Current status of neonatal jaundice management in Japan.

BACKGROUND: This nationwide survey aimed to determine the status of jaundice management in Japan. METHODS: A questionnaire about bilirubin level measurements and neonatal jaundice treatment was sent to 330 institutions providing neonatal care. The responses were analyzed according to institution level. RESULTS: Of 330 institutions, 172 responded (52.1% response rate). Total bilirubin levels were measured in the central laboratory using spectrophotometry at 134 institutions and a blood gas analyzer at 81 institutions. Unbound bilirubin (UB) levels were measured by 79 institutions, while transcutaneous bilirubin measurements were taken at 63 institutions. There was no association between institution level and UB or transcutaneous bilirubin measurement. For phototherapy criteria, the Murata-Imura criteria were adopted by 67 institutions, Nakamura criteria by 36, and Morioka criteria by 39. Light-emitting diodes (LED) were used by 160 institutions versus fluorescent lights by 31. When a blue LED was used, 119 institutions used the high mode. There is no standard for increasing light intensity. No association was found between institution level and phototherapy criteria. UB was measured in 14 of 63 institutions using the Murata-Imura criteria. CONCLUSIONS: There is a large variation in the management and treatment of neonatal jaundice among institutes in Japan.

Quantitative effects of bilirubin structural photoisomers on the measurement of direct bilirubin via the vanadate oxidation method.

BACKGROUND: Exposing blood serum samples to ambient white light-emitting diode (WLED) light may accelerate bilirubin photoisomer production. We previously demonstrated the quantitative effect of bilirubin configurational isomers (BCI) on direct bilirubin (DB) value using the vanadate oxidation method. However, the effects of bilirubin structural photoisomers (BSI) remain unclear. METHODS: In Study 1, the relationship between WLED irradiation time and BSI production was examined. Serum samples from five neonates were irradiated with WLED light for 0, 10, 30, 60 and 180 min. Bilirubin isomer concentration and BSI production rates were calculated. In Study 2, we performed quantitative investigation of BSI effect on DB values: Differences in DB, BCI and BSI values before and after irradiation were calculated as ⊿DB, ⊿BCI and ⊿BSI, respectively. Assuming the coefficient of BCI affecting DB values was 'a', relational expression was ⊿DB = a*⊿BSI + 0.19*⊿BCI. Serum samples from 15 neonates were irradiated with green LED light for 10 and 30 s. The respective bilirubin isomer levels were measured, and the coefficient was derived. RESULTS: In Study 1, the median BSI production rate was 0.022 mg/dL per min in specimens with an unconjugated bilirubin concentration of 10.88 mg/dL. In Study 2, assuming that ⊿DB-0.19*⊿BCI was Y and ⊿BSI was X, the relational expression was Y = 0.34X-0.03 (R2 = 0.87; p < .01) and a = 0.34. CONCLUSIONS: Under ambient WLED light, serum sample generated 1.3 mg/dL BSIs in 1 h. Approximately 34% (0.44 mg/dL) of BSI concentrations was measured as DB when using the vanadate oxidation method according to the above equation.

Transcutaneous bilirubin-based screening reduces the need for blood exchange transfusion in Myanmar newborns: A single-center, retrospective study.

Background: Neonatal hyperbilirubinemia is a significant health problem in Myanmar. We introduced transcutaneous bilirubin (TcB) measurements in 2017 and developed an hour-specific TcB nomogram for early detection and treatment of hyperbilirubinemia in Myanmar neonates. This study aimed to evaluate whether our screening method for hyperbilirubinemia decreased the requirement of blood exchange therapy (ET). Methods: This retrospective cohort study was conducted at the Central Women's Hospital, Yangon. Two groups were included as follows: group 1 (control group; comprising infants born in 2016 and screened on the basis of Kramer's rule), and group 2 (intervention group; comprising infants born in 2019 and screened by TcB measurement using a nomogram). The number of ETs was analyzed based on causes of hyperbilirubinemia and number of days after birth. Results: Groups 1 and 2 comprised 12,968 and 10,090 infants, respectively. Forty-six and two infants in Groups 1 and 2, respectively, required an ET. The odds ratio for ET was 18.0 (Group 1 to Group 2; 95% confidence interval [CI]: 4.8-67.1; p = 0.000). Serum bilirubin values at the time ET was administered were significantly higher in Group 1 than those in Group 2 (median: 23.0 and 16.8, respectively). Conclusion: The management of hyperbilirubinemia using our screening method (TcB Nomogram) can effectively reduce the need for ET in neonates in Myanmar.

