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To verify validity of the criteria used for the Japan Obstetric Compensation System for Cerebral Palsy (JOCS-CP) in preterm infants, the association between the criteria and the development of CP was studied using a neonatal database. Our hypothesis was that the criteria would not be sufficient due to the recent advances made in perinatal care.Preterm infants born between 2003 and 2019 and registered in the Neonatal Research Network of Japan database with a birth weight of 1500 g or less or a gestational age of less than 32 weeks were analyzed. The database included the clinical information of registered infants during their stay in NICUs and outcomes at 3 years of age.The database included 73 615 infants. After excluding those with an unknown outcome at discharge, 73 464 infants were analyzed for short-term outcomes, including mortality and morbidities. The incidence of CP at 3 years of age was analyzed in 36 151 infants. Furthermore, 16 467 infants born between 28 and 31 weeks of gestation were examined in terms of the validity of the current eligibility criteria. The mortality and incidences of severe intraventricular hemorrhage and periventricular leukomalacia significantly decreased during the study period (Cochrane-Armitage test, p 0.01). Furthermore, the eligibility criteria were not sufficiently nor strongly associated with indicators for detecting perinatal hypoxia-ischemia resulting in CP.The existing eligibility criteria of the JOCS-CP used for preterm infants born between 28 and 31 weeks were no longer suitable because of the advances in perinatal care in Japan.

Objective This study aimed to compare the short- and long-term outcomes of extremely preterm small for gestational age (SGA) infants and appropriate for gestational age (AGA) infants in Japan. Study Design We retrospectively assessed 434 SGA and 1,716 AGA infants born at 22 to 27 weeks of gestational age (GA) and examined their outcomes on singletons and inborn births between 2003 and 2012. Infants were followed-up for 3 years, and the clinical characteristics and outcomes were compared. Fisher's exact and Student's t-tests were used for independent sample comparison. Logistic regression was used to identify associated factors. Results The prevalence of intraventricular hemorrhage ≥ grade 3 was significantly lower (adjusted odds ratio [aOR]: 0.28; 95% confidence interval [CI]: 0.11 − 0.72), and the prevalence of bronchopulmonary dysplasia at 36 weeks of GA and the need for home oxygen therapy were significantly higher (aOR: 2.20; 95% CI: 1.66 − 2.91 and aOR: 2.46; 95% CI: 1.75–3.47, respectively) in SGA infants than in AGA infants. SGA infants born at 24 to 25 weeks of GA had a significantly higher prevalence of developmental quotient (DQ) Conclusion In SGA infants, birth at 24 to 25 weeks of GA is an independent risk factor for DQ Key Points

Ductus arteriosus aneurysm (DAA) is a rare cardiovascular anomaly, and thrombosis of DAA is even less common. The management of asymptomatic DAA with a thrombus is controversial. We here report a neonate with a thrombus from a DAA that grew rapidly into the pulmonary artery. The thrombus was detected incidentally in the main pulmonary artery by routine screening echocardiography. There was no clinical evidence of its presence until a few days after birth. The thrombus grew rapidly, despite administration of heparin. Six days after birth, the patient became cyanotic and had developed right ventricular pressure overload as a result of obstruction of the left pulmonary artery. The thrombus was immediately removed and the DAA resected. The patient was discharged home without any complications. Complications related to thrombus of a DAA can be critical and therefore require careful monitoring. LEARNING OBJECTIVE: A thrombus extending from a ductus arteriosus aneurysm into the pulmonary artery can have serious consequences; thus, careful monitoring is required. Any signs of such complications should prompt immediate consideration of removal of the aneurysm and thrombus.

Background Patent ductus arteriosus (PDA), which disrupts the hemodynamics early after birth, causes intraventricular hemorrhage and neonatal necrotizing. Unlike medical treatment for hemodynamically significant PDA, there are disparities between institutions regarding the timing of surgery, considering the complications associated with surgery or access to surgery. Methods We aimed clarify the clinical picture of postoperative complications and examined whether there were risk factors regarding that indication of surgery for hemodynamically significant PDA from the point of postoperative complications associated with surgery. Results There were 36 cases of extremely low birth weight infants who required video-assisted thoracoscopic surgery for PDA (VATS-PDA). The median gestational age was 25.2 weeks, and the median birth weight was 699 g. The treatment indication of VATS-PDA was medical treatment resistance in 17 cases, relapsed PDA in 15 cases, and no additional administration of indomethacin because of severe side effects in four cases. Complications with VATS-PDA occurred in eight out of 36 cases. There were three cases of pneumothorax, two of thoracotomy transition, two of pulmonary hemorrhage, and four of post-ligation cardiac syndrome (PLCS). VATS-PDA-related death occurred in two cases because of PLCS. The frequency of four or more times of indomethacin with or without postoperative complications was 88% vs. 39% (p=0.04), respectively. Conclusions All postoperative deaths were caused by PLCS, which had the highest risk of poor prognosis. VATS-PDA should be considered for unclosed PDA after one course of indomethacin administration.

