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Objective This study aimed to evaluate whether elevated urine desmosine levels at 3 weeks of age were associated with severe radiological findings, bronchopulmonary dysplasia (BPD), and post-prematurity respiratory disease (PRD) in extremely preterm (EP) or extremely low birth weight (ELBW) infants. Study Design This study recruited 37 EP (22–27 completed weeks) or ELBW ( Results Elevated urine desmosine/creatinine levels higher than the threshold were significantly associated with bubbly/cystic lungs (8/13 [61.5%] vs. 2/24 [8.3%], p = 0.001), BPD (10/13 [76.9%] vs. 8/24 [33.3%], p = 0.02), and PRD (6/13 [46.2%] vs. 2/24 [8.3%], p = 0.01). After adjusting for gestational age, birth weight, and sex, the urine desmosine/creatinine levels were significantly higher in those who were highly at risk of bubbly/cystic lungs (odds ratio [OR], 13.2; 95% CI, 1.67–105) and PRD (OR, 13.8; 95% CI, 1.31–144). Conclusion Elevated urine desmosine/creatinine levels on the third postnatal week were associated with bubbly/cystic lungs on day 28 and PRD at 18 months of corrected age in EP or ELBW infants. Key Points

The long-term follow-up of lung function (LF) in extremely preterm (EP) infants with bronchopulmonary dysplasia (BPD) has shown a worldwide increase in small airway obstructions (SAO).We investigated the relationships between intrauterine Ureplasma infection in EP infants and bubbly/cystic lung, BPD, and SAO at school age.Placental pathology, placental Ureaplasma DNA (pU-DNA), and cord blood immunoglobulin M (IgM) (C-IgM) were investigated in 360 EP infants born from 1981 to 2004. Maternal amniotic inflammatory response (M-AIR) scores and hemosiderin deposition (HD) were estimated in the chorioamnion. The study subjects were divided into groups based on their M-AIR scores. Their LF at school age was compared with those of 33 healthy siblings.pU-DNA and C-IgM were significantly related to SAO at school age (p 0.012). M-AIR score 3 and pU-DNA1000 units had an odds ratio (OR) of 35 (95% confidence interval: 10-172) and 18 (5.6-67) for bubbly/cystic lung, and 11 (3.1 - 43) and 31 (4.5-349) for severe BPD, and 5.3 (2.1-11) and 12 (2.4-74) for SAO, respectively. The ORs of surfactant treatment, BPD grade III, OOur long-term cohort study of LF in EP infants revealed that intrauterine Ureaplasma was associated with bubbly/cystic lung, severe BPD, and SAO at school age.

BackgroundOutcomes of prenatal covariate-adjusted outborn very-low-birth-weight infants (VLBWIs) (≤1500 g) remain uncertain.ObjectiveTo compare morbidity and mortality between outborn and inborn VLBWIs.DesignObservational cohort study using inverse-probability-of-treatment weighting.SettingNeonatal Research Network of Japan.PatientsSingleton VLBWIs with no major anomalies admitted to a neonatal intensive care unit from 2012 to 2016.MethodsInverse-probability-of-treatment weighting with propensity scores was used to reduce imbalances in prenatal covariates (gestational age (GA), birth weight, small for GA, sex, maternal age, premature rupture of membranes, chorioamnionitis, preeclampsia, maternal diabetes mellitus, antenatal steroids and caesarean section). The primary outcome was severe intraventricular haemorrhage (IVH). The secondary outcomes were outcomes at resuscitation, other neonatal morbidities and mortality.ResultsThe full cohort comprised 15 842 VLBWIs (668 outborns). The median (IQR) GA and birth weight were 28.9 (26.4–31.0) weeks and 1128 (862–1351) g for outborns and 28.7 (26.3–30.9) weeks and 1042 (758–1295) g for inborns. Outborn VLBWIs had a higher incidence of severe IVH (8.2% vs 4.1%; OR, 3.45; 95% CI 1.16 to 10.3) and pulmonary haemorrhage (3.7% vs 2.8%; OR, 5.21; 95% CI 1.41 to 19.2). There were no significant differences in Apgar scores, oxygen rates at delivery, intubation ratio at delivery, persistent pulmonary hypertension of the newborn, IVH of any grade, periventricular leukomalacia, chronic lung disease, oxygen at discharge, patent ductus arteriosus, retinopathy of prematurity, necrotising enterocolitis, sepsis or mortality.ConclusionOutborn delivery of VLBWIs was associated with an increased risk of severe IVH.

OBJECTIVES Outborn (born outside tertiary centers) infants, especially extremely preterm infants, are at an increased risk of mortality and morbidity in comparison to inborn (born in tertiary centers) infants. Extremely preterm infants require not only skilled neonatal healthcare providers but also highly specialized equipment and environment surroundings. Maternal transport at an appropriate timing must be done to avoid the delivery of extremely preterm infants in a facility without the necessary capabilities. Cases of unexpected deliveries at birth centers or level I maternity hospitals need to be attended emergently. We compared the differences in short- and long-term outcomes between outborn and inborn infants to improve our regional perinatal system. DESIGN Retrospective cohort study. SETTING Neonatal Research Network of Japan database. PATIENTS Extremely preterm infants (gestational age between 22 + 0 and 27 + 6 wk) in the Neonatal Research Network of Japan database between 2003 and 2011. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS A total of 12,164 extremely preterm infants, who were divided into outborn (n = 785, 6.5%) and inborn (n = 11,379, 93.5%) groups, were analyzed. Significant differences were observed in demographic and clinical factors between the two groups. Outborn infants had higher short-term odds of severe intraventricular hemorrhage (adjusted odds ratio, 1.49; 95% CI, 1.11-2.00; p < 0.01), necrotizing enterocolitis (adjusted odds ratio, 1.49; 95% CI, 1.11-2.00; p < 0.01), and focal intestinal perforation (adjusted odds ratio, 1.58; 95% CI, 1.09-2.30; p = 0.02). There were no significant differences in long-term outcomes between the two groups, except in the rate of cognitive impairment (adjusted odds ratio, 1.49; 95% CI, 1.01-2.20; p = 0.04). CONCLUSIONS The frequency of severe intraventricular hemorrhage, necrotizing enterocolitis or focal intestinal perforation, and cognitive impairment was significantly higher in outborn infants. Thus, outborn/inborn birth status may play a role in short- and long-term outcomes of extremely preterm infants. However, more data and evaluation of improvement in the current perinatal environment are needed.