The Trajectory of Expressed Colostrum Volume in the First 48 Hours Postpartum: An Observational Study.

Objective: Colostrum, the first form of human milk, is strongly encouraged for infants due to its benefits. During the early postpartum (PP) period, the secreted colostrum volume can be minimal, causing concerns among mothers about sufficient milk supply. Few studies have examined temporal changes in the colostrum. This study aimed to elucidate the trajectory of expressed colostrum volume in the first 48 hours after delivery. Materials and Methods: This was a cross-sectional observational study performed at Kagawa National Children's Hospital. One hundred five mothers who did not directly breastfeed in the first 48 hours after delivery were enrolled in the study. Well-trained midwives instructed the mothers on how to express human milk, and mothers started to express as soon as possible after delivery. Mothers were advised to express human milk every 3 hours, and the milk volume was measured. Results: Within 3 hours PP, 60% of mothers expressed milk, and the median frequency of expression was 14 (interquartile range, 11-16) times in the first 48 hours. At 0-3 and 3-6 hours PP, the volume of initially expressed milk was 0.4 (0.0-2.0) mL and 1.0 (0.0-6.0) mL, respectively. Subsequently, milk volume decreased. The volume remained low until 30 hours PP and increased dramatically; this phenomenon is termed secretory activation, which began later in primiparous women than in multiparous women. Conclusion: The decline in expressed milk volume during the early PP period caused concern among mothers. Therefore, mothers should be informed of the PP trajectory of human milk volume.

Neonatal Jaundice in Preterm Infants with Bilirubin Encephalopathy.

INTRODUCTION: The aim of this study is to clarify bilirubin parameters and its treatment in preterm infants with bilirubin encephalopathy (pBE). METHODS: We asked the responders to an earlier nationwide Japanese survey on pBE to provide additional information. pBE was diagnosed based on the criteria used in the nationwide survey. We collected data on serum total bilirubin (TB), direct bilirubin (DB), albumin, and unbound bilirubin (UB) levels during the first 8 weeks of life, and on phototherapy and exchange transfusion treatments. RESULTS: We obtained clinical data from 75 patients with pBE from 58 hospitals (response rate of 59%), who were born between 2002 and 2016. The average peak TB level was 12.6 mg/dL (215 µmol/L), and the average age at peak attainment was 19.7 days after birth. Albumin level was <2.5 g/dL in 44 patients, and the peak DB level was ≥2 mg/dL (34.2 µmol/L) in 20 patients. The average peak bilirubin/albumin (B/A) (mg/g) ratio was 3.8 (molar ratio of 0.475), and the average age at peak attainment was 18.6 days. The average peak UB level was 0.67 µg/dL (11.5 nmol/L). The median duration of phototherapy was 6 days, and the median day of the last session was 12. The peak TB level occurred after the last day of phototherapy in 30 of the 61 patients available for comparison. CONCLUSIONS: Most patients with pBE lacked marked elevations in serum TB levels and the B/A ratio, the peaks of which were sometimes delayed to >4 weeks after birth.

Characteristics of bilirubin photochemical changes under green light-emitting diodes in humans compared with animal species.

