Japanese Neonates Research Articles

Complications of percutaneously inserted central venous catheters in Japanese neonates

To determine institutional policies concerning percutaneously inserted central venous catheter (PICC) utilization and also frequencies of complications such as pericardial effusion (PCE), cardiac tamponade (CT), pleural effusion, ascites, venous thrombosis, and catheter removal difficulties. Nationwide postal questionnaire survey was carried out that included institutional policies on PICC and numbers of complications recorded from January 1999 to December 2003. A total of 98 replies were received from 193 neonatal intensive care units (NICU) in Japan. As a catheter tip location, positions outside of the heart were highly preferred, while only 9% accepted a right atrial position. Twenty-eight cases of PCE or CT were reported, representing an estimated frequency of 0.07-0.11% of PICC insertions. Pleural effusion/ascites and removal difficulties (36 and 35 cases, respectively) were encountered in approximately 0.09-0.14% of insertions. Frequency of PCE/CT appeared comparable to previously reported occurrences. Also, pleural effusion/ascites and removal difficulty appeared to be rare complications.

Craniotabes in Normal Newborns: The Earliest Sign of Subclinical Vitamin D Deficiency

Craniotabes in otherwise normal neonates has been regarded as physiological and left untreated. Our objective was to investigate the role of vitamin D deficiency in the development of craniotabes in normal neonates. Newborn screening of craniotabes was conducted at the single largest obstetrical facility in Kyoto, Japan. Follow-up study at 1 month was conducted at Kyoto University Hospital. A total of 1120 consecutive normal Japanese neonates born in May, 2006, through April, 2007, were included in the study. The incidence of craniotabes was scored each month. Neonates with craniotabes were followed up at 1 month with measurements of serum calcium, phosphorus, alkaline phosphatase (ALP), intact PTH, 25-OH vitamin D (25-OHD), urinary calcium, phosphorus, creatinine, and hand x-rays. Craniotabes was present in 246 (22.0%) neonates, and the incidence had obvious seasonal variations, highest in April-May and lowest in November. At 1 month, infants with craniotabes had significantly higher serum ALP compared with normal neonates; 6.9% of them had elevated intact PTH over 60 pg/ml, and 37.3% had 25-OHD less than 10 ng/ml. When separately analyzed according to the method of feeding, 56.9% of breast-fed infants showed 25-OHD less than 10 ng/ml, whereas none of formula/mixed-fed infants did, and breast-fed infants had significantly higher serum PTH and ALP compared with formula/mixed-fed infants. These results suggest that craniotabes in normal neonates is associated with vitamin D deficiency in utero, and the deficiency persists at 1 month in many of them, especially when breast-fed.

Population pharmacokinetic investigation of digoxin in Japanese neonates

To establish the role of patient characteristics in estimating doses of digoxin for neonates using routine therapeutic drug monitoring data. The steady-state blood level data (n = 129) after repetitive oral administration in 71 hospitalized neonates were analysed using Nonlinear Mixed Effects Modelling (nonmem), a computer program designed for analysing drug pharmacokinetics in study populations through pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished using a one-compartment open pharmacokinetic model. The effect of a variety of developmental and demographic factors on digoxin disposition was investigated. Estimates generated by nonmem indicated that the clearance of digoxin (CL/F; L/h) was influenced by the demographic variables: total body weight (TBW), gestational age (GA) and neonate clearance factor (trough serum concentration of digoxin; Conc). These influences could be modelled by the equation CL/F = 0.0261 x TBW (kg)0.645 x Conc (ng/mL)(-0.724) x GA (weeks)0.8. The interindividual variability in digoxin clearance was modelled with proportional errors. The estimated coefficient of variation was 7.0%, and the residual variability was 13.1%. Clinical application of the model to patient care may permit selection of an appropriate initial maintenance dose, thus enabling the clinician to achieve the desired therapeutic effect. However, the digoxin dosage regimen for the individual patient should be based on a careful appraisal of their clinical need for the drug.