Survival of preterm newborn infants have increased steadily since the introduction of surfactant treatment and antenatal steroids. In the absence of randomized controlled trials on ventilatory strategies in extremely preterm infants, we present ventilatory strategies applied during the initial phase and the continued ventilatory care as applied in three centers with proactive prenatal and postnatal management and well documented good outcomes in terms of mortality and morbidity in this cohort of infants.

To determine the trends in inhaled nitric oxide (iNO) utilization in the late phase of hospitalization in a large Japanese cohort of extremely preterm infants and evaluate its benefit on long-term outcomes.This was a retrospective multicenter cohort study of 15 977 extremely preterm infants born at28 weeks of gestational age between 2003 and 2016, in the Neonatal Research Network, Japan. Demographic characteristics, morbidity, and mortality were compared between extremely preterm infants with and without post-acute iNO therapy. Multivariable logistic analysis was performed to determine factors associated with post-acute iNO and its impact on neurodevelopmental outcomes at 3 years of age.Post-acute iNO utilization rates increased from 0.3% in 2009 to 1.9% in 2016, even under strict insurance coverage rules starting in 2009. Gestational age (1-week increment; aOR 0.82, 95% CI 0.76-0.88), small for gestational age (1.47, 1.08-1.99), histologic chorioamnionitis (1.50, 1.21-1.86), 5-minute Apgar score4 (1.51, 1.10-2.07), air leak (1.92, 1.30-2.83), and bubbly/cystic appearance on chest X-Ray (1.68, 1.37-2.06) were associated with post-acute iNO. Post-acute iNO was not associated with neurodevelopmental outcomes at 3 years of age.The increasing post-acute iNO utilization rate among extremely preterm infants has been concurrent with improved survival rates of extremely preterm infants in Japan. Infants treated with post-acute iNO had more severe disease and complications than the comparison group, but there were no differences in neurodevelopmental outcome at 3 years. This suggests post-acute iNO may benefit extremely preterm infants.

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..

Laser photocoagulation, which is the standard treatment for retinopathy of prematurity (ROP), can have adverse events. Studies of anti-vascular endothelial growth factor injections have suggested efficacy in the treatment of ROP, but few studies have directly compared them with laser treatments.To compare intravitreal aflibercept vs laser photocoagulation in infants with ROP requiring treatment.This noninferiority, phase 3, 24-week, randomized clinical trial was conducted in 27 countries (64 hospital sites) throughout Asia, Europe, and South America. Overall, 118 infants (gestational age ≤32 weeks at birth or birth weight ≤1500 g) with ROP severity (zone I stage 1+ [stage 1 plus increased disease activity], zone I stage 2+, zone I stage 3, zone I stage 3+, zone II stage 2+, or zone II stage 3+) requiring treatment or with aggressive posterior ROP in at least 1 eye were enrolled between September 25, 2019, and August 28, 2020 (the last visit occurred on February 12, 2021).Infants were randomized 2:1 to receive a 0.4-mg dose of intravitreal aflibercept (n = 75) or laser photocoagulation (n = 43) at baseline. Additional treatment was allowed as prespecified.The primary outcome was the proportion of infants without active ROP and unfavorable structural outcomes 24 weeks after starting treatment (assessed by investigators). The requirement for rescue treatment was considered treatment failure. Intravitreal aflibercept was deemed noninferior if the lower limit of the 1-sided 95% bayesian credible interval for the treatment difference was greater than -5%.Among 118 infants randomized, 113 were treated (mean gestational age, 26.3 [SD, 1.9] weeks; 53 [46.9%] were female; 16.8% had aggressive posterior ROP, 19.5% had zone I ROP, and 63.7% had zone II ROP) and 104 completed the study. Treatment (intravitreal aflibercept: n = 75; laser photocoagulation: n = 38) was mostly bilateral (92.9%), and 82.2% of eyes in the intravitreal aflibercept group received 1 injection per eye. Treatment success was 85.5% with intravitreal aflibercept vs 82.1% with laser photocoagulation (between-group difference, 3.4% [1-sided 95% credible interval, -8.0% to ∞]). Rescue treatment was required in 4.8% (95% CI, 1.9% to 9.6%) of eyes in the intravitreal aflibercept group vs 11.1% (95% CI, 4.9% to 20.7%) of eyes in the laser photocoagulation group. The serious adverse event rates were 13.3% (ocular) and 24.0% (systemic) in the intravitreal aflibercept group compared with 7.9% and 36.8%, respectively, in the laser photocoagulation group. Three deaths, which occurred 4 to 9 weeks after intravitreal aflibercept treatment, were considered unrelated to aflibercept by the investigators.Among infants with ROP, intravitreal aflibercept compared with laser photocoagulation did not meet criteria for noninferiority with respect to the primary outcome of the proportion of infants achieving treatment success at week 24. Further data would be required for more definitive conclusions regarding the comparative effects of intravitreal aflibercept and laser photocoagulation in this population.ClinicalTrials.gov Identifier: NCT04004208.