Phototherapy using light-emitting diodes (LEDs) centered on the green spectrum, which has a high cyclobilirubin production rate, was as effective as that centered on the blue spectrum for neonatal hyperbilirubinemia. There are no reports of species differences in bilirubin photochemical changes in this spectrum, and the characteristics of bilirubin photochemical changes in humans must be elucidated to proceed with the development of new light sources that include these spectra. This report describes the characteristic photochemical kinetics of bilirubin under green-spectrum LEDs in human, rat, rabbit, dog, pig, sheep, bovine and chicken serum albumin and rhesus monkey serum. These albumin-bilirubin complex solutions were irradiated by green LEDs, and the time-course changes in bilirubin photoisomers were measured by high-performance liquid chromatography. The cyclobilirubin production rates in humans, pigs, and monkeys were significantly higher than those in other species. The rate constant of (EZ)-cyclobilirubin production from (EZ)-bilirubin 'k' was significantly higher in humans and monkeys than in other species. In conclusion, bilirubin photochemical kinetics under green spectrum LEDs in humans were characterized by a high cyclobilirubin production rate at a low substrate concentration. The bilirubin photochemical kinetics in monkeys were similar to those in humans.

Green light-emitting diode phototherapy for neonatal hyperbilirubinemia: Randomized controlled trial.

BACKGROUND: The main photochemical pathway in phototherapy for neonatal hyperbilirubinemia is the production and elimination (in bile or urine) of cyclobilirubin, which is a structural photoisomer of bilirubin, and which is most efficiently produced by green light. Green light-emitting diode (LED) phototherapy, however, has not been evaluated in the clinical setting because it is not recommended in American Academy of Pediatrics guidelines. We therefore compared the efficacy of green LED phototherapy and blue LED phototherapy in patients with neonatal hyperbilirubinemia. METHODS: In this prospective randomized controlled trial, neonates with hyperbilirubinemia were randomly allocated to a green LED or blue LED phototherapy group. Both groups underwent 24 h of phototherapy, and blood was sampled before and after 24 h of phototherapy. Total serum bilirubin (TSB) was measured using enzymatic methods and bilirubin photoisomers were measured on high-performance liquid chromatography. RESULTS: Thirty-four infants were randomized (green, n = 16; blue, n = 18). TSB decreased significantly from 15.3 ± 1.5 to 13.9 ± 1.5 mg/dL in the green LED group (P < 0.01) and from 16.2 ± 1.3 to 14.5 ± 1.7 mg/dL in the blue LED group (P < 0.01) after 24 h of phototherapy. No significant difference was found in TSB reduction after phototherapy between the groups. CONCLUSIONS: Both light sources produced a significant reduction in TSB, indicating clinical effectiveness.

Bilirubin photoisomers in rhesus monkey serum.

As rhesus monkeys exhibit physiological jaundice during the neonatal period, we used rhesus monkey serum to examine changes in bilirubin photoisomers. Bilirubin-rhesus monkey serum solution was irradiated with blue light-emitting diode, and changes in the absorbance and bilirubin fraction were compared with those in bilirubin- human serum albumin (HSA) and bilirubin-rat albumin solutions. The λmax decreased with light irradiation. The mean production rate of cyclobilirubin IXα was 1.98, 199 and 0.76 × 10-2/min in rhesus monkey serum, HSA and rat albumin, respectively. There was no significant difference between rhesus monkey serum and HSA. The (ZE)-bilirubin IXα/(ZZ)-bilirubin IXα ratio was 0.33, 0.45, and 0.10, respectively, differing significantly among the groups. The (EZ)-bilirubin IXα/(ZZ)-bilirubin IXα ratio was 0.020, 0.010, and 0.062, respectively, with no significant difference between rhesus monkey serum and HSA. The production rate of (EZ)-cyclobilirubin XIIIα(= (ZE)-cyclobilirubin XIIIα) was 0.73, 1.60, and 0.51 × 10-2/min, respectively, with differing significantly among the groups. The (EZ)-bilirubin IIIα/(ZZ)-bilirubin IIIα ratio was significantly different among the groups at 0.20, 0.38, and 0.15, respectively. This is the first report demonstrating the photoisomerization of bilirubin in rhesus monkey serum and the animal with the same cyclobilirubin production rate as HSA.Rhesus monkeys may be used as an animal model for neonatal hyperbilirubinemia in humans to evaluate the efficacy of phototherapy.

