vitro using adult blood.     

Cholic acid,chenodeoxycholic acid,alpha-1-fetoprotein and alpha-1-antitrypsin serum concentrations in breast-fed infants with prolonged jaundice

Thirteen breast-fed one-month-old infants with prolonged jaundice not due to known causes were included in this study. All infants were investigated at one and twelve months of age. Serum concentrations of total (TB) and conjugated bilirubin (CB), aspartate (ASAT) and alanine aminotransferase (ALAT), alkaline phosphatase (AP), -1-antitrypsin (-1-AT), -1-fetoprotein (AFP) and the two primary bile acids; cholic (CA) and chenodeoxycholic acid (CDCA) were determined at both ages. The Pi-phenotype of -1-AT was determined at the age of twelve months. The serum concentrations of TB, CB, AP and AFP were elevated at the age of one month but were normal at the age of twelve months. No changes in the serum concentrations of ASAT or ALAT were observed between one and twelve months of age, and the values were within the reference ranges. The serum concentrations of -1-AT were within the reference range at both ages. Two infants were heterozygous for MZ, and they had normal serum -1-AT concentrations. The serum concentrations of CA and CDCA were elevated at the age of one month and were still significantly elevated at the age of twelve months indicating that the infants had slight cholestasis at the age of one month, and that the cholestasis had largely subsided by the end of the first year of life.     

DEPENDENCE OF THE EFFICIENCY OF PHOTOTHERAPY ON PLASMA BILIRUBIN CONCENTRATION

ABSTRACT. 407 newborns with idiopathic transitory hyperbilirubinaemia were examined with regard to the decrease in serum bilirubin levels during 24 hours of intermittent phototherapy (12 hours of light exposure). The photoeffect (i. e. decrease of serum bilirubin concentration after 24 hours of therapy) showed a unique and predictable nonlinear correlation with the plasma bilirubin concentration before treatment. This relationship can be used for individualizing the duration of phototherapy and the dose of light. The apparent effect of birth weight, gestational age, and postnatal age on the efficiency of phototreatment is only due to differing initial levels of bilirubin concentration. Intermittent illumination seemed to be more efficient than continuous.     

CHOLIC ACID AND CHENODEOXYCHOLIC ACID CONCENTRATIONS IN SERUM DURING INFANCY AND CHILDHOOD

Abstract. Heikura, S., Similä, S., Finni, K., Mäentausta, O. and Jänne, O. (Departments of Clinical Chemistry, Biochemistry and Paediatrics, University of Oulu, Oulu, Finland). Cholic acid and chenodeoxycholic acid concentrations in serum during infancy and childhood. Acta Paediatr Scand, 69: 659, 1980.—Concentrations of two primary bile acids (cholic and chenodeoxycholic acids) were determined by radioimmunoassay in the serum of infants and children at ages ranging from 1 hour to 15 years. The same bile acids were also measured in umbilical cord serum. Concentrations of the primary bile acids were significantly higher in the serum of 1-hour old infants than those in the umbilical cord serum or the peripheral vein serum of adults. The levels of cholic and chenodeoxycholic acid remained high until the age of 6 months, being about 5-fold higher than those in the sera of adults. Primary bile acid concentrations reached the adult level by the age of 1–2 years. These results indicate that developmental changes occur in the metabolism and excretion of bile acids in man. The relatively high concentrations of the primary bile acids in serum during the first 6 months of life suggest that up to this age, the mature ability of the liver to excrete the bile salts into the bile and/or to clear them from the circulation has not yet been reached.     

Perinatal bile acid metabolism: analysis of urinary unsaturated ketonic bile acids in preterm and full-term infants

AIM: To compare urinary concentrations of unsaturated ketonic bile acids in preterm and full-term infants. METHODS: Urinary unsaturated ketonic bile acids were determined using gas chromatography-mass spectrometry. RESULTS: Urinary concentrations of total bile acids in early preterm infants (of less than 29wk gestational age) exceeded concentrations in late preterm (between 30 and 37 wk) and full-term infants (between 38 and 41 wk; p < 0.01). The percentage of ketonic bile acids (7alpha, 12alpha-dihydroxy-3-oxo-4-cholenoic acid and 7alpha-hydroxy-3-oxo-4-cholenoic acid) among total urinary bile acids in full-term infants (20.2 +/- 14.1%) was higher than that in early preterm infants (8.94 +/- 8.1%; p < 0.05). The percentage of unsaturated bile acids (3beta-hydroxy-delta5-bile acids) among total bile acids in urine did not differ greatly between groups. CONCLUSION: The percentage of 3-oxo-delta4 bile acids among total bile acids in urine gradually increased from early to late preterm infants, while healthy full-term infants excreted large amounts of 3-oxo-delta4 bile acids in urine at delivery.     