We examined the effects of maternal hypertensive disorders of pregnancy (HDP) on the mortality and neurodevelopmental outcomes in preterm very low birth weight (VLBW) infants (BW ≤1,500 g) based on their intrauterine growth status and gestational age (GA).We included singleton VLBW infants born at32 weeks' gestation registered in the Neonatal Research Network Japan database. The composite outcomes including death, cerebral palsy (CP), and developmental delay (DD) at 3 years of age were retrospectively compared among three groups: appropriate for GA (AGA) infants of mothers with and without HDP (H-AGA and N-AGA) and small for GA (SGA) infants of mothers with HDP (H-SGA). The adjusted odds ratios (AOR) and 95% confidence intervals (CI) stratified by the groups of every two gestational weeks were calculated after adjusting for the center, year of birth, sex, maternal age, maternal diabetes, antenatal steroid use, clinical chorioamnionitis, premature rupture of membranes, non-life-threatening congenital anomalies, and GA.Of 19,323 eligible infants, outcomes were evaluated in 10,192 infants: 683 were H-AGA, 1,719 were H-SGA, and 7,790 were N-AGA. Between H-AGA and N-AGA, no significant difference was observed in the risk for death, CP, or DD in any GA groups. H-AGA had a lower risk for death, CP, or DD than H-SGA in the 24 to 25 weeks group (AOR: 0.434, 95% CI: 0.202-0.930). The odds for death, CP, or DD of H-SGA against N-AGA were found to be higher in the 24 to 25 weeks (AOR: 2.558, 95% CI: 1.558-3.272) and 26 to 27 weeks (AOR: 1.898, 95% CI: 1.427-2.526) groups, but lower in the 30 to 31 weeks group (AOR: 0.518, 95% CI: 0.335-0.800).There was a lack of follow-up data; however, the outcomes of liveborn preterm VLBW infants of mothers with HDP depended on their intrauterine growth status and GA at birth.· The effects of HDP on preterm low birth weight infants need to be further examined.. · The outcomes were not different between AGA infants with and without maternal HDP.. · The outcomes of SGA infants with maternal HDP were dependent on their GA..

Background The assessment of long-term outcomes in survivors born with extremely low birth weights (ELBWs) has become increasingly important. However, little has been reported on the physical fitness of non-disabled school-aged children born with ELBWs. Aims To assess the physical fitness of non-disabled school-aged children born with ELBWs. Study design Retrospective cohort study. Subjects We analyzed 169 ELBW infants without cerebral palsy or intellectual disability (based on the Wechsler Intelligence Scale for Children—Third Edition (WISC-III) Full Scale intelligence quotient (IQ) test Outcome measures Physical fitness was assessed using the grip strength, sit-up repetitions, sit & reach, side steps, standing long jump, and softball throw tests. T-scores were calculated using national survey data. Results The T-scores for the grip strength, sit-up repetitions, sit & reach, side steps, standing long jump, softball throw tests, and the overall T-score were 43.7 ± 7.5, 44.2 ± 10.5, 46.0 ± 9.7, 40.9 ± 8.0, 40.0 ± 9.8, 42.4 ± 8.1, and 42.9 ± 5.5, respectively. After adjusting for other age-related factors, the height (SD score), WISC-III Performance IQ score, and percent predicted forced vital capacity (FVC) independently predicted the overall T-scores. Their standardized partial regression coefficients (β) were 0.334 (p = 0.009), 0.190 (p = 0.022), and 0.187 (p = 0.032), respectively. Conclusions Our cohort's physical fitness at approximately 8 years of age was significantly impaired compared to average Japanese children of the same age. Height, FVC, and Performance IQ independently predicted physical fitness, with height being the strongest predictor.

OBJECTIVES To assess lung function and long-term respiratory outcomes in extremely low birth weight (ELBW) survivors. WORKING HYPOTHESIS ELBW, especially with respiratory complications in the neonatal period, affects lung function at a later age. STUDY DESIGN Longitudinal retrospective study. PATIENT-SUBJECT SELECTION Lung function was evaluated in 89 ELBW survivors (at ages 8 and 12) with or without a history of bronchopulmonary dysplasia (BPD) or a bubbly/cystic lung appearance in the neonatal period. METHODOLOGY FVC, FEV1, FEF50, and FEF75 were measured using spirometry. Two-way repeated-measures ANOVA was used to compare lung function and deterioration time course from 8 to 12 years of age. RESULTS Lung function variables were significantly and positively correlated between 8 and 12 years: %FVC (R2 = 0.558), %FEV1 (R2 = 0.539), %FEF50 (R2 = 0.412), and %FEF75 (R2 = 0.429). Lung function values were lower than Japanese reference values, especially in children with a history of severe BPD or a bubbly/cystic appearance. %FEV1 and FEV1/FVC ratio worsened from 8 to 12 years of age: 83.0 ± 17.0% versus 76.6 ± 17.8% (mean difference, 95%CI: −6.43, −9.10 to −3.75) and 84.0 ± 10.1% versus 78.2 ± 13.4% (mean difference, 95%CI: −5.82, −8.56 to −3.08), regardless of whether or not there was a history of neonatal respiratory disease. CONCLUSIONS In ELBW survivors, the obstructive pattern of lung function impairment deteriorated from 8 to 12 years of age, independent of the presence of severe BPD or bubbly/cystic appearance in the neonatal period.

Objective We hypothesised that a prophylactic inhaled steroid would prevent the progression of bronchopulmonary dysplasia (BPD) in extremely low birthweight infants (ELBWIs). Design This study was a multicentre, randomised, double-blinded, placebo-controlled trial. Setting This investigation was conducted in 12 level III neonatal intensive care units (NICUs). Patients A total of 211 ELBWIs requiring ventilator support were enrolled. Intervention Starting within 24 h of birth and continuing until 6 weeks of age or extubation, two doses of 50 μg fluticasone propionate (FP) or placebo were administered every 24 h. Main outcome measurement The primary outcome measure used to indicate the morbidity of severe BPD incidence was death or oxygen dependence at discharge from the NICU. The secondary measures were neurodevelopmental impairments (NDIs) at 18 months of postmenstrual age and 3 years of age. We performed subgroup analyses based on gestational week (GW) and the presence of chorioamnionitis (CAM). Results Infants were randomised into the FP (n=107) or placebo (n=104) groups. No significant differences were detected between the FP and placebo groups with respect to either the frequency of death or the oxygen dependence at discharge or NDIs. In subgroup analyses, the frequencies of death and oxygen dependence at discharge were significantly decreased in the FP group for infants born at 24–26 GWs and for infants with CAM, regardless of the GW at birth. Conclusions Inhaled steroids have no effect on the prevention of severe BPD or long-term NDI but might decrease the severity of BPD for ELBWIs with a risk factor. Trial registration number UMIN-CTR C000000405.