Case of pediatric traditional serrated adenoma resected via endoscopic submucosal dissection.

Traditional serrated adenoma (TSA) is a type of serrated polyp of the colorectum and is thought to be a precancerous lesion. There are three types of serrated polyps, namely, hyperplastic polyps, sessile serrated adenomas/polyps, and TSAs. TSA is the least common of the three types and accounts for about 5% of serrated polyps. Here we report a pediatric case of TSA that was successfully resected by endoscopic submucosal dissection (ESD). This rare case report describes a pediatric patient with no family history of colonic polyp who was admitted to our hospital with hematochezia. On colonoscopy, we found a polypoid lesion measuring 10 mm in diameter in the lower rectum. We selected ESD as a surgical option for en bloc resection, and histopathological examination revealed TSA. The findings in this case suggest that TSA with precancerous potential can occur in children, and that ESD is useful for treating this lesion.

Phototherapy for neonatal hyperbilirubinemia.

Approximately 60 years ago in England, phototherapy for neonatal hyperbilirubinemia was used in clinical practice. It was introduced in Japan approximately 50 years ago. At that time, the mechanism underlying the serum bilirubin concentration decrease by phototherapy was still unknown. The mechanism was identified by chemists, biochemists, and pediatricians. Clarification started with the report that unconjugated bilirubin was excreted into bile after photoirradiation in Gunn rats. After confirmation of the molecular structure of bilirubin on X-ray analysis, the mechanism for bile excretion of unconjugated bilirubin was verified based on geometric configurational photoisomers in the Gunn rat. Finally, the reaction and excretion of structural bilirubin photoisomers was proved to be the main mechanism for the decrease in serum bilirubin during phototherapy for neonatal hyperbilirubinemia, which differs from the mechanism in the Gunn rat. The most effective and safest light source and the optimal method to evaluate phototherapy, however, remain unknown. Moreover, as for bronze baby syndrome, which is a well-known adverse reaction to phototherapy, the etiology is unclear. Hence, we review phototherapy for hyperbilirubinemia including a fundamental understanding of the bilirubin photochemical reactions, and discuss the subclinical carcinogenic risk of phototherapy and the increased mortality rate of extremely low-birthweight infants due to aggressive phototherapy, which is becoming an increasing problem.

Influence of bilirubin photoisomers on unbound bilirubin measurement in clinical settings.

BACKGROUND: Measured unbound bilirubin concentration is influenced by bilirubin photoisomers. Bilirubin photoisomers are produced even with only a slight light exposure, and clinical samples are inevitably exposed to light. The objective of the study was to evaluate the influence of bilirubin photoisomers on the measurement of unbound bilirubin using serum of jaundiced neonates during blue light phototherapy. METHODS: Five neonates treated with phototherapy for hyperbilirubinaemia were enrolled. The samples were taken 12 h after initiation of phototherapy. Samples were processed by irradiation with blue light, by indoor ceiling light, by both blue light and indoor ceiling light or shaded. Bilirubin subfractions, total bilirubin and unbound bilirubin were measured. RESULTS: Compared with the non-irradiated samples, the (EZ)-cyclobilirubin concentration and (ZE)-bilirubin/(ZZ)-bilirubin ratio significantly increased in the blue light-irradiated samples, the (ZE)-bilirubin/(ZZ)-bilirubin ratio significantly increased in the indoor ceiling light-irradiated samples, and the (EZ)-cyclobilirubin, (EZ)-bilirubin and (ZE)-bilirubin/(ZZ)-bilirubin ratio significantly increased in the samples irradiated with both lights. No change was noted in unbound bilirubin in any group. CONCLUSIONS: We consider that changes in bilirubin photoisomers induced by light exposure during clinical practice do not influence the measured unbound bilirubin concentration.