SERUM BILE ACIDS IN NEWBORNS: EVIDENCE FOR AN HEPATIC DYSFUNCTION IN LOW-BIRTH-WEIGHT INFANTS

ABSTRACT. The post-prandial pattern of total serum bile acids was studied in 47 newborns: 12 prematures (less than 36 weeks), 17 term low-birth-weight infants (less than the 3rd percentile), 18 term normals. The study was made at the end of the first month. Blood was collected in a peripheral vein using a microcatheter. Samples were taken at fasting time and 30, 60, 120, 180 min after a test meal intake (40 ml/kg of "humanized" milk based formula). Bile acids were assayed using an original enzymatic micromethod which needed only 50 μl of serum and showed a sensitivity of 0.3 pmol in 200 μl of reaction medium. The response of serum bile acids after the test meal was very similar in normal term newborns and in adults. Prematures exhibited bile acid levels slightly higher than normals, but this difference was significant only at 0 and 180 min. Low-birth-weight infants showed very high values of serum bile acids at all times during the test, compared to normal and premature infants. Serum levels of total bilirubin and alkaline phosphatase were similar in all 3 groups. These results are not consistent with cholestasis but rather indicate a specific dysfunction in bile acid metabolism in low-birth-weight infants.     

Serum thyroxine and triiodothyronine levels in newborns: effect of gestational age

Serum T₄ and T₃ were measured in 31 newborns of gestational ages 32–43 weeks. Out of 31, 11 were term, 12 preterm and 8 postterm. Blood samples were taken from cord blood and from peripheral vein at 24 and 72 hours of age. Serum T₄ and T₃ values were low in cord blood samples, raised in 24 hours samples and then declined in 72 hour samples. In pretern newborns cord T₄ and T₃ values were significantly lower and there was a blunted rise and fall in 24 and 72 hours samples as compared to term newborns. In post term newborns cord serum T₄ and T₃ values were significantly raised while in peripheral vein samples difference was statistically insignificant as compared to term newborns. This high incidence of low cord values and transient hypothyroxinemia observed in preterm and postnatal surge of T₄ may give rise to false results while screening for hypothyroidism.     

Development of Bile Acid Metabolism in Neonates during Perinatal Period Part 1: Bile acid levels in sera of Mothers, fetuses and neonates

To eluidate the development of bile acid metabolism in neonates during the perinatal period, the present author measured the bile acid levels in amniotic fludis and sera of mothers, umbilical cords and neonates. The subjects were 166 samples of amniotic fluids and sera of mothers, umbilical cords and neonates (at 2 days, 1 week, 2 weeks, 3 weeks and 4 weeks of life). The bile acid levels in amniotic fluids were measured by radioimmunoassay (RIA) and the levels in sear were measured by high-performance liquid chromatography (HPLC). Total chenodeoxycholic acid (unconjugated chenodeoxycholic acid (free CDC), glycochenodeoxycholic acid (GCDCA) and taurochenodeoxycholi acid (TCDCA)) were predominant in amniotic fluids and sera of early neonates before 1 week of life. Total bile acid (TBA) levels gradually increased for 4 weeks after birth. The mean glycine to taurine (G/T) conjugation ratio of bile acids of mothers was higher than that of umbilical cords and early neonates before 1 week of life. The mean conjugation rate of bile acids in sera of neonates at 1 week after birth was higher than that of mothers and umbilical cords. There were distinct individualities in TBA levels, the presene of lithocholic acid (LCA), total cholic acid to total chenodeoxycholic acid (CA/CDCA) ratio and G/T ratio at the same age, and in bile acid patterns in the same pair of mothers and umbilical cords.     

High-dose intravenous immunoglobulin therapy in neonatal immune haemolytic jaundice

A controlled study was conducted to assess the role of high-dose i.v. immunoglobulin (HDIVIG) therapy in neonatal immune haemolytic jaundice. Patients with ABO and/or Rh incompatibilities proved by significant hyperbilirubinaemia (>204 mmol l(-1)), positive direct antiglobulin test and high reticulocyte count (> or =10%) were randomly assigned to receive either conventional phototherapy alone or phototherapy with high-dose i.v. immunoglobulin (1 g kg(-1), over 4 h) as soon as the diagnosis was established. Exchange transfusions were performed if serum bilirubin concentrations exceeded 290 mmol l(-1) and increased by more than 17 mmol l(-1) per h despite both treatment manoeuvres. Eight of 58 patients in the HDIVIG group required exchange transfusions, whereas it became necessary in 22 of 58 patients in the control group (p<0.001). The durations of phototherapy and hospitalization in terms of hours were significantly shorter in the HDIVIG group (p<0.05). No side effects of HDIVIG therapy were observed. In conclusion, HDIVIG therapy in newborns with ABO or Rh haemolytic diseases reduces haemolysis, serum bilirubin levels and the need for blood exchange transfusion, a procedure which has potential complications and carries a risk of mortality.     

