Japanese Neonates Research Articles

Cord blood triglyceride and total cholesterol in preterm and term neonates: reference values and associated factors from the Japan Environment and Children's Study.

This study aimed to investigate the associations between cord serum total cholesterol (TC) and triglyceride (TG)levels and perinatal factors and determine the reference levels of cord blood TC and TG in Japanese neonates. This was a prospective birth cohort study using data from the Japan Environment and Children's Study, which included data on births from 2011 to 2014 in Japan. TC and TG levels were determined in cord blood samples. A total of 70,535 pairs of neonates (male: 36,001, female: 34,524) and mothers were included. The mean cord blood TC and TG levels were 72.2mg/dL and 24.4mg/dL, respectively. Multiple regression analyses revealed that gestational age and birth weight were significantly associated with cord blood TC (coefficient -2.35, 95% confidence interval [CI] -2.40 - -2.22 and coefficient 0.002, 95% CI 0.002-0.003, respectively) and TG (coefficient 3.09, 95% CI 3.01-3.17 and coefficient - 0.009, 95% CI - 0.009-0.008, respectively) levels. Mean cord blood TG and TC levels decreased over the preterm period; however, these parameters increased during the term. Furthermore, the mean cord blood TC and TG levels decreased over the entire range of birth weight categories. Conclusion: Mean cord blood TG and TC levels decreased over the preterm period; however, these parameters increased during the term. Furthermore, the mean cord blood TC and TG levels decreased over the entire range of birth weight categories in Japanese newborns. Maternal complications such as maternal parity, HDP, PROM, maternal obesity and income level were associated with cord TC and TG levels. What is Known: • No studies have ascertained the reference levels of cord blood lipid levels in Japan. What is New: • Mean cord blood TG and TC levels decreased over the preterm period; however, these parameters increased during the term.

Cardiac mucosa in neonates

The histology of the cardiac mucosa at the esophagogastric junction (EGJ) at birth is still a controversy. We conducted a histopathological study of the EGJ to clarify the morphology, and to determine the presence or absence of cardiac mucosa at birth.We examined 43 Japanese neonates and infants that are born prematurely or at full term. Death had occurred between 1 and 231 days after birth.Cardiac mucosa without parietal cells showing positivity for anti-proton pump antibody, adjacent to the most distal squamous epithelium, was observed in 32 (74%) of the 43cases. Such mucosa was evident in neonates that were full-term and had died within 14 days after birth. On the other hand, cardiac mucosa with parietal cells adjacent to squamous epithelium was noted in 10 cases (23%); the remaining one (2%) had columnar-lined esophagus. Squamous and columnar islands were observed in a single histological section from the EGJ in 22 (51%) of the 43 cases. Parietal cells were sparsely or densely present in the gastric antral mucosa.On the basis of these histological findings, we consider that cardiac mucosa exists in neonates and infants and can be defined as such, irrespective of the presence or absence of parietal cells (so-called oxyntocardiac mucosa). Neonates born prematurely or at full-term have cardiac mucosa in the EGJ just after birth, as is the case for Caucasian neonates.

Incidence and clinical risk factors of Bednar's aphthae in Japanese newborns.

The etiology of Bednar's aphthae remains unclear. Our aim was to investigate the incidence of, and factors associated with, Bednar's aphthae in a Japanese newborn cohort. A retrospective cross-sectional study was conducted on neonates discharged from the well-baby nursery at Saitama City Hospital, Japan. The principal investigator carefully examined each neonate's oral cavity, up to and including the pharynx, with a light-emitting diode (LED) headlight to determine the presence of Bednar's aphthae. Maternal and neonatal clinical characteristics were first compared between neonates with and those without Bednar's aphthae by univariate analysis. Variables with significant inter-group differences upon univariate analysis were entered into a multivariable logistic-regression model. This study enrolled 1996 infants. We observed Bednar's aphthae in 9.3% of the Japanese newborn infants who were included. When restricted to infants who were born via vaginal delivery, 13.2% of them had aphthae. Multivariable logistic regression analysis identified vaginal delivery (odds ratio = 6.19, p < 0.0001) in Model 1, and vaginal delivery (odds ratio = 6.73, p < 0.0001) and birth weight (odds ratio = 0.9995, p = 0.034) in Model 2 as independent risk factors for the disease. This is the first report of the prevalence of Bednar's aphthae among Japanese neonates. Vaginal delivery was identified as the strongest risk factor. Although confounding between mode of delivery and mechanical stimuli associated with sucking was not found in this study, the findings pave the way for a better understanding of the etiology of Bednar's aphthae.