Management of phototherapy for neonatal hyperbilirubinemia: is a new radiometer applicable for all wavelengths and light source types?

BACKGROUND: To evaluate the clinical effects of phototherapy for neonatal hyperbilirubinemia, it is necessary to measure the rate of cyclobilirubin production, which represents the main photochemical pathway of bilirubin metabolism. Since the Atom Phototherapy Analyzer can be used to calculate the theoretical relative light energy of irradiance as a means of assessing the cyclobilirubin production rate for each wavelength spectrum, the clinical effect of phototherapy can be evaluated regardless of the light source type. Using the Atom Phototherapy Analyzer, the correlation between the irradiance of various light sources with different peak wavelengths and the rate of cyclobilirubin production was investigated in vitro. We also investigated the utility of green LED in vitro. METHODS: A bilirubin-albumin complex solution was prepared, poured into tubes, and irradiated using various light sources. All light sources used were bed-type phototherapy devices; that is, green and blue LED and green and blue fluorescence tubes. The concentrations of photoisomers were measured after irradiation and compared with the irradiance of the light sources. RESULTS: The irradiance measured by the Atom Phototherapy Analyzer decreased in the following order: blue fluorescence tube > green LED > blue LED > green fluorescence tube. The cyclobilirubin production rates and irradiance values of the light sources were significantly positively correlated (R(2) = 0.93, P < 0.05). CONCLUSION: Our data indicate that the Atom Phototherapy Analyzer can be used to objectively evaluate the effects of phototherapy using various light sources. Further, the effects of green LED were similar to those of other light sources in vitro.

Extrauterine environment affects the cortical responses to verbal stimulation in preterm infants.

Using optical topography, changes in the cerebral oxygenation were compared in the parieto-temporal lobe of preterm and term infants of equal postconceptional age in response to verbal stimulation. Eight preterm infants of gestational age 23-34 weeks were studied at postconceptional term age (38-46 weeks). Ten term infants were studied at 2-11 days after birth. Twenty-four-channel near-infrared optical topography (NIOT) was used to measure changes in concentration of oxyhemoglobin ([oxyHb]), deoxyhemoglobin ([deoxyHb]) and total hemoglobin ([totalHb]) in the bilateral temporal cortices. Verbal stimulation was provided by a recording of a Japanese fairy tale. The latency in response to verbal stimulation was significantly shorter in the preterm infants than in the term infants. This time is thought to reflect brain development, particularly the development of the neuro-vascular coupling mechanisms in the cerebral cortex. The present results indicate that the number of days after birth is more closely related to development of auditory system and neuro-vascular coupling than is postconceptional age. Thus, this suggests that early extrauterine environment affects the cortical responses to verbal stimulation in preterm infants.

In vitro production of bilirubin photoisomers by light irradiation using neoBLUE.

BACKGROUND: The light-emitting diode is used as one of the new light sources for phototherapy. NeoBLUE (Atom Medical, Tokyo, Japan) incorporates blue light-emitting diodes for the treatment of neonatal hyperbilirubinemia. The authors compared the in vitro efficacy of neoBLUE with conventional phototherapy devices. METHODS: The three light devices used included neoBLUE and two conventional phototherapy devices with six blue-white (BW) or six green (GR) fluorescent tubes. A bilirubin/human serum albumin solution (15 mg/dL) in 200 x 300 mm elliptical bag was irradiated with each three light device. The average light intensity of neoBLUE, BW and GR was 22.5, 10.2 and 2.6 microW/cm(2) per nm, respectively, for the irradiated area. Bilirubin photoisomers and native bilirubin were measured by high-performance liquid chromatography. RESULTS: In neoBLUE, BW and GR, the respective production rate of cyclobilirubin was 6.0, 3.7 and 3.9 x 10(-2) mg/dL/min, and the respective (4Z, 15E)-bilirubin/(4Z, 15Z)-bilirubin ratio after irradiation was 0.44, 0.33 and 0.12; the (4Z, 15Z)-bilirubin reduction rate at 20 min after irradiation was 60, 68 and 82%, respectively. The reduction rate of (4Z, 15Z)-bilirubin correlated with the (4Z, 15E)-bilirubin/(4Z, 15Z)-bilirubin ratio. CONCLUSION: Phototherapy using the neoBLUE under high level may be clinically more effective than therapy using the conventional light source from the results of the production rate of cyclobilirubin.

