Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Hirosuke Inoue Last modified date:2021.08.04

Assistant Professor / Department of Pediatrics / Comprehensive Maternity and Perinatal Care Center / Kyushu University Hospital

1. Toshinori Nakashima, Hirosuke Inoue, Yoshihiro Sakemi, Masayuki Ochiai, Hironori Yamashita, Shouichi Ohga, Trends in Bronchopulmonary Dysplasia Among Extremely Preterm Infants in Japan, 2003-2016., The Journal of pediatrics, 10.1016/j.jpeds.2020.11.041, 230, 119-125, 2021.03, OBJECTIVE: To investigate recent trends in bronchopulmonary dysplasia (BPD) and its risk factors among extremely preterm infants. STUDY DESIGN: Demographic and clinical data were reviewed for 19 370 infants born at 22-27 weeks of gestation registered in the affiliated hospitals of the Neonatal Research Network of Japan between 2003 and 2016. We investigated the overall survival and prevalence of bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age and risk factors for developing BPD among the survivors. RESULTS: Among 19 370 infants, 2244 (11.6%) died by 36 weeks' postmenstrual age. The mortality rate decreased from 19.0% (99% CI, 15.7%-22.8%) in 2003 to 8.0% (99% CI, 6.2%-10.3%) in 2016. Among 17 126 survivors, BPD developed in 7792 (45.5%) infants, and its proportion significantly increased from 41.4% (99% CI, 36.5%-46.4%) in 2003 to 52.0% (99% CI, 48.2%-55.9%) in 2016. A multivariable analysis of the survivors showed a positive association of BPD with ≥4 weeks' supplemental oxygen or invasive ventilation, birth weight <750 g, small for gestational age, ≥4 weeks' noninvasive positive pressure ventilation, chorioamnionitis, <26 weeks' gestational age, <20 cases per year of center patient volume, or treated patent ductus arteriosus. Although the median duration of invasive ventilation was shortened, the proportions of factors associated adversely with BPD generally showed increasing trends over time. CONCLUSIONS: The mortality rate of extremely preterm infants has decreased, but the rate of BPD has increased in survivors between 2003 and 2016. Despite the decreasing duration of invasive ventilation over time, increasing rates of BPD suggest that differences in the patient population or other management strategies influence the development of BPD..
2. Ryoji Taira, Hirosuke Inoue, Toru Sawano, Junko Fujiyoshi, Yuko Ichimiya, Michiko Torio, Masafumi Sanefuji, Masayuki Ochiai, Yasunari Sakai, Shouichi Ohga, Management of apnea in infants with trisomy 18, Developmental Medicine and Child Neurology, 10.1111/dmcn.14403, 62, 7, 874-878, 2019.01, This case series aimed to characterize the clinical features, management, and outcomes of apnea in infants with trisomy 18. Participants in this study were infants with trisomy 18 who were born alive and admitted to the neonatal intensive care unit in Kyushu University Hospital from 2000 to 2018. Retrospective analysis was performed on clinical data recorded in our department. Twenty-seven infants with trisomy 18 were admitted to our hospital during the study period, of which 25 (nine males, 16 females) were enrolled as eligible participants in this study. Among them, 14 started presenting with apnea from median 3.5 days of age (range 0–47d). In these infants with apnea, eight received respiratory support of positive pressure ventilation (PPV). The 1-year survival rate of infants in the PPV group was higher than that of non-PPV-supported infants (5 out of 8 vs 0 out of 6 infants). Five PPV-supported infants received a diagnosis of epilepsy, which was controlled by antiepileptic drugs. Postnatal respiratory intervention provides better prognosis in infants with trisomy 18. Improved survival leads to accurate diagnosis and treatment of apneic events in association with epilepsy. What this paper adds: Respiratory support is effective against apnea in infants with trisomy 18. Intervention with ventilation provides a higher chance of prolonged survival. Improved survival leads to the accurate diagnosis and treatment of epilepsy-associated apnea..