Group B streptococcus neonatal umbilical colonization managed by dry cord care in nurseries: A retrospective cohort study

Screening-based intrapartum antibiotic prophylaxis (IAP) has reduced the prevalence of early-onset group B Streptococcus (GBS) infection in newborns. Nevertheless, early-onset disease still occurs despite IAP, and IAP is not effective in preventing late-onset disease. This study aimed to determine the prevalence and risk factors of GBS neonatal umbilical colonization managed by dry cord care in Japan. Of 735 healthy newborns in the well-baby nursery at Saitama City Hospital, 353 from whom umbilical bacterial swabs were obtained before discharge were included in the analysis. Maternal and neonatal clinical characteristics were retrospectively reviewed. GBS was detected in 4.2% (15/353) of umbilical swabs; 13/15 (86.8%) were born to GBS-negative mothers. The median (IQR) age at umbilical swab collection was 4.0 (4.0-5.0) days. Comparison of clinical characteristics between GBS-positive and negative neonates revealed a significant difference in the proportion of vaginal deliveries (15/15 [100%] in GBS-positive neonates vs. 115/338 [34.0%] in GBS-negative neonates, p<0.0001). Of 15 GBS-positive neonates, 10 (66.7%) were also co-colonized with other enteric bacteria such as Escherichia coli. Vaginal delivery was a risk factor associated with GBS neonatal umbilical colonization in Japanese neonates. Co-colonization with multiple enteric bacterial species implicates vertical transmission of GBS from undetected carrier mothers during passage through the birth canal.

Factors associated with birthweight decline in Japan (1980\u20132004)

BackgroundBirthweight has been declining consistently for more than 30 years in Japan. This rapid rise in low birthweight is one of the worst among the countries of the Organization for Economic Co-operation and Development. We examined potential determinants of birthweight decline in Japan.MethodsWe used population-based birth certificate data from vital statistics records and retrieved 40,968,266 birth certificates of neonates born between 1980 and 2004. We analyzed time trends using linear regression analysis in examining whether the decline in birthweight could be explained by obstetrical variables such as gestational age and multiple gestations.ResultsFrom 1980 to 2004, we observed a decline in mean birthweight with a yearly effect of − 8.07 g, which became steeper after 1985, persisted until 1999, and plateaued thereafter. After adjusting for gestational age, gender, birth order, multiple gestations, and fathers’ age, the yearly effect between 1980 and 2004 persisted at − 5.13 g.ConclusionRecent decreases in birthweight among Japanese neonates were not fully explained by trends in gestational age, gender, birth order, multiple gestations, and fathers’ age. Thus, additional factors such as pre-pregnancy maternal body mass index (BMI) and maternal diet should be considered. Reducing the rate of induced deliveries and improving the BMI or diet of young women should be a public health priority.

Proposal for a strategy on the follow-up in Japanese neonates with mild congenital hydronephrosis

先天性水腎症（congenital hydronephrosis: CH）は最も多い先天性腎尿路異常であるが，統一された診断基準がないため，その正確な頻度は明らかでない．また軽症例は自然軽快するとされているが，ほとんどが後方視的研究で，軽症CHの長期予後を前方視的に検討した報告はない．そこで筆者らは，日本人新生児の生後1か月時におけるCHの頻度を調査するとともに，生後1か月時に発見された軽症CHの自然経過を明らかにする目的で前方視的に検討を行った．その結果，生後1か月児の1,009人を対象に，CHの頻度は100例118腎（9.9%）であった．そのうちSFU1度が87腎（74%），SFU2度が30腎（25%），SFU3度が1腎（1%）およびSFU4度が0腎であった．またSFU（society for fetal urology）分類で1度または2度の軽症CHのうち，1度のCHは1年で90%，2年で99%が自然軽快し，2度のCHは1年で32%，2年で60%が自然軽快した．したがってSFU1度は症状を認めなければ以降のフォローは必要なく，SFU2度は1年ごとに腹部超音波検査で再検し，方針を決定すれば良いと思われた．

Prevalence and risk factors for hyperbilirubinemia among newborns from a low-risk birth setting using delayed cord clamping in Japan.