IntroductionThe remarkable improvement in the long-term prognosis of extremely premature infants has led to an increase in the number of cases of bronchopulmonary dysplasia (BPD). BPD affects pulmonary function and developmental outcomes, resulting in high chronic health burdens for infants and their families over the years. Therefore, identifying its risk factors in the early period of life and exploring better prophylactics and treatment strategies are important.The objectives of our scoping review are to screen available evidence, identify perinatal risk factors involved in the development and severity of BPD and devise a novel disease classification system that can predict long-term prognosis.Methods and analysisEligibility criteria are as follows: articles published from 2002 to 2021; studies conducted in developed countries; articles written in English (PubMed) or Japanese (Ichushi); randomised controlled trials, prospective/retrospective cohort studies or case-control studies; extremely premature infants born before 28 weeks of gestational age; and articles in which endpoint was severe BPD as classified by the National Institute of Child Health and Human Development.We will screen the titles and abstracts of studies identified by independent reviewers using the population-concept-context framework. After a full-text review and data charting, we will provide the perinatal risk factors for severe BPD along with the risk ratio or odds ratio, 95% confidence interval and p values.Ethics and disseminationInstitutional review board approval is not required due to the nature of the study. The results of this review will be disseminated through peer-reviewed publications and presentations at relevant conferences.Protocol V.1, 22 September 2021Trial registration numberUMIN000045529.

Background Global assessment of antimicrobial agents prescribed to infants in the neonatal intensive care unit (NICU) may inform antimicrobial stewardship efforts. Methods We conducted a one-day global point prevalence study of all antimicrobials provided to NICU infants. Demographic, clinical, and microbiologic data were obtained including NICU level, census, birth weight, gestational/chronologic age, diagnoses, antimicrobial therapy (reason for use; length of therapy), antimicrobial stewardship program (ASP), and 30-day in-hospital mortality. Findings On July 1, 2019, 26% of infants (580/2,265; range, 0-100%; median gestational age, 33 weeks; median birth weight, 1800 g) in 84 NICUs (51, high-income; 33, low-to-middle income) from 29 countries (14, high-income; 15, low-to-middle income) in five continents received ≥1 antimicrobial agent (92%, antibacterial; 19%, antifungal; 4%, antiviral). The most common reasons for antibiotic therapy were "rule-out" sepsis (32%) and "culture-negative" sepsis (16%) with ampicillin (40%), gentamicin (35%), amikacin (19%), vancomycin (15%), and meropenem (9%) used most frequently. For definitive treatment of presumed/confirmed infection, vancomycin (26%), amikacin (20%), and meropenem (16%) were the most prescribed agents. Length of therapy for culture-positive and "culture-negative" infections was 12 days (median; IQR, 8-14) and 7 days (median; IQR, 5-10), respectively. Mortality was 6% (42%, infection-related). An NICU ASP was associated with lower rate of antibiotic utilization (p = 0·02). Interpretation Global NICU antibiotic use was frequent and prolonged regardless of culture results. NICU-specific ASPs were associated with lower antibiotic utilization rates, suggesting the need for their implementation worldwide. Funding Merck & Co.; The Ohio State University College of Medicine Barnes Medical Student Research Scholarship.

There are no standardized procedures for the resuscitation of micropreemies but respiratory and circulatory stabilization immediately after birth should be prioritized. Without aggressive support by positive pressure ventilation, establishing effective respiration among micropreemies is not possible. The first step in postnatal stabilization is initiated by positive airway pressure with a bag and mask. Once the heart rate increases above 100 beats/m, intratracheal intubation should be achieved because it is unusual for a micropreemie to breathe spontaneously or by non-invasive respiratory support for a protracted duration. Until further information is available, initial FiO

Out of East Asian languages which do not use the Latin alphabet, Japanese is a very complicated writing system that uses “kanji,” which are ideograms, and “kana,” which are phonetic characters. Most of the Japanese papers published so far using Journal Article Tag Suite (JATS) are science, technology, and medicine fields adapting horizontal writing systems, which are structurally consistent with English papers. Most of them only replace Latin letters with Japanese characters. In this presentation, we suggested method of presenting vertically oriented Japanese humanities articles in JATS XML. For vertical description of Chinese numeric, we would like to propose the introduction of an element which specifies description direction. Alternatively, could be used as a hidden command when creating a document. We propose the following notation in the part of the number that can be converted: 六五. Chinese numeric 六五 is a Arabic numeric 65. With this, it is shown that 六五 of Chinese numerals can be converted to 65 in Arabic numerals. For vertical text description with JATS, we would like to suggest adding @ writing-mode as an attribute to :. Furthermore, note and references should be differentiated for example, between a and a in the future. As Kanji are ideograms, there are variations that cannot be expressed with UTF-8. If these difficult Kanji are included in the JATS text, it will be necessary to decide on their description method. For the propagation of use of JATS XML for non-Latin characters articles, the structure of the document for example, vertical description, and special presentation should be considered more widely.