3. Kazuaki Yasuoka, Hirosuke Inoue, N. Egami, Masayuki Ochiai, Koichi Tanaka, Toru Sawano, Hiroaki Kurata, Masako Ichiyama, J. Fujiyoshi, Yuki Matsushita, Yasunari Sakai, Shouichi Ohga, Late-Onset Circulatory Collapse and Risk of Cerebral Palsy in Extremely Preterm Infants, Journal of Pediatrics, 10.1016/j.jpeds.2019.05.033, 212, 117-123.e4, 2019.09, Objective: To investigate whether the development of postnatal, late-onset refractory hypotension, referred to as late-onset circulatory collapse, was associated with an increased risk of developing cerebral palsy (CP) at 3 years of age in extremely preterm infants. Methods: In this historical cohort study, infants who were born at 22-27 weeks of gestation from 2008 to 2012 in the Neonatal Research Network of Japan were eligible. The study sample consisted of 3474 infants (45.6% of 7613 potentially eligible infants) who were evaluated at 36-42 months of age. Late-onset circulatory collapse was defined as a clinical diagnosis of late-onset circulatory collapse requiring treatment with corticosteroids. We compared the neurodevelopmental outcomes between infants with and without late-onset circulatory collapse. Results: Late-onset circulatory collapse was diagnosed in 666 of the infants studied. Infants with late-onset circulatory collapse had a higher incidence of CP than those without late-onset circulatory collapse (18.0% vs 9.8%; P < .01). In multivariable logistic analysis, late-onset circulatory collapse was independently associated with CP (aOR, 1.52; 95% CI, 1.13-2.04) and developmental quotient score of <50 (OR, 1.83; 95% CI, 1.23-2.72). Conclusions: Late-onset circulatory collapse may be a relatively common event occurring in extremely preterm infants and an independent risk factor for CP at 3 years of age..
4. Hiroaki Kurata, Masayuki Ochiai, Hirosuke Inoue, Takeshi Kusuda, Junko Fujiyoshi, Masako Ichiyama, Yoshifumi Wakata, Hidetoshi Takada, Inflammation in the neonatal period and intrauterine growth restriction aggravate bronchopulmonary dysplasia, Pediatrics and Neonatology, 10.1016/j.pedneo.2018.11.007, 60, 5, 496-503, 2019.10, Background: To investigate the hematological features of infants with bronchopulmonary dysplasia (BPD) and their relationships with clinical severity. Methods: This prospective observational study enrolled 73 BPD patients from a total of 331 infants with a birth weight of <1500 g from 2005 to 2013. The clinical severity of BPD was defined by the duration of oxygen supplementation and positive pressure ventilation (PPV) in line with the diagnostic criteria of BPD. The hematological status and cytokine levels were surveyed from blood samples at birth and at 2 and 4 weeks of life. Results: Thirty-four (46.6%) cases were classified as “moderate-to-severe” BPD. Small-for-gestational-age (SGA) was associated with the severity of BPD (OR: 5.05; 95% CI: 1.45 to 17.2). The CRP level at 2 weeks (partial regression coefficient [rc]: 21.8; 4.01 to 39.7) and the neutrophil count at 4 weeks (0.005; 0.001 to 0.007) were positively correlated with the oxygenation period. The PPV period was found to be correlated with the CRP level at 2 weeks (27.2; 14.9 to 39.5), and the neutrophil count (0.003; 0.001 to 0.004) at 4 weeks. Conclusion: The aggravation of BPD was associated with both SGA at birth and inflammation during neonatal period..
5. Yuki Matsushita, Yasunari Sakai, Michiko Torio, Hirosuke Inoue, Masayuki Ochiai, Kazuaki Yasuoka, Hiroaki Kurata, Junko Fujiyoshi, Masako Ichiyama, Tomoaki Taguchi, Kiyoko Kato, Shouichi Ohga, Association of perinatal factors of epilepsy in very low birth weight infants, using a nationwide database in Japan, Journal of Perinatology, 10.1038/s41372-019-0494-7, 39, 11, 1472-1479, 2019.11, Objective: To determine clinical features of very low birth weight infants (VLBWIs) who had developed epilepsy by age 3 years. Study design: Multicenter cohort study using the Neonatal Research Network of Japan database. We analyzed clinical variables of 8431 VLBWIs who had recorded data of neurological sequelae at age 3 years. Logistic regression identified the association between variables and development of epilepsy. Result: One hundred and forty-three (1.7%) infants developed epilepsy, 683 (8.1%) showed cerebral palsy (CP), and 1114 (13.2%) had psychomotor delay. Epilepsy was associated with history of sepsis [adjusted odds ratio (AOR) 3.23], severe intraventricular hemorrhage (IVH; AOR 5.13), and cystic periventricular leukomalacia (PVL; AOR 12.7). Severe IVH and cystic PVL were also frequently associated with CP and psychomotor delay. Conclusion: Severe IVH and cystic PVL are strongly associated with development of epilepsy, as well as other neurological sequelae, and are potential critical therapeutic targets..