Neonatal jaundice is a common problem among infants. Among the several risk factors are East Asian race and delayed cord clamping. Birth centers manage low-risk term deliveries using physiological management, which may include delayed cord clamping. This study aimed to investigate the occurrence of hyperbilirubinemia, a pathological process of jaundice, and its risk factors among neonates born at a Japanese birth center. This was a retrospective cohort study. Data were collected from March 2006 to October 2014 from healthy mothers and neonates at a birth center in a metropolitan area of Japan. Demographic data and background factors of hyperbilirubinemia, including blood and transcutaneous values of jaundice, were collected and statistically analyzed. Of the 1,211 neonates analyzed, 4.7% exceeded the standard transcutaneous bilirubin value, and 1.8% needed phototherapy. Multiple logistic regression with adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) was used to identify the risk factors of hyperbilirubinemia, which were found to be cephalohematoma (OR = 30.18, 95% CI 5.63-161.69), delay of meconium elimination (OR = 2.66, 95% CI 1.28-5.51), previous history of phototherapy of siblings (OR = 10.28, 95% CI 3.53-29.92), and primiparity (OR = 4.55, 95% CI 2.59-8.02). In low-risk Japanese neonates delivered at a birth center expected to practice delayed cord clamping, the rate of neonates requiring phototherapy was not high compared to previous studies, and the identified risk factors of hyperbilirubinemia were related to bilirubin metabolism.

Longitudinal changes in dynamic characteristics of neonatal external and middle ears

ObjectivesNeonates have smaller and less mature ears than adults. Developmental changes in structure and function continually occur after birth and may affect the diagnostic results obtained by audiometric assessment instrumentation, such as tympanometry and otoacoustic emission. In the present study, we investigated longitudinal changes in external and middle ear dynamic characteristics by performing sweep frequency impedance (SFI) tests. MethodsSFI tests were longitudinally performed on healthy Japanese neonates (1 female and 1 male) from birth to 3 and 5 months, respectively. A sound of sweeping sinusoidal frequency, ranging from 0.1 kHz to 2 kHz, was presented to the ear canal at 50-daPa intervals of static pressure from +200 to −200 daPa. Test results were expressed a curve showing the sound pressure level (SPL) relative to probe tone frequency, called SPL curve. ResultsThe first fluctuation in resonance frequency (RF1) and SPL (ΔSPL1), related to the external ear, showed significant developmental changes as chronological age increased; that is, RF1 and ΔSPL1 were respectively increased and decreased and thereafter became unmeasurable by 5 months of age. In contrast, the second fluctuation in resonance frequency (RF2) and SPL (ΔSPL2), related to the middle ear, did not show significant changes over the measurement period. ConclusionsThe present results suggest that the dynamic characteristics of the external ear canal wall changed with increases in chronological age; the resonance of the wall at about 0.3 kHz at birth tended to increase to about 0.7 kHz and to be unmeasurable by 5 months of age, while those of the middle ear did not significantly changed. These results showing how neonatal-ear dynamics changes with chronological age may be an important key in further hearing research and the development of hearing devices and diagnostic tools suitable for neonates.

Genetic and Serological Diversity of Chlamydia trachomatis Strains Detected from Japanese Infants