Delayed thyrotropin (TSH) elevation (dTSHe) is common in low birthweight infants. We aimed to clarify the risk factors for the development of dTSHe in infants weighing2000 g at birth.According to Japanese guidelines, infants with birthweight2000 g underwent second capillary TSH screening within 30 days, either at 1 month of age; or when weight reached 2.5 kg; or at discharge. dTSHe was defined as TSH20 mIU/L by venous sampling following a normal result (15 mIU/L) at first screening aged 4-6 days. For each infant who developed dTHSe three babies without dTSHe were selected and matched for gestational age and birth year. Small for gestational age (SGA) was defined as a birthweight10th percentile for the gestational age and sex. A multivariate analysis was performed to identify risk factors for the development of dTSHe.Among the 911 study infants, 17 infants (1.9%) had dTSHe. The median (range) birthweight in the dTSHe group (796 [388-1912] g) was significantly smaller than the comparison group (961 [408-1981] g) (P = 0.04). The number (%) of SGA infants was significantly higher in the dTSHe group (12 [71%]) than in the comparison group (13 [25%]) (P = 0.001). The multivariate analysis revealed that SGA was an independent risk factor for the development of dTSHe (adjusted odds ratio, 9.0; 95% confidence interval, 2.5-32.8; P = 0.001).Small for gestational age is an independent risk factor for the development of dTSHe in infants with a birthweight2000 g. The influence of prematurity, a matching criterion for this study, on dTSHe requires additional study.

Pulmonary microvascular injury is associated with the pathogenesis of bronchopulmonary dysplasia (BPD). To characterize the mechanisms of pulmonary vascular disease resulting from BPD, we studied the ultrastructural changes affecting pulmonary microvasculature.Newborn ICR mice were exposed to 85% hyperoxia or normoxia for 14 days, and then normal air replacement conditions for the following 7 days. At postnatal day (P)14 and P21, lungs were harvested for ultrastructural examination and assessment of pulmonary hypertension.The ultrastructure of pulmonary microvasculature in the hyperoxia-exposed lungs revealed a collapsed capillary lumen. This was due to the abnormal morphology of endothelial cells (ECs) characterized by heterogeneously thick cytoplasm. Compared to normal air controls, the specimens displayed also remarkably thick blood-air barriers (BABs), most of which were occupied by EC layer components. Structural changes were accompanied by increased pulmonary artery medial thickness and right ventricular hypertrophy (RVH). Moreover, abnormalities in ECs persisted even after exposure to 7 days of normal air replacement conditions. Results were confirmed by morphometric quantification.Our results suggest that the abnormal morphology of capillary ECs and thick BABs correlates with pulmonary artery remodeling and RVH. These ultrastructural changes might represent possible mechanisms of secondary pulmonary hypertension in BPD.

Objectives: To evaluate the impact of pulmonary hypertension (PH) on long-term growth and neurodevelopmental outcomes of extremely preterm infants with bronchopulmonary dysplasia (BPD). Study Design: A single-center retrospective cohort of preterm infants born at

OBJECTIVE In order to evaluate safety and usefulness of peripherally inserted double lumen central catheter (PIDLCC) in very low birth weight (VLBW) infants, outcomes of VLBW infants who had PIDLCC was studied. SUBJECTIVE Thirty-nine VLBW infants who were admitted to our NICU in 2013 were retrospectively analyzed. RESULTS Mean birth weight and gestational age was 1042.7 gram and 28.5 weeks, respectively. Total duration of indwelling PIDLCC was 1121 days (mean 28.5+18.2 days) with 85 PIDLCCs used. Dressing at the insertion site was done twice weekly with 10% povidone iodine. Four (10.3% with mean of 48 days) infants had catheter-related blood stream infection (CRBSI), with a 3.57 infection per 1000 catheter-day. The mean for days of PIDLCC in 35 infants without CRBSI was 26.5 days. Organisms isolated were Staphylococcus epidermidis, Staphylococcus aureus and Staphylococcus capitis ureolytic. Our study showed significant difference in the duration of indwelling catheter (p = 0.023) and intraventricular hemorrhage (p = 0.043) between the CRBSI group and non-CRBSI group. Five (12.8%) infants had abnormal thyroid function test, in which two infants required thyroxine supplementation upon discharge. However, duration of PIDLCC and abnormal thyroid function test was not statistically significant (p = 0.218). One (2.5%) infant died (death was not related to CRBSI). There was no serious adverse effects secondary to PIDLCC. CONCLUSION It is concluded that the use and maintenance of PIDLCC is safe for VLBW infants, but close monitoring should be observed to detect early signs of infection.