6. Motoshi Sonoda, Masataka Ishimura, Katsuhide Eguchi, Akira Shiraishi, Shunsuke Kanno, Noriyuki Kaku, Hirosuke Inoue, Yoshitomo Motomura, Masayuki Ochiai, Yasunari Sakai, Manabu Nakayama, Osamu Ohara, Shouichi Ohga, Prognostic factors for survival of herpes simplex virus-associated hemophagocytic lymphohistiocytosis, International journal of hematology, 10.1007/s12185-019-02738-3, 111, 1, 131-136, 2020.01, Hemophagocytic lymphohistiocytosis (HLH) occurs in neonates with disseminated infection of herpes simplex virus (HSV). Little has been reported on the control of rapid HLH progression. We studied the cytokine profile and genetic basis of two index cases with divergent outcomes after early treatment of type 2 HSV infection. One survivor had fever and elevated serum levels of tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), interferon (IFN)-β, and IFN-γ at diagnosis. The other neonate had no fever or TNF-α production, but significant IL-6 or IFN responses during the treatment course, and died 19 days after birth. Among 16 reported cases of neonatal HSV-HLH including index cases, eight deceased neonates experienced significantly less fever at presentation (p = 0.028), lower platelet counts (p = 0.019), and lower ratios of soluble IL-2 receptor (sIL-2R) to ferritin levels (p = 0.044) than eight survivors. The 100-day overall survival rates were significantly higher in patients with fever (p = 0.004), > 100 × 109/L of platelet counts (p = 0.035) or > 20 of sIL-2R/ferritin ratio at diagnosis (p = 0.004). The first febrile and cytokine responses to HSV infection predict the early outcome of neonatal HSV-HLH..
7. Mitsuru Arima, Masato Akiyama, Kohta Fujiwara, Yujiro Mori, Hirosuke Inoue, Eiko Seki, Takahito Nakama, Shoko Tsukamoto, Masayuki Ochiai, Shouichi Ohga, Koh Hei Sonoda, Neurodevelopmental outcomes following intravitreal bevacizumab injection in Japanese preterm infants with type 1 retinopathy of prematurity, PloS one, 10.1371/journal.pone.0230678, 15, 3, 2020.01, Purpose The purpose of this study was to evaluate neurodevelopmental outcomes in 18-month old (corrected age) preterm infants who received an intravitreal bevacizumab (IVB) injection for the treatment of type 1 retinopathy of prematurity (ROP). Methods In this ten-year retrospective study, we reviewed the medical records of patients who underwent ROP screening at Kyushu University Hospital. Among the patients who received IVB or laser photocoagulation (LPC) for the treatment of type 1 ROP, we included infants whose neurodevelopmental examination (the Kyoto Scale of Psychological Development [KSPD]) results at 18 months corrected age were available. Then, the effect of IVB on the developmental quotient (DQ) in each KSPD domain (Postural-Movement, Cognitive-Adaptive, or Language-Social domain) or the overall DQ was investigated by performing linear regression analysis. Results Out of the 513 patients reviewed, 53 were included in the study. IVB and LPC were performed for 14 and 39 patients, respectively. Administration of IVB was significantly associated with neurodevelopmental delay in the Language-Social domain (p = 0.01). The observed association remained even after adjusting for gestational age and birth weight (p = 0.03). Conclusions Administration of IVB may introduce a risk of developmental impairment of interpersonal relationships, socializations, and/or verbal abilities of preterm children. We recommended that preterm infants who received IVB undergo a neurodevelopmental reassessment during their school years or in adulthood..