Background: Classical fifteen serovars and variants of Chlamydia trachomatis were originally classified by the micro-immunofluorescence test which principally distinguished epitopes on the major outer-membrane protein (MOMP). The sequences of MOMP gene including four variable domains (VDs) have been determined for all classic 15 serovars. The PCR assay was used to amplify a large part of the MOMP gene (ompA or omp1) including four VDs and then cataloged restriction fragment length polymorphism (RFLP) was used to identify the serovars from genotypes of C. trachomatis as reported previously. Materials and Methods: Nasopharyngeal specimens were collected from 15 Japanese infants with pneumonia, from 1 month to 1 year old, during the period May 1990 to September 2013. Conjunctival swabs were also collected from 12 Japanese neonates under 1 month old with inclusion conjunctivitis during the same period. The specimens were collected and placed into Abbott LCR proprietary medium and then tested by PCR for typing. The sequencing strategy used was the double-stranded DNA cycle sequencing method. Results: Applied to 15 reference strains, this PCR-RFLP procedure allowed us to determine 13 of the 15 serovars of C. trachomatis. Thirteen of 15 isolates of nasopharyngeal origin and 11 of 12 isolates of conjunctival origin could be un-equivocally assigned to one of the 15 reference serovars with a restriction endonuclease profile identical to that of the prototype. The typing of 15 nasopharyngeal isolates gave the following results: 11 as E, 2 as H, and 2 as unclassified serovars. The typing of 12 conjunctival isolates gave the following results: 5 as D, 4 as E, 1 as F, 1 as H and 1 as unclassified serovar. Among the unclassified serovars, one was B-like and the rest was D-like. Discussion: The sequences of MOMP gene for all classic 15 serovars allowed the construction of restriction endonuclease cleavage-site maps that confirm the fragment-size patterns observed by electrophoresis. Sequencing the entire MOMP gene and cataloging the sequences of VDs of all serovars has confirmed the molecular basis of the serotyping procedure and provided a method for determining serovars by PCR-RFLP. Although geno-variants have also been reported for most serovars the PCR-RFLP method for typing allows quick and objective identification of serovars of C. trachomatis. Antigenic variations of C. trachomatis were also considered among the strains from nasopharyngeal and conjunctival origins.

Monitoring Bilirubin Binding Parameters in a Cohort of Japanese Neonates

Monitoring Bilirubin Binding Parameters in a Cohort of Japanese Neonates

Efficacy of inhaled nitric oxide in neonates with hypoxic respiratory failure and pulmonary hypertension: the Japanese experience.

To analyze data from a registry of Japanese neonates with hypoxic respiratory failure associated with pulmonary hypertension (PH) to compare the effectiveness of inhaled nitric oxide (iNO) in neonates born <34 weeks vs. ≥34 weeks gestational age (GA). iNO was administered according to approved Japanese product labeling. Study data were collected before iNO administration and at predefined intervals until discontinuation. A total of 1,114 neonates were included (n=431, <34 weeks GA; n=675, ≥34 weeks GA; n=8, missing age data). Mean decrease from baseline oxygenation index (OI) was similar in both age groups. OI reduction was more pronounced in the <34 weeks subgroups with baseline OI ≥25. Survival rates were similar in the <34 weeks GA and ≥34 weeks GA groups stratified by baseline OI (OI<15, 89% vs. 93%; 15≤OI<25, 85% vs. 91%; 25≤OI≤40, 73% vs. 79%; OI>40, 64% vs. 66%). iNO improved oxygenation in preterm neonates as effectively as in late preterm and term neonates, without negative impact on survival. If clinically significant PH is present, as measured by pulse oximetry or echocardiography, a therapeutic trial of iNO might be indicated for preterm neonates.

Enzyme activities of α-glucosidase in Japanese neonates with pseudodeficiency alleles

Lysosomal storage disorders (LSDs) are caused by defective enzyme activities in lysosomes, characterized by the accumulation of sphingolipids, glycolipids, oligosaccharides, mucopolysaccharides, the oxidation products of cholesterol, and other biological substances. A growing number of clinical studies have suggested the enhanced efficacy of existing therapies, including enzyme replacement therapy, which is effective when it is initiated during the presymptomatic period. Thus, the identification of disease-affected individuals by newborn screening has been considered an effective platform. Previous studies have suggested that the discrimination of infantile-onset Pompe disease (IOPD) requires multi-step examination of GAA enzyme activity using the fluorometric technique. In sharp contrast, the MS/MS-based technique can identify the population of IOPD and the pseudodeficiency alleles of the GAA enzyme [Liao HC et al. Clin Chem (2017) in press; doi: http://dx.doi.org/10.1373/clinchem.2016.269027]. To determine whether MS/MS-based assay can identify these two populations in Japanese neonates, we first performed a validation study of this assay using flow-injection analysis (FIA)-MS/MS and liquid chromatography (LC)-MS/MS followed by examination of GAA enzyme activity in our population. By minimizing the effect of substrate-derived in-source decomposition products, the activities of 6 LSD enzymes were quantified in FIA-MS/MS and LC-MS/MS. The mean value of GAA activity with IOPD, pseudodeficiency alleles, and healthy controls by FIA-MS/MS were 1.0±0.3μmol/h/L (max, 1.3; min, 0.7; median, 1.2; n=3), 2.7±0.7μmol/h/L (max, 4.5; min, 1.5; median, 2.5; n=19), and 12.9±5.4μmol/h/L (max, 29.6; min, 2.5; median, 11.0; n=83), respectively. These results suggest that the population of GAA with pseudodeficiency alleles has approximately 20% of GAA enzyme activity compared to controls, providing the preliminary evidence to estimate the cut-off values in the Japanese population using this technique.