Insight into a “new disorder”—Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD)

Citrullinemia is an autosomal recessive disease caused by a deficiency of argininosuccinate synthetase and is characterized by elevated serum and urine citrulline levels. Classic citrullinemia (CTLN1) is caused by mutations in the gene encoding argininosuccinate synthetase (ASS). Citrullinemia type II (CTLN2) is now recognized to occur in two different phenotypes: adult-onset type II citrullinemia and neonatal-onset type II citrullinemia (also known as Neonatal Intrahepatic Cholestasis Caused By Citrin Deficiency (NICCD). Both are caused by mutation in the SLC25A13 gene (gene map locus 7q21.3) (Nature Genet 1999;22:159). There have been multiple recent reports of Japanese neonates with NICCD. Affected infants presented with intrahepatic cholestasis associated with hypercitrullinemia, hypermethioninemia, or hypergalactosemia detected by a neonatal mass screening. Liver biopsy findings consisted of marked fatty changes and variable degrees of fibrosis. Without specific treatment other than feeding formula containing medium-chain triglycerides or a lactose-free formula, most patients had favorable clinical courses, with amino acid profiles and clinical signs of cholestasis normalizing within the first year. It was found that citrin deficiency causes NICCD and adult-onset CTLN2 with an epigenetic effect of genetic or environmental modifiers. Since citrin is a mitochondrial aspartate glutamate carrier, NICCD and CTLN2 are presumably related to defective aspartate export from the mitochondria to the cytosol along with defects in the malate aspartate shuttle (J Hum Genet 2002;47:333). It is commonly reported that CTLN2, both the neonatal and the adult onset forms, are found exclusively in Japanese subjects. In this issue of The Journal, Yeh et al report NICCD in Taiwanese infants. This disorder accounted for ∼15% of the infants in their clinic being evaluated for idiopathic intrahepatic cholestasis. This observation is an important milestone in the emerging history of this “new disease” and should lead to greater recognition. This disorder should also be a consideration–in any infant–when elevated amino acid profiles are detected by neonatal screening programs.

CMV DNA detection in dried blood spots for diagnosing congenital CMV infection in Japan

Human cytomegalovirus (CMV) is a leading congenital infectious agent in developed countries. In the past, the incidence of congenital infection has been rather low in Japan because a high seroprevalence of CMV present in young women. However, this seroprevalence has been decreasing in recent years, so that the incidence of congenital CMV infection in Japanese neonates may increase and approach the level seen in other developed countries. The method was used for detecting CMV DNA reported by Barbi et al. [Barbi et al. (1996): Clin Diagn Virol 6:27-32] using a dried blood spot on filter paper, to diagnose congenital CMV infection in Japanese neonates. This method is effective and less laborious than virus isolation both for epidemiological studies and for identifying asymptomatic infected babies. Japanese neonates (1,176) were examined; two of who were asymptomatic were found to be infected.

Cross-cultural comparison of the neurobehavioral characteristics of Chinese and Japanese neonates

Similarities and differences in the neurobehavioral repertoire of neonates from different cultures have been noted using the Brazelton Neonatal Behavioral Assessment Scale (NBAS). By identifying the behavioral attributes of newborns that are seen more universally versus those that are culture-specific, comparative studies increase understanding of the roles of cultural factors in shaping the behavioral trajectory of infants. This study compared the neurobehavioral characteristics of neonates in Chengdu, China and Nagasaki, Japan. The Brazelton NBAS was administered within the first week of life to 40 Chinese and 62 Japanese healthy, full-term neonates in Chengdu and Nagasaki. The two groups differed significantly in birthweight, gender, age at time of exam, mode of delivery, and gestational age. When these variables, in addition to group status (Chinese or Japanese), were entered into multiple linear analyses with NBAS cluster scores as dependent variables, group status independently predicted Range of State and Habituation scores. The group status did not predict Orientation, Motor, Regulation of States, Autonomic Stability, and Abnormal Reflexes cluster scores. These results suggest that Japanese newborns habituated more readily to stimuli, and were less irritable than newborns in the Chinese sample. The infants in the two groups shared many similar neurobehavioral characteristics as well. The implications of these similarities and differences were discussed.