8. Masayuki Ochiai, Hiroaki Kurata, Hirosuke Inoue, Masako Ichiyama, Junko Fujiyoshi, Shinichi Watabe, Takehiko Hiroma, Tomohiko Nakamura, Shouichi Ohga, Transcutaneous blood gas monitoring among neonatal intensive care units in Japan, Pediatrics International, 10.1111/ped.14107, 62, 2, 169-174, 2020.02, Background: This study aimed to investigate the utility of transcutaneous (tc) measurements of partial pressure of oxygen (tcPO2) and carbon dioxide (tcPCO2) monitoring in neonatal intensive care units (NICUs) in Japan. Methods: At the end of 2016,we sent a survey questionnaire on tc monitoring to all 106 NICUs registered with the Japanese Neonatologist Association. The questions included usage, subjects, methods, management, and the practical usefulness of tc monitoring. Results: The questionnaire was returned by 69 NICUs (65.1% of response rate). Seventeen institutions (24.6%) measured both tcPCO2 and tcPO2, and 42 (60.9%) measured tcPCO2 alone. Transcutaneous PCO2 or tcPO2 monitoring was applied for “pre-viable” infants born at 22–23 weeks’ gestational age (18.6% vs 23.5%), and infants of <500 g birthweight (30.5% vs 17.6%). The tcPCO2 and tcPO2 monitoring was started at birth in 49.2% and 70.6% of the newborn infants, respectively. The temperature of the sensor was set at <38°C for tcPCO2 in 54.3% and >42°C for tcPO2 in 58.9% of NICUs. The accuracy for tcPO2 was rated as good in 35.3% or moderate in 64.7%, of institutions but or for tcPCO2 as 1.7% or 93.2%of institutions, respectively. Conclusion: Transcutaneous monitoring was widely, but limitedly, used for preterm infants. The lower temperature of the tcPCO2 sensor compared to that reported in other developed countries might compromise the accuracy but increase the feasibility of tc monitoring in Japan..
9. Hirosuke Inoue, Takayuki Hoshina, Tadamune Kinjo, Mitsumasa Saito, Koichi Kusuhara, Toshiro Hara, Toxic shock syndrome-like exanthematous disease in a 2-month-old infant, Pediatrics International, 10.1111/j.1442-200X.2010.03044.x, 52, 2, 2010.04.
10. Hirosuke Inoue, Hidetoshi Takada, Takeshi Kusuda, Takako Goto, Masayuki Ochiai, Tadamune Kinjo, Jun Muneuchi, Yasushi Takahata, Naomi Takahashi, Tomohiro Morio, Kenjiro Kosaki, Toshiro Hara, Successful cord blood transplantation for a CHARGE syndrome with CHD7 mutation showing DiGeorge sequence including hypoparathyroidism, European Journal of Pediatrics, 10.1007/s00431-009-1126-6, 169, 7, 839-844, 2010.07, It is rare that coloboma, heart anomalies, choanal atresia, retarded growth and development, and genital and ear anomalies (CHARGE) syndrome patients have DiGeorge sequence showing severe immunodeficiency due to the defect of the thymus. Although the only treatment to achieve immunological recovery for these patients in countries where thymic transplantation is not ethically approved would be hematopoietic cell transplantation, long-term survival has not been obtained in most patients. On the other hand, it is still not clarified whether hypoparathyroidism is one of the manifestations of CHARGE syndrome. We observed a CHARGE syndrome patient with chromodomain helicase DNA-binding protein 7 mutation showing DiGeorge sequence including the defect of T cells accompanied with the aplasia of the thymus, severe hypoparathyroidism, and conotruncal cardiac anomaly. He received unrelated cord blood transplantation without conditioning at 4 months of age. Recovery of T cell number and of proliferative response against mitogens was achieved by peripheral expansion of mature T cells in cord blood without thymic output. Although he is still suffering from severe hypoparathyroidism, he is alive without serious infections for 10 months..
11. Kenichiro Yamamura, Jun Muneuchi, Kiyoshi Uike, Kazuyuki Ikeda, Hirosuke Inoue, Yasushi Takahata, Yuichi Shiokawa, Yukako Yoshikane, Takeru Makiyama, Minoru Horie, Toshiro Hara, A novel SCN5A mutation associated with the linker between III and IV domains of Na v 1.5 in a neonate with fatal long QT syndrome, International Journal of Cardiology, 10.1016/j.ijcard.2009.04.023, 145, 1, 61-64, 2010.11.
12. Hirosuke Inoue, K. Ihara, Masayuki Ochiai, Y. Takahata, H. Kohno, T. Hara, Congenital multiple pituitary hormone deficiency associated with hyperammonemia A case report with a short review of the literature, Journal of Perinatology, 10.1038/jp.2010.143, 31, 2, 146-148, 2011.02, We herein report a case study of a female newborn with multiple pituitary hormone deficiencies who presented with generalized seizures, hypoglycemia and hyperammonemia at 18 h after birth. In addition, we review the association of hyperammonemia in neonates with multiple pituitary hormone deficiencies reported in the previous literature. This unrecognized association should be taken into account for the early diagnosis and treatment of these patients..