The aim of this study was to clarify the effects of gestational age and birth weight on outcomes of the infants. Medical records of 36 infants with trisomy 18 admitted to Tokyo Women's Medical University Hospital from 1991 to 2012 were reviewed retrospectively. We compared clinical characteristics between term infants (n = 15) and preterm infants (n = 21). There were one very‐low‐birth‐weight (VLBW) term infant (5%) and 12 VLBW preterm infants (80%). Although there were no significant differences in clinical characteristics and provided management between the two groups, none of the preterm infants achieved survival to discharge. On the other hand, 6 of 21 term infants (29%) achieved survival to discharge (P

A Japanese-language journal has been converted into the Journal Article Tag Suite (JATS) extensible markup language (XML) format, and typeset automatically via XSL formatting objects (XSL-FO) to produce both the printed issues and online journals which are published on the J-STAGE e-journal platform in full-text hypertext markup language. As there is no established XML workflow tools available for Japanese language journals, the Nakanishi Printing Company has developed its own workflow using Antenna House (AH) Formatter. AS scientific, technical, and medical journals are by-and-large in international standards even in Japanese-language, typesetting is fairly straightforward. Still, there are several challenges in processing agglutinative languages which are common in Asian counties such as Japanese, such as identifying family names/given names in a name string, or inserting “Zero Width Joiner” to avoid unfavorable line breaks. Also we had to develop individual extensible stylesheet language transformations (XSLT) for each article to position tables and figures rightly. As we go on and work with humanities journals we should face more challenges.

Objective To evaluate changes in the outcomes of infants born at

To determine the trends in mortality and the prevalence of abnormal neurodevelopmental outcomes among preterm Japanese infants. A retrospective multicenter cohort of 30,793 preterm infants born at a gestational age ≤32 weeks, between 2003 and 2012, in the Neonatal Research Network, Japan, was evaluated in the primary analysis. Finally, 13,661 infants were followed-up until 3 years of age and evaluated for neurodevelopmental outcomes, including cerebral palsy (CP), home oxygen therapy (HOT) use, and visual, hearing, and cognitive impairments. Multivariable logistic regression analysis was performed to determine the risk-adjusted trends in mortality and long-term neurodevelopmental outcomes. The trends in overall mortality (adjusted odds ratio, (AOR): 0.92; 95% confidence interval, (CI): 0.89–0.94), the prevalence of CP (AOR: 0.95, 95% CI: 0.92–0.98), HOT use (AOR: 0.84, 95% CI: 0.75–0.93), and visual (AOR: 0.84, 95% CI: 0.81–0.87) and hearing impairments (AOR: 0.78, 95% CI: 0.63–0.97) showed a significant downward trend, while cognitive impairment showed no significant changes (AOR: 1.02, 95% CI: 0.99–1.05). Intravenous hyperalimentation was significantly correlated with visual impairment (AOR 0.74, 95% CI 0.59–0.91). Early establishment of enteral feeding was associated with improved long-term outcomes. Mortality was improved, and this did not lead to increased risks for abnormal neurodevelopmental outcomes. Nutritional support might improve long-term neurodevelopmental outcomes.

ObjectiveTo investigate the characteristics of persistent pulmonary hypertension of the newborn (PPHN) in extremely preterm infants and its impact on neurodevelopmental outcomes at 3 years of age.DesignA retrospective multicentre cohort study.Settings202 tertiary perinatal centres registered in the Neonatal Research Network of Japan (NRNJ).PatientsInfants born at Main outcome measuresDemographic characteristics, morbidity, interventions and mortality were compared for infants with and without PPHN. Multivariable logistic analysis was performed to evaluate the impact of PPHN on long-term neurodevelopmental outcomes (the prevalence rate of cerebral palsy, need for home oxygen therapy, and visual, hearing and cognitive impairment) at 3 years of age.ResultsThe prevalence of PPHN among the 12 954 extremely preterm infants enrolled was 8.1% (95% CI 7.7% to 8.6%), with the trend increasing annually, and a higher proportion as GA decreased: 18.5% (range, 15.2% to 22.4%) for infants born at 22 weeks compared with 4.4% (range, 3.8% to 5.2%) for those born at 27 weeks. Clinical chorioamnionitis and premature rupture of membranes were associated with PPHN. On multivariate analysis of the data from 5923 infants followed up for 3 years, PPHN was a significant independent risk factor for visual impairment (adjusted OR, 1.42, 95% CI 1.03 to 1.97).ConclusionsThe prevalence of PPHN in extremely preterm infants has been increasing over the past decade in Japan. Clinicians should be aware of visual impairments as a neurodevelopmental abnormality among infants with PPHN.