Neonatal hyperbilirubinemia and the bilirubin uridine diphosphate‐glucuronosyltransferase gene: The common −3263T > G mutation of phenobarbital response enhancer module is not associated with the neonatal hyperbilirubinemia in Japanese

Neonatal hyperbilirubinemia is frequent and severe in Japanese newborns. Previously, it has been reported that half of the Japanese neonates with severe hyperbilirubinemia carried the 211G > A (p.G71R) mutation of the bilirubin uridine diphosphate-glucuronosyltransferase (UGT1A1) gene causing Gilbert syndrome. Recently, it was reported that the -3263T > G mutation in the phenobarbital response enhancer module in UGT1A1 was associated with the majority of cases of Gilbert syndrome. The gene frequency of the -3263T > G mutation was determined and the relation with neonatal hyperbilirubinemia in Japanese was studied. UGT1A1 in 119 neonates born at Yamagata University Hospital, Yamagata, Japan, and 26 subjects who had undergone phototherapy due to severe hyperbilirubinemia at four other hospitals were studied. The gene frequency of -3263T > G mutation in Japanese, Korean, Chinese and German healthy adult controls was also determined. Hyperbilirubinemia was assessed with a Jaundice Meter and UGT1A1 was analyzed by sequence determination or restriction enzyme method. The gene frequency of the -3263T > G mutation was 0.26 in Japanese subjects and was similar to the prevalence in Korean, Chinese and German populations. However, there was no significant increase in the gene frequency of the mutation in the neonates who required phototherapy for hyperbilirubinemia compared to that in the neonates without severe hyperbilirubinemia. In addition, neonates with or without the mutation did not show a significant change in the level of bilirubin and the mutation also did not show a synergic effect with the 211G > A mutation on the level of bilirubin. The -3263T > G mutation is not likely to be associated with the neonatal hyperbilirubinemia in Japanese.

Population pharmacokinetic investigation of phenobarbital by mixed effect modelling using routine clinical pharmacokinetic data in Japanese neonates and infants

The population pharmacokinetics of phenobarbital was evaluated using 69 serum concentration measurements obtained from the routine phenobarbital monitoring of 35 neonates and infants. The data were analysed using the nonlinear mixed effects model. A one-compartment open pharmacokinetic model with first-order elimination was used. Covariates screened were current bodyweight (TBW), gestational age, postnatal age (PNA), postconceptional age and gender. The final pharmacokinetic parameters were CL/F (mL/h) = 3.41.TBW (kg) + 1.64. PNA (weeks), Vd/F(L) = 1.09.TBW.(kg) [corrected] and F = 0.406 for oral administration and F = 1 for suppository. Application of the findings in this study to patient care may permit selection of an appropriate initial maintenance dosage to achieve target phenobarbital concentrations, thus enabling the clinician to achieve the desired therapeutic effect in neonates and infants.

Neonatal hyperbilirubinemia in Japanese neonates: analysis of the heme oxygenase-1 gene and fetal hemoglobin composition in cord blood.