Objective The aim of this study is to compare patent ductus arteriosus (PDA) management strategies and outcomes between the Neonatal Research Network of Japan (NRNJ) with proactive functional echocardiography and the Canadian Neonatal Network (CNN) with selective conventional echocardiography practice. Study Design Retrospective analyses examined very low-birth-weight infants admitted to the NRNJ or CNN in 2006 to 2008. Multivariable logistic regression analyses compared a composite outcome indicating a mortality or major morbidity (severe intraventricular hemorrhage, periventricular leukomalacia, severe retinopathy of prematurity, bronchopulmonary dysplasia, or necrotizing enterocolitis) between networks, according to PDA diagnosis and treatment, and tested the association between PDA treatment and the composite outcome within networks. Results PDA treatment (NRNJ:CNN) with conservative management (8%:16%), indomethacin only (77%:59%), ligation only (1%:13%), or indomethacin and ligation (14%:13%) varied significantly between networks. The composite outcome was lower in NRNJ versus CNN only among infants with PDA (odds ratio: 0.70; 95% confidence interval: 0.62–0.80). Surgical ligation was associated with higher composite outcome only in CNN (odds ratio: 1.79; 95% confidence interval: 1.40–2.28). Conclusion Lower composite mortality/morbidity outcome in Japan versus Canada only among infants with PDA, and association of surgical ligation with higher mortality/morbidity only in Canada, suggest differential PDA management and ligation processes contribute to outcome variation.

Aim: To evaluate the effect of antenatal corticosteroids (ANS) on short- and long-term outcomes in small-for-gestational age (SGA) infants. Methods: A retrospective database analysis was performed. A total of 1,931 single infants (birth weight

Wilson-Mikity syndrome (WMS) was first reported in 1960 by Wilson and Mikity. They described preterm infants who developed areas of cystic emphysema in the first month of life with subsequent progression to chronic lung disease (CLD) of infancy, although these infants did not exhibit early respiratory distress, such as respiratory distress syndrome (RDS). This condition was widely accepted over the next 20 years, but WMS is now rarely mentioned and is commonly considered an anachronism. In Japan, CLD is classified into six types according to the presence of RDS and/or intrauterine inflammation and appearance on chest X-ray. One type of CLD (type III, which accounts for 13.5% of all CLD) is defined as history of intrauterine inflammation and the typical bubbly and cystic appearance on chest X-ray described in the original report of WMS. There is insufficient evidence to determine whether WMS exists or whether WMS is relatively common only in Japan and not in other countries. It is important, however, to distinguish this type of CLD from other types because the strategy for the prevention or treatment of CLD should be different according to its origin, cause, and risk factors.

Objective To evaluate changes in the outcomes of infants born at

Aim Methods to improve the mental development of extremely low birthweight (ELBW) children are currently lacking. We assessed the effects of long-term supplementation of alpha-tocopherol on the neurological development of 259 school-aged ELBW children. Methods Extremely low birthweight participants were divided into three groups: group A with no alpha-tocopherol supplementation (n = 121); group B with the supplementation for

To evaluate the short- and long-term outcomes among very low birth weight (VLBW) preterm infants after histologic chorioamnionitis (HCA).We performed a retrospective analysis of 5849 single infants (birth weight1500 g) born at a gestational age between 22 + 0 and 33 + 6 weeks. Clinical data were obtained from the Neonatal Research Network Japan between 2003 and 2007. Multivariable logistic regression analyses were performed to assess the effect of HCA on short- and long-term outcome.According to logistic regression analysis, HCA was associated with lower incidence of respiratory distress syndrome (odds ratio [OR] = 0.54; p 0.001), increased chronic lung disease (OR = 1.68; p 0.001) and sepsis (OR = 1.71; p 0.001) and as a short-term outcomes. There was no significant association with intraventricular hemorrhage (OR = 1.11; p = 0.33), periventricular leukomalacia (OR = 1.07; p = .070) and death before discharge (OR = 0.97; p = 0.084). HCA was associated with increased home oxygen therapy (OR = 3.09; p 0.001), but not with cerebral palsy (CP; OR = 0.91; p = 0.63), develop quotient 70 (OR = 1.27; p = 0.17), visual impairment (OR = 1.08; p = 0.77), severe hearing impairment (OR = 1.28; p = 0.62) and death (OR = 0.98; p = 0.91) before three years of age.In this retrospective population-based study in Japan, HCA was not a risk factor for death, neurodevelopmental impairment and CP in VLBW three-year-old preterm infants.

Objective: This study aimed to re-evaluate the effectiveness of antenatal corticosteroids (ACS) and to analyze the association between ACS and the mode of delivery in the context of perinatal morbidity and mortality in very-low-birth-weight (VLBW) infants. Study Design: This retrospective cohort study involved 15,765 VLBW infants born between 2003 and 2008 at less than 34 weeks of gestation and weighing less than 1,500 g at birth. Data were obtained from the Japanese neonatal research network database. Univariate and multivariate logistic regression analyses were performed to evaluate the impact of ACS and mode of delivery on the risk of infant mortality and morbidity. Results: Administration of ACS was associated with decreases in mortality rate, intraventricular hemorrhage (IVH) and retinopathy of prematurity (ROP), and was not associated with the incidence of respiratory distress syndrome (RDS), periventricular leukomalacia or necrotizing enterocolitis (NEC). When the administration of ACS was analyzed in the context of different modes of delivery, the incidence of IVH and ROP tended to decrease with cesarean section deliveries, whereas the incidence of RDS tended to decrease and the incidence of NEC tended to increase for infants delivered vaginally. The incidence of chronic lung disease tended to increase in association with both delivery methods. Conclusions: This large cohort study reconfirms that ACS treatment is associated with decreases in infant mortality and severe morbidity. Furthermore, the delivery method may be associated with severe morbidity in VLBW infants exposed to ACS.