Levels of enzyme activities in six lysosomal storage diseases in Japanese neonates determined by liquid chromatography-tandem mass spectrometry

Lysosomal storage disorders (LSDs) are caused by defective enzyme activities in lysosomes, characterized by the accumulation of glycolipids, oligosaccharides, mucopolysaccharides, sphingolipids, and other biological substances. Accumulating evidence has suggested that early detection of individuals with LSDs, followed by the immediate initiation of appropriate therapy during the presymptomatic period, usually results in better therapeutic outcomes. The activities of individual enzymes are measured using fluorescent substrates. However, the simultaneous determination of multiple enzyme activities has been awaited in neonatal screening of LSDs because the prevalence of individual LSDs is rare. In this study, the activities of six enzymes associated with LSDs were examined with 6-plex enzyme assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The accumulation of enzyme products was almost linear for 0–20h at 37°C. Dried blood spots (DBSs) provided by the Centers for Disease Control and Prevention (CDC) were used for quality control (QC). The intraday and interday coefficient of variance values were <25%. The enzyme activities of healthy individuals were higher than those of LSD-confirmed individuals. These results suggest that the levels of enzyme activities of six LSDs in a Japanese population were comparable to those of a recent report [Elliott et al. Mol Genet Metab 118 (2016) 304–309], providing additional evidence that the 6-plex LSD enzyme assay is a reproducible analytical procedure for neonatal screening.

Association of HMOX1 gene promoter polymorphisms with hyperbilirubinemia in the early neonatal period.

Heme oxygenase (HO) is the rate-limiting enzyme in the heme degradation pathway that produces bilirubin. The promoter region of human heme oxygenase-1 (HMOX1) contains a polymorphic (GT)n repeat that can regulate gene expression. Here, we investigated the association of (GT)n repeat length in the HMOX1 promoter region with neonatal hyperbilirubinemia in a population of Japanese term neonates. Using polymerase chain reaction and fragment analysis, we determined the number of (GT)n repeats in 149 Japanese neonates. To omit the effects of the G71R mutation in uridine diphosphoglucuronosyltransferase on hyperbilirubinemia, we excluded 41 neonates with the G71R mutation. As a result, 25 neonates with hyperbilirubinemia and 83 non-hyperbilirubinemic controls were included in this prospective case-control study. Allele and genotype frequencies of (GT)n repeats in the HMOX1 gene were compared between hyperbilirubinemic and non-hyperbilirubinemic control neonates. The prevalence of short alleles (< 22 (GT)n repeats) was significantly higher in hyperbilirubinemic than in control neonates (18% vs 7%, P = 0.015). Hyperbilirubinemia was more frequent in homozygous or heterozygous short allele carriers than control neonates (28% vs 11%, respectively, P = 0.03). Possession of short alleles was significantly associated with the development of neonatal hyperbilirubinemia (OR, 3.1; 95%CI: 1.03-9.53). Infants carrying short alleles (< 22 (GT)n repeats) in the HMOX1 gene promoter region appear to be at a higher risk for developing neonatal hyperbilirubinemia.