Neonatal hyperbilirubinemia is frequent and severe in Japanese infants. Although the G71R mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene is associated with severe neonatal hyperbilirubinemia in this population, it accounts for only half of the neonates with severe hyperbilirubinemia. It was suggested that increased bilirubin production would also be associated with severe neonatal hyperbilirubinemia in Japanese infants. To elucidate the genetic factors causing severe hyperbilirubinemia in these patients, we studied two notable factors associated with bilirubin production: heme oxygenase-1, a key enzyme of heme metabolism, and fetal Hb composition, a factor possibly associated with heme load in neonates. We first determined the sequences of promoter and all coding regions of the heme oxygenase-1 gene in Japanese neonates who had undergone phototherapy, but found no mutation except for the polymorphic (GT)n repeats in the promoter region. These repeats modulate the transcription of the heme oxygenase-1 gene, and the longer repeat sequences are known to reduce the transcription. We detected a significant difference in the allele frequencies of each number of (GT)n repeats between Japanese and German populations. However, we could not find a relation between those polymorphisms and neonatal hyperbilirubinemia. We next analyzed the state of Hb switching of the gamma- to beta-globin chain and the phenotype of gamma-globin chain isoforms in cord blood. We found no relation between fetal Hb composition and neonatal hyperbilirubinemia. Further studies are required to elucidate genetic or environmental factors in neonatal hyperbilirubinemia in Japanese infants.

Chlamydia trachomatis infection in early neonatal period.

BackgroundThe clinical characteristics of Chlamydia trachomatis respiratory tract infections in Japanese neonates were investigated.MethodsClinical, laboratory and microbiological characteristics of five infants with pneumonia due to C. trachomatis in early neonatal period were analyzed.ResultsOnly C. trachomatis was identified in 4 infants. Both C. trachomatis and cytomegalovirus was identified in one. Wheezing, tachypnea and cyanosis were common in infants. Mothers of five infants had negative chlamydial EIAs at 20 weeks of gestation.ConclusionsWe identified five cases of C. trachomatis respiratory tract infections in early neonatal period with the possibility of intrauterine infection. Targeted screening, early diagnosis, and effective treatment of perinatal and neonatal chlamydial infections seems to be necessary

Population-based investigation of relative clearance of digoxin in Japanese neonates and infants by multiple-trough screen analysis

The steady-state concentrations of digoxin at trough levels were studied to establish the role of patient characteristics in estimating doses for digoxin using routine therapeutic drug monitoring data. The data (n = 448) showing steady state after repetitive oral administration in 172 hospitalized neonates and infants were analyzed using Nonlinear Mixed Effect Model (NONMEM), a computer program designed to analyze pharmacokinetics in study populations by allowing pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished using a simple steady-state pharmacokinetic model. The effects of a variety of developmental and demographic factors on the clearance of digoxin were investigated. Estimates generated using NONMEM indicated that clearance of digoxin (l.h-1) was influenced by the demographic variables of age, total body weight, serum creatinine, the coadministration of spironolactone, and the presence or absence of congestive heart failure. The interindividual variability in digoxin clearance was modeled with proportional errors with an estimated coefficient of variation of 32.1%, and the residual variability was 28.9%. In the validation set of 66 patients, the performance (bias, precision) of the final population model was good (mean prediction error -0.04 ng.ml-1; mean absolute prediction error 0.20 ng.ml-1).

Higher Serum Retinol-Binding Protein Concentration in Indonesian Neonates in Surabaya than Japanese Neonates in Kobe

The concentrations of serum retinol-binding protein (RBP), prealbumin (PA) and vitamin A of Indonesian neonates were compared with those of Japanese neonates. The mean serum concentrations of both PA and vitamin A did not differ significantly in Indonesian and Japanese neonates. Indonesian neonates had significantly higher serum RBP (2.75 +/- 0.87 mg/dl, mean +/- SD) than Japanese neonates (1.65 +/- 0.55 mg/dl, p less than 0.01). The molar ratio of vitamin A:RBP in Indonesian infants was significantly lower than in Japanese infants (p less than 0.02), and this in turn is indicative of increased concentrations of retinol-free RBP in the plasma of Indonesian neonates. The results suggest that RBP metabolism in Indonesian neonates differs from that in Japanese neonates.