To evaluate the effectiveness of antenatal corticosteroids (AC) therapy on outcomes of very low birthweight infants with histologic chorioamnionitis. We performed a retrospective analysis of 10,935 single infants born at a gestational age between 22 + 0 and 33 + 6 weeks and birth weight

OBJECTIVE: To provide instructive information on death and neurodevelopmental outcomes of infants born at 22 and 23 weeks’ gestational age. METHODS: The study cohort consisted of 1057 infants born at 22 to 25 weeks in the Neonatal Research Network, Japan. Neurodevelopmental impairment (NDI) at 36 to 42 months’ chronological age was defined as any of the following: cerebral palsy, hearing impairment, visual impairment, and a developmental quotient RESULTS: Numbers and incidences (%) of infants with death or NDI were 60 (80%) at 22 weeks and 156 (64%) at 23 weeks. In logistic regression analysis, gestational ages of 22 weeks (odds ratio [OR]: 5.40; 95% confidence interval [CI]: 2.48–11.76) and 23 weeks (OR: 2.14; 95% CI: 1.38–3.32) were associated with increased risk of death or NDI compared with 24 weeks, but a gestational age of 25 weeks (OR: 0.65; 95% CI: 0.45–0.95) was associated with decreased risk of death or NDI. In the systematic review, the medians (range) of the incidence of death or NDI in 8 cohorts were 99% (90%–100%) at 22 weeks and 98% (67%–100%) at 23 weeks. CONCLUSIONS: Infants born at 22 and 23 weeks’ gestation were at higher risk of death or NDI than infants at born at 24 weeks. However, outcomes were improved compared with those in previous studies. There is a need for additional discussions on interventions for infants born at 22 or 23 weeks’ gestation.

Aim The study aims to determine the risk factors associated with mortality and necrotising enterocolitis (NEC) among very low birthweight infants in 95 neonatal intensive care units in the Asian Network on Maternal and Newborn Health. Methods This is a cross-sectional study using an international collaborative database of 17 595 very low birthweight infants admitted within 28 days of birth between 2003 and 2006 in four Asian countries. Information on the mortality and morbidity of neonates admitted to the neonatal intensive care units was recorded. Factors associated with the death and diseases of infants were estimated using multilevel multivariate logistic regression. Random effects were included to account for the clustering of the observations. Results Overall discharge mortality was 15% and it was significantly different by countries and units. The mortality rate was found to be significantly higher in neonates with pulmonary haemorrhage (odds ratio 1.83, 95% confidence interval 1.63–2.04) and air leak syndrome (odds ratio 1.51, 95% confidence interval 1.30–1.72). The incidence of NEC was 4.3% and was strongly associated with other morbidities. Multivariate logistic regression showed that patent ductus arteriosus was the most significant risk factor associated with NEC. Conclusions Our analysis has highlighted the great potential that multi-country, collaborative datasets have in terms of epidemiologic research when it comes to identifying issues in perinatal health that are common throughout Asia, and in relation to particular issues pertaining to specific countries and neonatal units. Establishing collaborative networks, conducting analyses of common datasets and further epidemiologic research are now essential measures to improve newborn health in Asia.

To assess lung function and long-term respiratory outcomes in extremely low birth weight (ELBW) survivors.ELBW, especially with respiratory complications in the neonatal period, affects lung function at a later age.Longitudinal retrospective study.Lung function was evaluated in 89 ELBW survivors (at ages 8 and 12) with or without a history of bronchopulmonary dysplasia (BPD) or a bubbly/cystic lung appearance in the neonatal period.FVC, FEVLung function variables were significantly and positively correlated between 8 and 12 years: %FVC (RIn ELBW survivors, the obstructive pattern of lung function impairment deteriorated from 8 to 12 years of age, independent of the presence of severe BPD or bubbly/cystic appearance in the neonatal period.

OBJECTIVE:To compare neonatal outcomes of very low birth weight (VLBW) infants admitted to NICUs participating in the Canadian Neonatal Network and the Neonatal Research Network of Japan.METHODS:Secondary analyses of VLBW infants in both national databases between 2006 and 2008 were conducted. The primary outcome was a composite of mortality or any major morbidity defined as severe neurologic injury, bronchopulmonary dysplasia, necrotizing enterocolitis, or severe retinopathy of prematurity at discharge. Secondary outcomes included individual components of primary outcome and late-onset sepsis. Logistic regression adjusting for confounders was performed.RESULTS:A total of 5341 infants from the Canadian Neonatal Network and 9812 infants from the Neonatal Research Network of Japan were compared. There were higher rates of maternal hypertension, diabetes mellitus, outborn, prenatal steroid use, and multiples in Canada, whereas cesarean deliveries were higher in Japan. Composite primary outcome was better in Japan in comparison with Canada (adjusted odds ratio [AOR] 0.87, 95% confidence interval [CI] 0.79–0.96). The odds of mortality (AOR 0.40, 95% CI 0.34–0.47), severe neurologic injury (AOR 0.57, 95% CI 0.49–0.66), necrotizing enterocolitis (AOR 0.23, 95% CI 0.19–0.29), and late-onset sepsis (AOR 0.22, 95% CI 0.19–0.25) were lower in Japan; however, the odds of bronchopulmonary dysplasia (AOR 1.24, 95% CI 1.10–1.42) and severe retinopathy of prematurity (AOR 1.98, 95%CI 1.69–2.33) were higher in Japan.CONCLUSIONS:Composite outcome of mortality or major morbidity was significantly lower in Japan than Canada for VLBW infants. However, there were significant differences in various individual outcomes identifying areas for improvement for both networks.

Background: Although medical care for very-low-birth-weight (VLBW) infants has improved over time, it is unclear how this has affected mortality and morbidity. To characterize these trends, a network database was analyzed. Methods: This is a cohort study of VLBW infants born from 2003 through 2008. Results: Over the 6-y period, 19,344 infants were registered and analyzed. Crude mortality rates among the infants at discharge decreased significantly (from 10.8 to 8.7%) during the study period. The greatest improvement in mortality was observed among infants with birth weights between 501 and 750 g (25.6–17.7 %). The odds ratio (OR) of mortality over year adjusted for potential confounders by a logistic regression model was 0.94 (95% confidence interval 0.92–0.97). Significant increases were observed in some morbidities, including symptomatic patent ductus arteriosus with an OR of 1.11 (1.09–1.13); late-onset adrenal insufficiency, 1.21 (1.17–1.26); and necrotizing enterocolitis/intestinal perforation, 1.10 (1.01–1.12). However, the severe form of intraventricular hemorrhage, with an OR of 0.98 (0.92–0.99), decreased significantly. Risk-adjusted trends in other morbidities showed no significant change. Conclusion: Mortality of VLBW infants decreased significantly over the 6-y study period. Decreasing morbidity is essential for further improvement in the outcomes in VLBW infants.