NPC-11 Phase III Trial Concerning Apnea of Prematurity in Japanese Neonates: A Study of Safety, Efficacy and Pharmacokinetics

Objective: To study the safety, efficacy, and pharmacokinetics of caffeine citrate in the treatment of apnea of prematurity in Japanese neonates. Study design: A non-blind, uncontrolled, multicenter, collaborative clinical trial. Setting: Three neonatal intensive care units in Japan Patient inclusion criteria: Neonates at the post conceptional age of 28 weeks to 33 weeks who were diagnosed with apnea of prematurity. Main outcome measures: 50% or greater reduction in apneic episodes, adverse effects, and pharmacokinetics. Method: Day 1 - Intravenous (IV) administration of caffeine citrate loading dose of 20 mg/kg, administered over 30 minutes. From day 2 onward - Commencement of administration of maintenance dose (caffeine citrate dose of 5 mg/kg) once daily intravenously over 10 minutes or orally. In the case that event incidence was reduced, the maintenance dose continued to be administered until day 10. If the doctor judged the initial maintenance dose to be ineffective, or its efficacy to be insufficient, the maintenance dose was raised to 10 mg/kg/day. Results: 23 patients fitting the specifications were found, and dosing was commenced. The reduction rate in apneic episodes during the trial was from 43.5% to 60.9%. Severe adverse effects were not noted. Mean serum concentration was maintained within the therapeutic range, between 11.87 and 18.82 mg/L. Data from clinical trials (Study OPR-001) in the United States, which were similar in methodology to this trial, were used when analyzing population pharmacokinetics. No difference due to race Conclusion: Caffeine citrate dosing for treatment of apnea of prematurity was effective, produced no safety problems, and showed good tolerability. Additionally, no differences between Japanese and Americans with regard to efficacy, safety and pharmacokinetics were observed Identifier of this clinical trial: NCT01408173

Association of neonatal hyperbilirubinemia in breast-fed infants with UGT1A1 or SLCOs polymorphisms.

Neonates have physiologically increased bilirubin production and immature bilirubin metabolism, and present hyperbilirubinemia in association with genetic and or epigenetic factors. We previously reported that maximal body weight loss (inadequate feeding) is an independent risk factor for the development of hyperbilirubinemia in breast-fed Japanese neonates, and the UGT1A1 211G>A genotype becomes a risk factor under conditions of inadequate feeding. We extended the study to the association of other genetic factors, the UGT1A1 (TA)7 and solute-carrier organic anion transporters (SLCOs) polymorphisms with neonatal hyperbilirubinemia. We enrolled 401 full-term Japanese infants who were exclusively breastfeeding and classified them into two groups based on the degree of maximal body weight loss. We analyzed the clinical characteristics and UGT1A1 and SLCOs genotypes. Statistical analysis revealed that maximal body weight loss is the only independent risk factor for the development of neonatal hyperbilirubinemia. UGT1A1, SLCO1B1 and SLCO1B3 polymorphisms become risk factors in neonates showing 10% or greater body weight loss during the neonatal period. Inadequate feeding may increase the bilirubin burden and cause apparent hyperbilirubinemia in neonates, who have a polymorphic change in the genes involved in the transport and/or metabolism of bilirubin.

Population pharmacokinetics of doxapram in low-birth-weight Japanese infants with apnea.

This study aimed to determine the population pharmacokinetics of doxapram in low-birth-weight (LBW) infants. A total of 92 serum concentration measurements that were obtained from 34 Japanese neonates were analyzed using nonlinear mixed-effect modeling (NONMEM). Estimates generated by NONMEM indicated that clearance of doxapram (CL; L/kg/h) was affected by postmenstrual age (PMA; weeks), body weight (BW; g), and aspartate aminotransferase (AST; IU/L). In addition, the volume of distribution (Vd; L/kg) was affected by gestational age (GA; weeks). The final pharmacokinetic model was as follows: CL = BW / PMA × 0.0453 × serum AST(-0.373); Vd = 2.54 (if GA >28weeks) and Vd = 2.54 × 2.11 (if GA ≤28weeks). The interindividual variabilities in CL and Vd were 39.9 and 83.0%, respectively, and the residual variability was 20.9%. To clarify the reasons for large interindividual variations, the enzymes involved in the metabolic pathway of doxapram were also determined. We found that doxapram was metabolized by CYP3A4/5. We report the population pharmacokinetics of doxapram in neonates and the involvement of CYP3A4/5 in its metabolism. The final model of population pharmacokinetics may be useful for formulating a safe and effective dosage regimen and for predicting serum doxapram concentrations in neonates.