Follow-Up Study on the Behavioral Development of Japanese Neonates

The subjects were 53 healthy children from middle-class Japanese families. We examined them longitudinally with several kinds of assessment scales from 3 days to 36 months of age. The 30-day Motor score which was influenced by the mother's attitude to childbearing also had relationships with the later development. The clustering scores of the Neonatal Behavioral Assessment Scale (NBAS) on the 3 examination points accounted for 21-47% of the variance in developmental outcome. The stronger role of the grandmother at 10 days of age related to lower scores of the NBAS, but to higher scores of developmental indexes from the long-range viewpoint.

Breast-Feeding Frequency During the First 24 Hours After Birth in Full-Term Neonates

The relation between the frequency of breast-feeding and intake, weight loss, meconium passage, and bilirubin levels was studied in 140 healthy, full-term, breast-fed, Japanese neonates born vaginally without complications. Factors affecting the frequency of breast-feeding were also evaluated. Mothers nursed their neonates, on average, 4.3 +/- 2.5 (SD) times (range 0 to 11) during the first 24 hours after birth, and this frequency increased significantly to 7.4 +/- 3.9 times during the next 24 hours (P less than .001). There was a significant correlation between the frequency of breast-feeding during the first and second 24 hours after birth (r = .69, P less than .001). The frequency of breast-feeding during the first 24 hours correlated significantly with frequency of meconium passage (r = .37, P less than .01), maximum weight loss (r = -.22, P less than .05), breast milk intake on day 3 (r = .50, P less than .01) and day 5 (r = .34, P less than .05), transcutaneous bilirubin readings on day 6 (r = -.18, P less than .05), and weight loss from birth to time of discharge (day 7) (r = -.32, P less than .01). There was a strong dose-response relationship between feeding frequency and a decreased incidence of significant hyperbilirubinemia (transcutaneous bilirubin readings greater than or equal to 23.5) on day 6. The time of birth also affected the frequency of breast-feeding during the first 24 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Statistical Survey of Skin Changes in Japanese Neonates

We observed 5387 infants over 10 years in weekly visits to a neonatal ward and obtained the following frequency data on these skin changes: erythema toxicum neonatorum, 40.8%; perianal dermatitis, 18.9%; scrotal pigmentation, 15.2%; miliaria, 8.5%; and adnexal polyp of neonatal skin, 4.1%. The frequencies of the types of birthmarks were: mongolian spots, 81.5%; salmon patches, 22.3%; nevocellular nevi, 2.7%; port-wine stains, 2.1%; strawberry marks, 1.7%; café au lait spots, 1.7% (including a case of von Recklinghausen's disease); epidermal and sebaceous nevi, 0.3%; accessory auricles, 0.3%; and smooth muscle hamartomas, 0.2%. A positive relationship was observed between infant maturity and the prevalence of erythema toxicum neonatorum. Apart from candidiasis, neonatal skin infections were extremely rare.

High density lipoprotein cholesterol levels in the Japanese

High-density lipoprotein (HDL) cholesterol levels were measured in Japanese and Western residents in Japan with the heparin—MnCl 2 precipitation method. The mean HDL cholesterol level (± SD) in healthy Japanese was 56 ± 16 mg/dl for men and 61 ± 15 mg/dl for women. Females had significantly higher HDL cholesterol concentrations than males. HDL cholesterol showed a negative correlation with the obesity index and the plasma triglyceride level, and a positive correlation with alcohol intake. The mean HDL cholesterol level was significantly lower in patients with coronary heart disease (CHD) and cerebral infarction than in controls. The estimated ratio (total cholesterol—HDL cholesterol)/HDL cholesterol, referred to as the Atherogenic Index, was significantly higher in these patients. HDL cholesterol levels were found to be relatively high in the Japanese compared with those reported for Western populations. HDL cholesterol levels in cord blood from Japanese neonates were found to be similar to those reported for Western neonates. HDL cholesterol levels of Western residents in Japan were nearly the same as those of the Japanese. It was suggested that the relatively high level of HDL cholesterol in the Japanese might be related to the lower incidence of CHD in Japan than in the West, and that the difference in HDL cholesterol level between Japanese and Western populations seems related to environmental factors.