Background Late-onset circulatory collapse (LCC) is a disorder in which blood pressure decreases and oliguria suddenly occurs in preterm infants who have survived the acute stage, leading to shock, without contributing underlying factors. In order to evaluate hemodynamic changes during LCC, the correlation between myocardial functions and organ blood flow was investigated with echography. Methods Seven very-low-birthweight infants were given a diagnosis of LCC during the study period. Cardiovascular and organ flow parameters of the infants were recorded prospectively, once a week, and compared with eight control very-low-birthweight infants with matching gestational age. Echographic study was performed before LCC, at the onset of LCC, and after LCC among infants with LCC. Results A significant increase in ejection fraction and a significant decrease in end systolic wall stress were observed in infants with the LCC condition. At the same time, the mean blood flow velocity increased significantly in the superior mesenteric artery, while it decreased in the anterior cerebral artery. Systolic blood flow velocity increased and mean velocity was maintained in the renal artery during LCC. Conclusion LCC is a distributive shock, characterized by a hyperdynamic state and decreased afterload. Echographic examination of organ flow during LCC is useful in understanding the pathophysiology of the disorder.

Background: The aim of this study was to evaluate the efficacy and safety of early administration of Bifidobacterium bifidum OLB6378 (B. bifidum) on accelerating enteral feeding and bacterial colonization in very-low-birthweight (VLBW) infants. Methods: We conducted a single-center prospective pilot study. Thirty-six VLBW infants were randomly divided into two groups: group E, wherein B. bifidum was supplemented within 48 h of birth, and group L, wherein it was supplemented more than 48 h after birth. Results: Group E and group L reached a total feeding volume of 100 mL/(kg/day) after 10 [7–13] days and 11 [10–15] days, respectively (median [quartile]). The daily bodyweight gain in group E was significantly higher (21.4 ± 3.2 g/day vs 18.3 ± 4.0 g/day, P < 0.02; 11.1 ± 1.5 g/kg/day vs 10.4 ± 1.2 g/kg/day, P < 0.04). No significant differences were found in the fecal Bifidobacterium level between the groups quantitated with a real-time polymerase chain reaction assay at 1 and 4 weeks of age. However, the highest colonization rate of Bifidobacterium was observed when the supplementation started between 24 and 48 h after birth. The incidence of morbidities between the groups was similar. Conclusion: The early administration of B. bifidum to VLBW infants seems effective in promoting growth during the stay in the neonatal intensive care unit without increasing the incidence of morbidity. Furthermore, the preferable timing of starting the probiotic supplementation for VLBW infants is at latest less than 48 h after birth.

Background: The long-term effects of hydrocortisone (HDC) used for very-low-birthweight (VLBW) infants with chronic lung disease (CLD) are not fully understood. The aim of this study was to examine the short-term clinical effects and long-term impact of a physiological replacement dose of HDC on acute deterioration of CLD in VLBW infants. Methods: This prospective case–control study included 110 of the 174 VLBW infants admitted to our facility between 2003 and 2006 who were followed up to a corrected age of 18 months. Infant deaths and infants with congenital deformities were excluded from the study. The infants were classified into the following three groups: infants with CLD and treated with HDC (1–2 mg/kg/dose) due to progressive deterioration in oxygenation (CLD treatment group; n= 24); infants with CLD but not treated with HDC (CLD untreated group; n= 40); and infants without CLD (non-CLD group; n= 46). Results: The fraction of inspired oxygen (FIO2) in the CLD treatment group improved significantly after treatment (P < 0.01). There were no significant differences among the three groups in terms of growth and neurodevelopmental quotient at the corrected age of 18 months following adjustment for birthweight, sex, and presence of light-for-date infants. There were also no significant intergroup differences in all three areas of developmental quotient. Conclusions: Physiological doses of HDC replacement are effective in treating acute deterioration in oxygenation in VLBW infants with CLD. Furthermore, this treatment modality did not adversely affect the growth and development of infants at the corrected age of 18 months.

Objective: To characterize the risk factors for late-onset circulatory collapse (LCC) in preterm infants responsive to corticosteroid therapy and evaluate the long-term neurological prognosis. Study Design: A retrospective case–control study for preterm infants (⩽32 weeks' gestation) admitted to our neonatal intensive care unit from 1994 through 2002. Result: Sixty-five infants (11%) were diagnosed with LCC. Infants with a shorter gestation and lower birth weight had a higher incidence of LCC. LCC infants had a significantly lower 1-min Apgar score, significantly higher incidence of severe intraventricular hemorrhage, chronic lung disease, and postnatal periventricular leukomalacia, and significantly longer duration of ventilation use, oxygen use, and hospital stay. Somatic growth at 36 weeks' postmenstrual age was poorer in infants with LCC than without LCC (controls). LCC infants were significantly more likely than controls to have cerebral palsy at 3 years. Conclusion: LCC is associated with poor neurodevelopmental outcomes. Prevention of LCC can lead to improved neurological prognoses.