Percutaneously inserted central catheters (PICCs) are often used in neonatal medicine. Venous thrombosis (VT) is one of the complications associated with PICC use. According to some reports, fresh frozen plasma (FFP) may be a risk factor for VT. The purpose of this study was to determine whether FFP use is associated with VT in extremely low birth weight infants (ELBWIs). We performed a matched case-control study on risk factors for VT in ELBWIs born over a period of 5 years in the neonatal intensive care unit of a tertiary hospital. Controls were infants from the unit matched for gestational age and birth weight. We performed univariate analyses and created receiver operating characteristic (ROC) curves for the cut-off values of continuous parameters such as FFP. We also conducted multivariate conditional logistic regression analysis and calculated adjusted odds ratios and their 95% confidence intervals. Thirteen VT cases and 34 matched controls were examined. Using an ROC curve, FFP by day 550 mL/kg was selected as the cut-off value. In multivariate conditional logistic regression analysis, FFP by day 550 mL/kg exhibited an adjusted odds ratio of 5.88 (95% confidence interval: 1.12-41.81, p = 0.036). FFP by day 550 mL/kg may be a risk factor for VT in ELBWIs.

Background: The aim of the present study was to explore the relationships among neonatal morbidity, interventions and death or adverse neurodevelopmental outcomes in very low-birthweight (VLBW) infants. Methods: Subjects were infants with birthweight ≤1500 g who were cared for in the tertiary neonatal intensive care units in Japan. Multiple logistic regression analysis was performed to examine the odds ratios (OR) and 95% confidence intervals (CI) of neonatal factors for death or cerebral palsy (CP) and death or developmental delay (developmental quotient

Background: A nationwide survey on neonatal surgery conducted by the Japanese Society of Pediatric Surgeons has demonstrated that the mortality of neonatal intestinal perforation has risen over the past 15 years. The incidence of intestinal perforation in extremely low-birthweight (ELBW) neonates has been increasing as more ELBW neonates survive and as the live-birth rate of ELBW has increased. In contrast to necrotizing enterocolitis (NEC) and focal intestinal perforation (FIP), the pathogenesis of meconium-related ileus, defined as functional bowel obstruction characterized by delayed meconium excretion and microcolon, remains unclarified. Methods: The histology of 13 ELBW neonates with intestinal perforation secondary to meconium-related ileus was reviewed, and the radiology of 33 cases of meconium-related ileus diagnosed on contrast enema was reviewed. Specimens obtained from 16 ELBW neonates without gastrointestinal disease served as age-matched controls for histological assessment. Results: The size of the ganglion cell nucleus in meconium-related ileus and in control subjects was 47.3 ± 22.0 µm2 and 37.8 ± 11.6 µm2, respectively, which was not significantly different. In all cases of meconium-related ileus, contrast enema demonstrated a microcolon or small-sized colon, with a gradual caliber change in the ileum and filling defects due to meconium in the ileum or colon, showing not-identical locations of caliber changes and filling defects. Conclusion: Morphological immaturity of ganglia was not suggested to be the pathogenesis of meconium-related ileus. Impaction of inspissated meconium is not the cause of obstruction, but the result of excessive water absorption in the hypoperistaltic bowel before birth, although the underlying mechanism responsible for the fetal hypoperistalsis remains unclear.

Background: The aim of this study was to describe and compare neurodevelopmental outcomes with birthweight (BW) groups at 250-g intervals of very-low-birthweight (VLBW) infants at 3 years of age in a multicenter cohort in Japan. Methods: A total of 3104 VLBW infants born in 2003 and 2004 registered in a NICU-network database were followed in the study. Neurodevelopmental impairment (NDI) was defined as any of the following impairments: cerebral palsy, unilateral or bilateral blindness, severe hearing impairment, or developmental delay; a developmental quotient (DQ)

Background: Neonatal anthropometric charts of the distribution of measurements, mainly birth weight, taken at different gestational ages are widely used by obstetricians and pediatricians. However, the relationship between delivery mode and neonatal anthropometric data has not been investigated in Japan or other countries.Methods: The subjects were selected from the registration database of the Japan Society of Obstetrics and Gynecology (2003–2005). Tenth centile, median, and 90th centile of birth weight by sex, birth order, and delivery mode were observed by gestational age from 22 to 42 weeks among eligible singleton births.Results: After excluding 248 outliers and 5243 births that did not satisfy the inclusion criteria, 144 980 births were included in the analysis. The distribution of 10th centile curves was skewed toward lower birth weights during the preterm period among both first live births and second and later live births delivered by cesarean section. More than 40% of both male and female live births were delivered by cesarean section at 37 weeks or earlier.Conclusions: The large proportion of cesarean sections influenced the skewness of the birth weight distribution in the preterm period.

OBJECTIVE. Our goal was to investigate the neonatal mortality rate and the mortality rate during the NICU stay for extremely low birth weight infants born in Japan in 2005. METHODS. The Committee of Neonatal Medicine of the Japan Pediatric Society retrospectively surveyed the deaths of extremely low birth weight infants born and hospitalized between January 1 and December 31, 2005. From 297 institutions in Japan, data on 3065 extremely low birth weight infants, which represented 98.4% of those reported in the maternal and health statistics of Japan in 2005, were collected. RESULTS. The neonatal mortality rate and the mortality rate during the NICU stay were 13.0% and 17.0%, respectively, which were lower than 17.7% and 21.5% in the survey in 2000. The neonatal mortality rates and the mortality rates during the NICU stay were 53.3% and 67.7% in the CONCLUSION. The mortality rates of extremely low birth weight infants who were born in 2005 demonstrated definite improvement.