Evaluation of the pituitary-thyroidal axis in newborns undergoing exchange transfusion

To evaluate whether the hypothyroxinaemia, previously noted in hyperbilirubinaemic newborns immediately after exchange transfusion for Rh or AB0 incompatibility, was due to impairment in the secretion of thyroid stimulating hormone (TSH) by the pituitary, we studied the thyroid hormone response to thyrotropin releasing hormone (TRH) and compared this response to that seen in a control population of healthy neonates. All infants studied responded with a brisk TSH increase; 30 min after TRH injection the mean TSH concentration of the hyperbilirubinaemic patients was 37 U/ml, ten times their basal level, which was not different from the value noted in the control population.No significant change in total thyroxine (T₄), 3,5,3 triiodothyronine (T₃), free thyroxine (FT₄) or 3,3,5 triiodothyronine (rT₃), (FT₄) or (rT₃) was noted after TRH administration in either group of neonates. In addition the effect of exchange transfusion on the thyroid axis of hyperbilirubinaemic newborns was evaluated. Before the exchange transfusion TSH, T₄, rT₃, T₃ and FT₄ levels were higher in the hyperbilirubinaemic newborns than in donor blood; immediately post-exchange transfusion TSH and T₄ concentrations of the hyperbilirubinaemic neonates decreased significantly and remained significantly below pre-exchange values 30h later.Newborns undergoing an exchange transfusion respond appropriately to TRH stimulation and seem to have an intact pituitary-thyroidal axis.Abbreviations T₄ total thyroxine - FT₄ free thyroxine - T₃ (Ru) T₃ resin uptake - T₃ 3,5,3 triiodothyronine - rT₃ 3,3,5triiodothyronine - TSH thyroid stimulating hormone - TRH thyrotropin releasing hormone - RIA radioimmunoassay     

Alpha fetoprotein levels in neonatal hyperbilirubinaemia

Serum alpha fetoprotein (AFP) levels were studied in 15 neonatally hyperbilirubinaemic children and 15 controls matched for sex and gestational age. All children were born between 38 and 40 weeks of gestation. During the first seven weeks of postnatal life hyperbilirubinaemic children had serum AFP concentrations over twice as high as controls. At the age of 5-7 days the mean (+/- S.E.M.) serum AFP values were 52.4 +/- 5.8 mg/l for hyperbilirubinaemic children and 24.8 +/- 4.3 mg/l for controls (p less than 0.001). At 20-25 days of age they were 7.28 +/- 1.10 and 2.75 +/- 0.45 mg/l, respectively (p less than 0.001), and at 40-49 days 1.39 +/- 0.21 and 0.46 +/- 0.07 mg/l (p less than 0.001). However, no correlation was found between serum bilirubin and AFP concentrations in hyperbilirubinaemic children.     

Effect of clofibrate in non-hemolytic indirect hyperbilirubinemia in full term neonates

Objective Jaundice is a common clinical problem in neonatal period which may result in brain damage even in healthy full term newborns, when it is severe. The aim of this study was to characterize the therapeutic effect of clofibrate in full term neonates who present with nonhemolytic jaundice. Methods A clinical controlled study was performed on 60 full term neonates who presented with non-hemolytic jaundice. 30 neonates were treated with a single oral dose of clofibrate (100 mg/Kg) plus phototherapy (case group), while 30 neonates received only phototherapy (control group). Both groups were compared in regard to post therapeutic mean total and indirect plasma bilirubin levels, admission duration and the rate of exchange transfusion. Results The reduction rate of total and indirect plasma bilirubin levels were significantly higher in the clofibrate-treated group as compared with the control group (P<0.05). The mean duration of admission was found to be reduced from 2.9 +/− 0.9 days in the control groupl to 2.2 +/− 0.6 days in clofibrate-treated group (P=0.002). The mean plasma total bilirubin level was lower in the clofibrate-treated group. No cases required phototherapy after 48 hour in clofibrate-treated group, while 9 neonates (30%) and 2 neonates (6.7%) required phototherapy after 72 hour and 96 hour respectively in the control group. There was no difference between both the groups for sex, the time of developing jaundice and the rate of exchange transfusion. Conclusion A single dose of clofibrate (100 mg/Kg) alongwith phototherapy is more effective than phototherapy alone in treating non-hemolytic hyperbilirubinemia in term healthy newborn infants.