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Background: Combined therapy of inhaled nitric oxide (iNO) with pulmonary surfactant replacement was reported to improve oxygenation in patients or animal models of persistent pulmonary hypertension of the newborn with pulmonary surfactant deficiency lung. To evaluate the potential of iNO for the treatment of persistent pulmonary hypertension of the newborn, pulmonary arterial pressure (PAP) was measured during iNO before and after pulmonary surfactant replacement in an animal model of pulmonary hypertension with surfactant deficiency. Methods: Seven newborn piglets were injected with L-nitro-arginine-methylester to produce an animal model of pulmonary hypertension. After PAP increased, iNO (30 p.p.m.) was introduced. Then iNO was stopped, and animals were subjected to lung lavage with saline. After recording the effect of iNO, all animals then received exogenous pulmonary surfactant installation. After surfactant treatment, iNO was again introduced. Results: Pulmonary arterial pressure and systemic arterial pressure were increased significantly by >30% after infusion of L-nitro-arginine-methylester. During iNO only PAP was reduced significantly. Respiratory system compliance decreased significantly after lung lavage, and increased significantly after pulmonary surfactant replacement with concomitant increase of PaO2. In contrast, significant reduction of PAP with iNO before and after pulmonary surfactant replacement were also observed. The reduction ratios of PAP under each condition were 75.2 ± 7.4%, 81.3 ± 3.1%, and 79.1 ± 5.3%, respectively (not significant among conditions). Conclusion: These results suggest that iNO is still a potent pulmonary arterial vasodilator even under pulmonary surfactant deficiency in an animal model of pulmonary hypertension.

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.

Late-onset circulatory collapse (LCC) is a disorder in which blood pressure decreases and oliguria suddenly occurs in preterm infants who have survived the acute stage, leading to shock, without contributing underlying factors. In order to evaluate hemodynamic changes during LCC, the correlation between myocardial functions and organ blood flow was investigated with echography.Seven very-low-birthweight infants were given a diagnosis of LCC during the study period. Cardiovascular and organ flow parameters of the infants were recorded prospectively, once a week, and compared with eight control very-low-birthweight infants with matching gestational age. Echographic study was performed before LCC, at the onset of LCC, and after LCC among infants with LCC.A significant increase in ejection fraction and a significant decrease in end systolic wall stress were observed in infants with the LCC condition. At the same time, the mean blood flow velocity increased significantly in the superior mesenteric artery, while it decreased in the anterior cerebral artery. Systolic blood flow velocity increased and mean velocity was maintained in the renal artery during LCC.LCC is a distributive shock, characterized by a hyperdynamic state and decreased afterload. Echographic examination of organ flow during LCC is useful in understanding the pathophysiology of the disorder.

The aim of this study was to evaluate the efficacy and safety of early administration of Bifidobacterium bifidum OLB6378 (B. bifidum) on accelerating enteral feeding and bacterial colonization in very-low-birthweight (VLBW) infants.We conducted a single-center prospective pilot study. Thirty-six VLBW infants were randomly divided into two groups: group E, wherein B. bifidum was supplemented within 48 h of birth, and group L, wherein it was supplemented more than 48 h after birth.Group E and group L reached a total feeding volume of 100 mL/(kg/day) after 10 [7-13] days and 11 [10-15] days, respectively (median [quartile]). The daily bodyweight gain in group E was significantly higher (21.4 ± 3.2 g/day vs 18.3 ± 4.0 g/day, P0.02; 11.1 ± 1.5 g/kg/day vs 10.4 ± 1.2 g/kg/day, P0.04). No significant differences were found in the fecal Bifidobacterium level between the groups quantitated with a real-time polymerase chain reaction assay at 1 and 4 weeks of age. However, the highest colonization rate of Bifidobacterium was observed when the supplementation started between 24 and 48 h after birth. The incidence of morbidities between the groups was similar.The early administration of B. bifidum to VLBW infants seems effective in promoting growth during the stay in the neonatal intensive care unit without increasing the incidence of morbidity. Furthermore, the preferable timing of starting the probiotic supplementation for VLBW infants is at latest less than 48 h after birth.

The long-term effects of hydrocortisone (HDC) used for very-low-birthweight (VLBW) infants with chronic lung disease (CLD) are not fully understood. The aim of this study was to examine the short-term clinical effects and long-term impact of a physiological replacement dose of HDC on acute deterioration of CLD in VLBW infants.This prospective case-control study included 110 of the 174 VLBW infants admitted to our facility between 2003 and 2006 who were followed up to a corrected age of 18 months. Infant deaths and infants with congenital deformities were excluded from the study. The infants were classified into the following three groups: infants with CLD and treated with HDC (1-2 mg/kg/dose) due to progressive deterioration in oxygenation (CLD treatment group; n = 24); infants with CLD but not treated with HDC (CLD untreated group; n = 40); and infants without CLD (non-CLD group; n = 46).The fraction of inspired oxygen (F(I) O(2) ) in the CLD treatment group improved significantly after treatment (P0.01). There were no significant differences among the three groups in terms of growth and neurodevelopmental quotient at the corrected age of 18 months following adjustment for birthweight, sex, and presence of light-for-date infants. There were also no significant intergroup differences in all three areas of developmental quotient.Physiological doses of HDC replacement are effective in treating acute deterioration in oxygenation in VLBW infants with CLD. Furthermore, this treatment modality did not adversely affect the growth and development of infants at the corrected age of 18 months.