Wilson-Mikity syndrome (WMS) was first reported in 1960 by Wilson and Mikity. They described preterm infants who developed areas of cystic emphysema in the first month of life with subsequent progression to chronic lung disease (CLD) of infancy, although these infants did not exhibit early respiratory distress, such as respiratory distress syndrome (RDS). This condition was widely accepted over the next 20 years, but WMS is now rarely mentioned and is commonly considered an anachronism. In Japan, CLD is classified into six types according to the presence of RDS and/or intrauterine inflammation and appearance on chest X-ray. One type of CLD (type III, which accounts for 13.5% of all CLD) is defined as history of intrauterine inflammation and the typical bubbly and cystic appearance on chest X-ray described in the original report of WMS. There is insufficient evidence to determine whether WMS exists or whether WMS is relatively common only in Japan and not in other countries. It is important, however, to distinguish this type of CLD from other types because the strategy for the prevention or treatment of CLD should be different according to its origin, cause, and risk factors.

Background Clinical guidelines assist physicians to make decisions about suitable healthcare. We conducted a controlled before-and-after study to investigate the impact of professional-led guideline workshops for patent ductus arteriosus (PDA) management on physicians’ clinical practices, discharge mortality, and associated morbid conditions among preterm neonates. Methods We recruited physicians practicing at two neonatal intensive care units (NICUs) in Japan and used the data of all neonates weighing less than or equal to 1,500 g admitted to 90 NICUs (2 intervention NICUs and 88 control NICUs) in the Neonatal Research Network of Japan from April 2008 to March 2010. We held 1-day workshops for physicians on PDA clinical practice guidelines at the two intervention NICUs. Physicians’ skills assessed by confidence rating (CR) scores and the Sheffield Peer Review Assessment Tool (SPRAT) were compared between pre- and post-workshop month at the intervention NICUs using Wilcoxon signed-rank tests. Neonatal discharge mortality and morbidity were compared between pre- and post-workshop year at both the intervention and control NICUs using multivariable regression analyses adjusting for potential confounders. Results Fifteen physicians were included in the study. Physicians’ CR scores (2.14 vs. 2.47, p = 0.02) and SPRAT (4.14 vs. 4.50, p = 0.05) in PDA management improved after the workshops. The analyses of neonatal outcomes included 294 and 6,234 neonates in the intervention and control NICUs, respectively. Neonates’ discharge mortality declined sharply at the intervention NICUs (from 15/146 to 5/148, relative risk reduction −0.67; adjusted odds ratio 0.30, 95% confidence interval 0.10 to 0.89) during the post-workshop period. The mortality reduction was much greater than that in the control NICUs (from 207/3,322 to 147/2,912, relative risk reduction −0.19; adjusted odds ratio 0.75, 95% confidence interval 0.59 to 0.95), although the difference between the intervention and control NICUs were not statistically significant. Conclusions Overall, physicians’ confidence in PDA management improved after attending guideline workshops. Face-to-face workshops by guideline developers can be a useful strategy to improve physicians’ PDA management skills and, thereby, might reduce PDA-associated mortality in preterm neonates. Electronic supplementary material The online version of this article (doi:10.1186/s13012-015-0258-5) contains supplementary material, which is available to authorized users.

Intrauterine infection is associated with chorioamnionitis (CAM), which can lead to preterm delivery. We previously reported that the levels of IgM and the incidence of CAM were elevated in preterm infants with neonatal pulmonary emphysema. The pathogen and target of this IgM remain unclear. By using Western blot and amino acid sequences, we have determined one of the target proteins: annexin A2. Immunohistochemical analysis showed that annexin A2 was expressed at fetal chorion and amnion membranes. Among very low birth weight (VLBW) infants with hyper-IgM (> or = 30 mg/dL), 58.8% showed a high titer against annexin A2 (more than x 16), which accounted for about 20%-40% of the total IgM. Anti-annexin A2 IgM antibody inhibited plasmin generation. Furthermore, the median of anti-annexin A2 IgM titer from preterm infants who were delivered with high-grade (grade III) CAM was significantly higher than those from preterm infants without CAM (p = 0.011) and with low-grade CAM (grade I and II) (p = 0.010). Here, we indicate the fetal autoimmunoreactivity against the fetomaternal interface in preterm infants.

Fretting fatigue tests for Ti–6Al–4 V alloy were conducted by use of the plate fatigue specimen with bolt-tightened shoe on both sides of the plate. It was clarified that the repeated bending stress at the contact area where fretting fatigue failure starts linearly decreased as stress over the contact area increased. Fretting fatigue crack starts from the pit where stress concentrate. The pit initiates when fretting debris were removed from the surface striation formed due to the contact slip movement. The fretting fatigue crack initiation mode was transgranular, while the fretting fatigue crack propagation mode was striation.

OBJECTIVES. The objectives of this study were to describe the characteristics and morbidity of very low birth weight infants, to identify the medical intervention for these infants, and to evaluate the factors affecting the mortality of these infants among the participating hospitals.METHODS. A large multicenter neonatal research network that included level III NICUs from throughout Japan was established. A standardized mortality rate was formulated by giving a ratio of the observed deaths and the predicted deaths based on a 100-g birth weight interval mortality. A regression model was used to predict the factors that affect neonatal mortality.RESULTS. The network included 37 centers and 2145 infants weighing ≤1500 g, born or admitted to the centers in 2003. Gestational age and birth weight of studied infants were 28.6 ± 3.6 gestational weeks (mean ± SD) and 1025 ± 302 g, respectively. Overall, 11% of the infants died before being discharged from hospitals (range: 0%–21%). The standardized mortality rate varied among the facilities (range: 0%–30%). No association between the annual number of patients admitted and standardized mortality rate was found. Among all of the very low birth weight infants, 14% were outborn infants, 72% were delivered by cesarean sections, 27% had patent ductus arteriosus, 3% had gastrointestinal perforation, 8% had bacterial sepsis, and 13% had intraventricular hemorrhage. Medical interventions involved were: 41% antenatal corticosteroids, 54% surfactant therapy, 18% postnatal steroids for chronic lung disease, and 29% high-frequency oscillatory ventilation. We found variations in the medical interventions and the clinical outcomes among the centers.CONCLUSIONS. The overall survival rate for very low birth weight infants among neonatal centers in Japan was ∼90%. However, differences in the morbidity and mortality were observed among these centers.