Developmental changes in serum half-life of (EZ)-cyclobilirubin.

BACKGROUND: Phototherapy has been a standard treatment for neonatal hyperbilirubinemia for more than 40 years, but it has remained sub-optimal. AIMS: To clarify the developmental changes in parameters of (4E, 15Z)-cyclobilirubin ((EZ)-C) elimination in order to obtain basic data for establishing optimal phototherapy. STUDY DESIGN: Blood samples were taken at regular intervals after stopping phototherapy, and bilirubin fractions were analyzed by high-performance liquid chromatography. SUBJECTS AND METHODS: The subjects were 46 infants with hyperbilirubinemia who underwent phototherapy. The gestational age and birth weight of the subjects ranged from 25.0 to 41.0 weeks and from 656 to 3810 g, respectively, and the age at cessation of phototherapy was a median of 5 days. A kinetic model of (EZ)-C elimination was established, and the serum half-life of (EZ)-C was calculated on the basis of the determined model. Relationships of the half-life of (EZ)-C with birth weight and gestational age were investigated. RESULTS: Serum (EZ)-C elimination followed a first-order kinetic model in 43 infants and a zero-order kinetic model in three extremely low birth weight infants. The half-life of (EZ)-C calculated on the basis of a first-order elimination model in serum ranged from 68 to 274 min and showed weak negative correlations with birth weight and gestational age. CONCLUSIONS: Serum (EZ)-C excretion followed a first-order kinetic model in most of the neonates. The half-life of (EZ)-C becomes more prolonged in the very low birth weight infant and early gestational age.

Change of bilirubin photoisomers in the urine and serum before and after phototherapy compared with light source.

BACKGROUND: The clinical effect of phototherapy for neonatal hyperbilirubinemia is based on the production and elimination of cyclobilirubin. Generally, the clinical effect of light sources is estimated by the reduction in the total serum bilirubin level. One procedure with less invasiveness than blood collecting is urine collection. Whether the effectiveness of light sources used for phototherapy could be assessed using measurements of bilirubin photoisomers in urine was studied. METHODS: This study was a retrospective analysis of 38 term infants with hyperbilirubinemia who underwent phototherapy. Bilirubin fractions in serum and urine before and 24 h after the phototherapy were measured by high-performance liquid chromatography. The light sources used for the phototherapy were blue-white light (n = 11), Biliblanket plus high output (n = 13) or green light (n = 14). The relationships between serum and urine bilirubin photoisomers after phototherapy and whether the levels of urine bilirubin photoisomer are affected by the light sources with different wavelength characteristic were analyzed. RESULTS: There was no correlation between serum (ZE)-bilirubin and urine configurational isomers, but a weak positive correlation between serum (EZ)-cyclobilirubin and urine structural isomers after phototherapy. Although serum (ZE)-bilirubin levels depended on the wavelength characteristic of each light source during phototherapy, the urine configurational isomer levels did not depend on it. The increase in serum (EZ)-cyclobilirubin levels and the urine structural isomer levels were mostly in agreement. CONCLUSIONS: The urine bilirubin structural isomers may be used to estimate the serum (EZ)-cyclobilirubin levels and to evaluate the clinical effects of light sources.