Hour-specific nomogram for transcutaneous bilirubin in Japanese neonates

The measurement of transcutaneous bilirubin (TcB) is very important to screen for hyperbilirubinemia in newborns. Until now, however, there has been no hour-specific, percentile-based TcB nomogram during the early neonatal period in Japanese neonates. The aim of this study was to develop a TcB nomogram within 72 h of birth in Japanese neonates. A total of 3152 TcB measurements for 181 healthy Japanese neonates (gestational age ≥36 weeks, birthweight ≥2300 g) were obtained within 72 h of birth. All measurements were performed with a Konica Minolta jaundice meter, the JM-103. A nomogram curve was plotted to show the trend of TcB level over time. The nomogram curves rose almost linearly for all percentiles until 72 h after birth. An hour-specific, percentile-based TcB nomogram during the first 72 h after birth in Japanese neonates was successfully developed. Because Japanese neonates have higher and later peak bilirubin, an original hour-specific 97.5th percentile-based TcB nomogram may be needed to identify early-onset jaundice and manage neonatal hyperbilirubinemia.

Acquiring genome‐wide gene expression profiles in Guthrie card blood spots using microarrays

Standard Guthrie cards have been widely used to collect blood samples from essentially all USA and Japanese neonates for newborn screening programs. Thus, archival blood spot samples are a unique and comprehensive resource for molecular pathology studies. However, the challenge in using these samples is the presumed low quantity and degraded quality of nucleic acids that can be isolated from these samples, particularly the RNA. Here, we report a new assay using Agilent 4x44K microarrays for acquiring genome-wide gene expression profiles from blood spots on Guthrie cards. Due to the small amount of RNA obtained from each sample, major modifications, such as concentrating and amplifying the RNA and using a different labeling procedure, were performed. Approximately 9000 expressed genes can be detected after normalization of data, an increment of 260% in detection power compared with previously reported cDNA microarrays made in-house with standard procedures. The correlation coefficients in technical and biological replicates were 0.92 and 0.85, respectively, confirming the reproducibility of this study. This new and comprehensive assay will add value to the utility of archival Guthrie cards (e.g. neonatal blood spot cards) and open new opportunities to molecular epidemiology, pathology, genomic, and diagnostic studies of perinatal diseases.

Population pharmacokinetics of phenobarbital by mixed effect modelling using routine clinical pharmacokinetic data in Japanese neonates and infants: an update

Optimal use of phenobarbital in the neonatal population requires information regarding the drug's pharmacokinetics and the influence of various factors, such as different routes of administration, on the drug's disposition. However, because of sampling restrictions, it is often difficult to perform traditional pharmacokinetic studies in neonates and infants. This study was conducted to establish the role of patient characteristics in estimating doses of phenobarbital for neonates and infants using routine therapeutic drug monitoring data. The population pharmacokinetics of phenobarbital was evaluated using 109 serum concentration measurements obtained from routine phenobarbital monitoring of 70 neonates and infants. The data were analysed using the non-linear mixed effects model. A one-compartment pharmacokinetic model with first-order elimination was used. Covariates screened were current total bodyweight (TBW), gestational age, postnatal age (PNA), post-conceptional age, gender and neonates-infants clearance factor (serum concentration of phenobarbital; Conc). The final pharmacokinetic parameters were CL/F (mL/h) = (5.95.TBW (kg) +1.41.PNA (weeks)) Conc (serum phenobarbital concentration >50 μg/mL)(-0.221),Vd/F(L) =1.01.TBW (kg), and F = 0.483 for oral administration and F = 1 was assumed for suppository. Conc(-0.221) is 1 for phenobarbital concentration <50 μg/mL. The important variables for predicting phenobarbital clearance in this study were TBW, PNA and Conc. Phenobarbital clearance increases proportionately with increasing TBW, and an older newborn was expected to have a higher rate of clearance than a younger newborn of equal bodyweight. Moreover, the clearance of phenobarbital decreased nonlinearly with increasing serum concentration of phenobarbital >50 μg/mL (Conc(-0.221) ). We developed a new model for neonate and infant dosing of phenobarbital with good predictive performance. Clinical application of our model should permit more accurate selection of initial and maintenance doses to achieve target phenobarbital concentrations in Japanese neonates and infants, thereby enabling the clinician to achieve the desired therapeutic effect. A similar approach can be used to validate our model for use in other neonate and infant populations.