Background: In Japan, palivizumab was approved in 2002 for prophylaxis of severe respiratory syncytial virus disease in high-risk infants. In order to evaluate the efficacy and safety of this drug, a questionnaire survey was conducted. Methods: A questionnaire was sent to member institutions of the Japan Neonatologist Association. The subjects were premature infants who were considered possible candidates for treatment with palivizumab. Results: A total of 6302 case reports, including those of 2806 infants receiving palivizumab (group P) and 3496 infants not receiving palivizumab (group NP), respectively, were retrieved. Background characteristics revealed significant lower gestational age (GA) and birthweight for group P (P < 0.0001). Sex ratio did not differ significantly, while use of oxygen and mechanical ventilation in the neonatal intensive care unit, and presence of chronic lung disease were significantly higher for infants in group P (P < 0.0001). When comparison of hospitalization rate for respiratory symptoms was performed with stratification by eligibility criteria, in the group of infants born at 29–35 weeks GA the hospitalization rate was 4.0% and 5.7% in groups P and NP, respectively (P < 0.05). Multivariate analysis also showed that prophylaxis with palivizumab was the only variable that significantly decreased rate of hospitalization (odds ratio 0.630, P= 0.0053). The incidence of adverse events associated with the administration of palivizumab was low. Conclusion: In this non-randomized questionnaire survey, multivariate analysis showed that palivizumab significantly decreased the rate of hospitalization due to respiratory symptoms for infants born prematurely at 29–35 weeks GA. These data confirmed the efficacy and safety of palivizumab.

Background: The aim of the present study was to examine the presence of motilin in the duodenal epithelial cells of premature infants of

Objective. Evaluation of the placenta provides some important insights into pathophysiologic changes that take place during the prenatal and intrapartum process. We investigated the relationship between placental findings and periventricular leukomalacia (PVL) to obtain a better understanding of its cause.Methods. Thirty-two preterm infants with PVL delivered before 34 weeks’ gestation, between 1990 and 1999, were classified into 4 groups according to the onset of brain injury assumed from ultrasonographic presentation and clinical course: 2 Antenatal, 22 Peripartum, 5 Postnatal, and 3 in an unknown time of onset group. We evaluated the gross and histopathologic features of the placentas of each group and compared them with those of a control group matched by birth weight and gestational age in terms of the frequency of major placental findings. Potential confounding factors were controlled in logistic regression analyses.Results. Gross lesions with disturbance of uteroplacental circulation, including massive retroplacental hematoma, extensive infarction or thrombosis, and marked basal or perivillous fibrin deposition, were observed more frequently in the Antenatal + Peripartum combined subgroup than in the controls (41.7% vs 13.7%). Placentas from the Antenatal + Peripartum subgroup also demonstrated a significantly higher frequency of ischemic changes in villi, based on histopathologic examination, as compared with the control group (54.2% vs 13.7%). These associations remained after adjustment for confounding factors in logistic regression analyses (odds ratio: 4.04, 95% confidence interval: 1.40–11.67; and odds ratio: 7.28, 95% confidence interval: 2.50–21.20; respectively). Frequencies of chorioamnionitis and twin placentation tended to be higher in PVL cases than in the controls, although the differences were not statistically significant (46.9% vs 37.9%, 37.5% vs 20.0%, respectively).Conclusions. These results suggest that disturbed placental circulation underlies the development of PVL in the majority of cases with prenatal and peripartum brain injury. In chorioamnionitis cases, certain additional factors were suggested in the genesis of PVL. Thus, placental examination is essential for elucidating the pathophysiologic changes leading to PVL in the perinatal process.

To evaluate the effect of antenatal corticosteroids (AC) therapy on short- and long-term outcomes among very low birth weight preterm infants after histologic chorioamnionitis (HCA). We performed a retrospective analysis of 5240 single very low birth weight (VLBW) infants born at 22 + 0 and 33 + 6 weeks of gestation between 2003 and 2007, who registered to the Neonatal Research Network Japan. The effects of AC therapy on mortality, neurodevelopmental outcomes at 3 years of age and neonatal morbidities were analyzed in the groups with or without HCA using logistic regression analysis. In the study subjects, 840 were with HCA, 2734 were without HCA, and 1666 were excluded without data for HCA. AC therapy was significantly associated with decreasing mortality before 3 years of age; [0.52 (0.32–0.86)], [odds ratio (95 % confidence intervals]. There were no differences between the two groups regarding neurodevelopmental outcomes, including cerebral palsy [0.90 (0.41–1.99)], development quotient

To assess lung function at 8 years old in extremely low birthweight (ELBW) survivors and to identify perinatal determinants associated with impaired lung function.Retrospective cohort study.Level III neonatal intensive care unit.ELBW survivors born in 1990-2004 with available spirometry at 8 years old were studied. Children were excluded if they had a Wechsler Intelligence Scale for Children Third Edition full IQ70.Multivariate logistic regression analysis was used to identify perinatal determinants associated with airway obstruction (forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio80%) at school age and the predictive power of potential determinants. Potential risk factors and predictors assessed in this study were gestational age, birth weight, small for gestational age, sex, chorioamnionitis, premature rupture of membranes, antenatal steroids, surfactant administration, respiratory distress syndrome, postnatal steroids, severe bronchopulmonary dysplasia and bubbly/cystic appearances of the lungs by X-ray during the neonatal period.Of 656 ELBW survivors, 301 (45.9%) had attended a school-age follow-up at 8 years old. A total of 201 eligible children completed the lung function test. Bubbly/cystic appearance of the lungs (OR 4.84, 95% CI 1.26 to 18.70) was associated with a low FEV1/FVC ratio. Children with bubbly/cystic appearance had characteristics of immaturity and intrauterine inflammation.Within a cohort of ELBW infants, a bubbly/cystic appearance of the lungs in the neonatal period was the strongest determinant of a low FEV1/FVC ratio at school age.