Nitric oxide signaling has an important role in regulating pulmonary development and function. Expression of soluble guanylate cyclase (sGC) and cGMP-dependent protein kinase I (PKGI), both critical mediators of nitric oxide (NO) signaling, is diminished in the injured newborn lung through unknown mechanisms. Recent studies suggest that excessive transforming growth factor-β (TGF-β) activity inhibits injured newborn lung development. To explore mechanisms that regulate pulmonary NO signaling, we tested whether TGF-β decreases sGC and PKGI expression in the injured developing lung and pulmonary vascular smooth muscle cells (SMC). We found that chronic oxygen-induced lung injury decreased pulmonary sGCα1and PKGI immunoreactivity in mouse pups and that exposure to a TGF-β-neutralizing antibody prevented this reduction of sGC and PKGI protein expression. In addition, TGF-β1decreased expression of NO signaling enzymes in freshly isolated pulmonary microvascular SMC/myofibroblasts, suggesting that TGF-β has a direct role in modulating NO signaling in the pup lung. Moreover, TGF-β1decreased sGC and PKGI expression in pulmonary artery and aortic SMC from adult rats and mice, suggesting a general role for TGF-β in modulating NO signaling in vascular SMC. Although other cytokines decrease sGC mRNA stability, TGF-β did not modulate sGCα1or PKGIβ mRNA turnover in vascular SMC. These studies indicate for the first time that TGF-β decreases NO signaling enzyme expression in the injured developing lung and pulmonary vascular SMC. Moreover, they suggest that TGF-β-neutralizing molecules might counteract the effects of injury on NO signaling in the newborn lung.

Pulmonary injury is associated with the disruption of alveologenesis in the developing lung and causes bronchopulmonary dysplasia (BPD) in prematurely born infants. Transforming growth factor (TGF)-β is an important regulator of cellular differentiation and early lung development, and its levels are increased in newborn lung injury. Although overexpression of TGF-β in the lungs of newborn animals causes pathological features that are consistent with BPD, the role of endogenous TGF-β in the inhibition of the terminal stage of lung development is incompletely understood. In this investigation, the hypothesis that O2-induced injury of the maturing lung is associated with TGF-β-mediated disruption of alveologenesis and microvascular development was tested using a murine model of BPD. Here we report that treatment of developing mouse lungs with TGF-β-neutralizing antibodies attenuates the increase in pulmonary cell phospho-Smad2 nuclear localization, which is indicative of augmented TGF-β signaling, associated with pulmonary injury induced by chronic inhalation of 85% oxygen. Importantly, the neutralization of the abnormal TGF-β activity improves quantitative morphometric indicators of alveologenesis, extracellular matrix assembly, and microvascular development in the injured developing lung. Furthermore, exposure to anti-TGF-β antibodies is associated with improved somatic growth in hyperoxic mouse pups and not with an increase in pulmonary inflammation. These studies indicate that excessive pulmonary TGF-β signaling in the injured newborn lung has an important role in the disruption of the terminal stage of lung development. In addition, they suggest that anti-TGF-β antibodies may be an effective therapy for preventing some important developmental diseases of the newborn lung.

To clarify the participation of inducible NOS (iNOS) in the hypoxia–ischemia, we examined iNOS and its tetrahydrobiopterin co-factor in the cerebral cortex and plasma in a newborn-piglet model. We also investigated the role of hypothermia in iNOS expression and biopterin production. Male newborn piglets were ventilated 6% oxygen for 45 min. Their common carotid arteries were clamped during hypoxia. Then they were resuscitated with 30% oxygen (HI group). Piglets of the hypothermia group were treated as the HI group and their body was cooled to 35.5 °C after hypoxic–ischemic insults. Sham-treated piglets were also reserved. In the HI group, iNOS was present in neurons and macrophages of the cerebral cortex 12 h after the insult. The concentrations of nitrite and nitrate were elevated in the cerebral cortex 12 h after hypoxic–ischemic insults but the biopterin level was unchanged. The plasma biopterin concentration after the insult (377.9 ± 78.7 nM) was five times higher than before the insult (80.1 ± 4.3 nM); this level peaked 4 h after the insult (604.8 ± 200.9 nM) and only slightly decreased after 12 h (445.9 ± 57.8 nM). In the hypothermia group, no iNOS expression was observed 12 h after the insult. The plasma biopterin concentration after the insult (464.2 ± 92.3 nM) was similar to that in the HI group, but was suppressed by 4 h of hypothermia (229.3 ± 106.8 nM). In this study, neuronal iNOS expression and increase of NO production were found in the acute phase of hypoxia–ischemia. Brain biopterin did not increase in hypoxia–ischemia although plasma biopterin was five-fold elevated. The discrepancy may also affect hypoxic–ischemic organ damage.