Background: There is a significant association between hepatoblastoma and low birthweight. A case-control study was conducted to reveal risk factors for hepatoblastoma in children of extremely low birthweight (

To evaluate the incidence of respiratory distress syndrome (RDS) in infants born to mothers with placenta previa and to assess the risk factors for RDS.Ninety-nine pregnant women with placenta previa who delivered by cesarean section at 30-35 weeks of gestation were compared retrospectively with 102 pregnant women matched for week of gestation and birth year, who underwent elective cesarean section. Maternal characteristics, neonatal outcome, and incidence of RDS were analyzed. Umbilical cord blood samples were collected at delivery and were used to determine cortisol, epinephrine, and norepinephrine levels. Student's t-test, the chi-square test, and Fisher's exact test were used for statistical comparisons. P0.05 was considered significant. The Mann-Whitney U test was used for comparison of continuous variables.Preeclampsia, histological chorioamnionitis, and premature rupture of membranes were significantly lower in the placenta previa group (placenta previa: 2.0% vs. control: 14.7%, P0.01; 14.1% vs. 30.1%, P0.01; 7.1% vs. 17.6%, P0.05, respectively). The incidence of RDS was significantly higher in the placenta previa group than in the control group (29.3% vs. 6.9%, P0.0001). The cortisol level in umbilical cord blood in the placenta previa group was lower than in the control group (median 7.3, range 4.4-14.9 microg/dl vs. median 10.6, range 4.9-30.3 microg/dl, P0.05). There were no significant differences in epinephrine or norepinephrine levels between the two groups.The incidence of RDS in infants delivered at 30-35 weeks' gestation by cesarean section was significantly higher in mothers with placenta previa than in women without placenta previa. This may reflect decreased fetal stress since the cord blood cortisol levels were found to be lower in women with placenta previa.

AIM—To investigate the colonisation with Bifidobacterium breve of the bowels of very low birthweight (VLBW) infants. METHODS—The adverse effects of B breve were examined in 66 VLBW infants (preliminary study). A prospective randomised clinical study of 91 VLBW infants was also completed and these infants were followed up for three years. Precise viable bacterial counts of serial stool specimens were examined for the first eight weeks after birth in 10 infants. The colonisation rates of administered bacteria were examined using immunohistochemical staining of stool specimens with a B breve specific monoclonal antibody. RESULTS—In the preliminary study there were no side effects attributable to the bacteria. Immunohistochemical staining of stool specimens showed that the colonisation rates of the administered bacteria were 73% at 2 weeks of age, but only 12% in the control group. Early administration of B breve significantly decreased aspirated air volume from the stomach and improved weight gain. CONCLUSIONS—B breve can colonise the immature bowel very effectively and is associated with fewer abnormal abdominal signs and better weight gain in VLBW infants, probably as a result of stabilisation of their intestinal flora and accelerated feeding schedules. Keywords: Bifidobacterium breve; stool specimens; necrotising enterocolitis; very low birthweight.

Objectives To determine the feasibility of clinical trials of newly developed treatments or standardisation of existing practices to further improve outcomes among very low birth weight (VLBW) infants, a nationwide database was analysed with a two-dimensional approach using two multivariate logistic models. Design Retrospective observational analysis. Setting Level III perinatal centres in Japan. Participants 15 920 VLBW infants admitted at 38 participating centres from 2003 through 2010. Outcome measures Clinical information for the infants was collected until discharge from the centres. A multivariate logistic model identified practices and morbidities associated with mortality. Then, those which were significantly associated with mortality were analysed using a multilevel logistic model. The residues calculated by the multilevel analysis were used as an indicator of centre variation. Results Among practices, antenatal steroids and intubation at birth showed relatively high centre variations (0.9 and 0.8) and favourable ORs (0.7 and 0.5) for mortality, while caesarean section showed a low centre variation (0.4) and a favourable OR (0.8). Sepsis and air leak showed high centre variations (0.4 and 0.4) and high ORs (3.8 and 3.4) among morbidities. Pulmonary haemorrhage, persistent pulmonary hypertension of the newborn, and intraventricular haemorrhage showed moderate variations (0.2, 0.3 and 0.2, respectively) and high ORs (5.6, 4.1 and 2.9, respectively). In contrast, necrotising enterocolitis showed the lowest variation (0.1) and a high OR (4.9). Conclusions The two-dimensional approach has clearly demonstrated the importance of clinical trial or standardisation. The practices and morbidities with low centre variations and high ORs for mortality must be improved through clinical trials of newly introduced techniques, while standardisation must be considered for practices and morbidities with a high centre variation. Trial registration The database was registered as UMIN000006961.

In neonatal medicine, it is thought that retinol is useful for preventing CLD and for fetal development. However, beta-carotene had other vitamin A precursors have not been studied in neonates with CLD or others disorders. Cord blood of neonates including ELBW and VLBW infants was assayed for plasma levels of retinol, RBP, beta-carotene and cryptoxanthin. Plasma beta-carotene levels in ELBW and VLBW were lower than that in term infants, but plasma cryptoxanthin levels in ELBW and VLBW were about the same as in term infants. Plasma retinol and RBP levels showed almost same levels during 23-41 gestational weeks. Maternal smoking reduced plasma beta-carotene but not cryptoxanthin, retinol, or RBP levels. IUGR was associated with increased cryptoxanthin levels in cord blood. Serious neonatal diseases, including CLD and ROP manifested no significant effects on the cord blood vitamin levels. Thus, the occurrence of these diseases at birth could not be predicted by examination of vitamin levels in cord blood.

The study aims to determine the risk factors associated with mortality and necrotising enterocolitis (NEC) among very low birthweight infants in 95 neonatal intensive care units in the Asian Network on Maternal and Newborn Health.This is a cross-sectional study using an international collaborative database of 17,595 very low birthweight infants admitted within 28 days of birth between 2003 and 2006 in four Asian countries. Information on the mortality and morbidity of neonates admitted to the neonatal intensive care units was recorded. Factors associated with the death and diseases of infants were estimated using multilevel multivariate logistic regression. Random effects were included to account for the clustering of the observations.Overall discharge mortality was 15% and it was significantly different by countries and units. The mortality rate was found to be significantly higher in neonates with pulmonary haemorrhage (odds ratio 1.83, 95% confidence interval 1.63-2.04) and air leak syndrome (odds ratio 1.51, 95% confidence interval 1.30-1.72). The incidence of NEC was 4.3% and was strongly associated with other morbidities. Multivariate logistic regression showed that patent ductus arteriosus was the most significant risk factor associated with NEC.Our analysis has highlighted the great potential that multi-country, collaborative datasets have in terms of epidemiologic research when it comes to identifying issues in perinatal health that are common throughout Asia, and in relation to particular issues pertaining to specific countries and neonatal units. Establishing collaborative networks, conducting analyses of common datasets and further epidemiologic research are now essential measures to improve newborn health in Asia.