13. Shunji Hikino, Shoichi Ohga, Tadamune Kinjo, Takeshi Kusuda, Masayuki Ochiai, Hirosuke Inoue, Satoshi Honjo, Kenji Ihara, Koichi Ohshima, Toshiro Hara, Tracheal aspirate gene expression in preterm newborns and development of bronchopulmonary dysplasia, Pediatrics International, 10.1111/j.1442-200X.2011.03510.x, 54, 2, 208-214, 2012.04, Background: Bronchopulmonary dysplasia (BPD) occurs in association with prenatal conditions predisposing infants to inflammation and remodeling of the premature lungs. Because of the lack of useful biomarkers for BPD, the gene expression of tracheal aspirate fluid (TAF) cells in premature infants was analyzed. Methods: Of 148 consecutive patients, 26 preterm infants (gestational age <34 weeks) were enrolled, who underwent assisted ventilation at birth for respiratory failure. Patients with congenital disorders were excluded. Half of these infants developed BPD. Interleukin (IL)-10, interferon (IFN)-γ, transforming growth factor (TGF)-β1, and platelet-derived growth factor (PDGF)-B mRNA of TAF cells were quantified on real-time polymerase chain reaction. Results: IL-10 (P < 0.01) and IFN-γ (P= 0.03) but not TGF-β1 or PDGF-B mRNA levels at birth were higher in BPD than in non-BPD infants. IL-10 expression differentiated BPD with the highest sensitivity (92%) and specificity (77%). IL-10 levels correlated with TGF-β1 (P= 0.03) and IFN-γ (P= 0.01), but not with PDGF-B levels. When BPD infants were classified according to comorbidity (group 1, six patients who suffered respiratory distress syndrome [RDS] but not chorioamnionitis [CAM]; group 2, five patients who had CAM but not RDS), PDGF-B levels were higher in group 2 (P= 0.01). High IL-10 expression was selected as a risk factor for BPD in infants who had CAM but not RDS (P= 0.01), although prolonged oxygen therapy was the most sensitive indicator for BPD (P < 0.01) on multivariate analysis. Conclusions: High IL-10 expression in TAF cells at birth could predict the evolution of BPD, but with less impact than oxygen requirement. PDGF might play a different role in the inflammatory process of premature lungs..
14. Junko Kitajima, Hirosuke Inoue, Shoichi Ohga, Tadamune Kinjo, Masayuki Ochiai, Takahisa Yoshida, Koichi Kusuhara, Toshiro Hara, Differential transmission and postnatal outcomes in triplets with intrauterine cytomegalovirus infection, Pediatric and Developmental Pathology, 10.2350/11-05-1034-CR.1, 15, 2, 151-155, 2012.07, We present a case of triplets with intrauterine cytomegalovirus (CMV) infection, each of whom showed differential transmission, placental pathology, and postnatal outcome. The first- and second-born infants were both vigorous and asymptomatic at birth, although the first-, but not the second-born, triplet had a high copy number of CMV DNA in the peripheral blood (1.2 × 103 copy/mL). The third-born triplet suffered from symptomatic CMV infection with a high viral load (6.0 × 106 copy/mL). The triamniotic-trichorionic placentas were not fused to each other. The histopathologic analysis showed that CMVpositive cells were frequently found in the decidua, villi, and amnion of the third-born triplet's placenta but were limited and scattered in the decidua or villi but not amnion of the other 2 placentas. The third-born triplet underwent ganciclovir therapy. None of the infants had physical or auditory problems at 4 years of age, whereas the third-born triplet had been diagnosed with an autistic disorder. This observation exemplifies the preventive roles of the individual placentas of triplets with regard to virus infection, thus suggesting that developing CMV disease largely depends on the placental function..
15. Tadamune Kinjo, Hirosuke Inoue, Takeshi Kusuda, Junko Fujiyoshi, Masayuki Ochiai, Yasushi Takahata, Satoshi Honjo, Yuhki Koga, Toshiro Hara, Shoichi Ohga, Chemokine levels predict progressive liver disease in Down syndrome patients with transient abnormal myelopoiesis, Pediatrics and Neonatology, 10.1016/j.pedneo.2018.09.005, 2018.01, Background: Transient abnormal myelopoiesis (TAM) is a neonatal preleukemic syndrome that occurs exclusively in neonates with Down syndrome (DS). Most affected infants spontaneously resolve, although some patients culminate in hepatic failure despite the hematological remission. It is impossible to determine the patients who are at high risk of progressive liver disease and leukemic transformation. The objective is to search for biomarkers predicting the development of hepatic failure in DS infants with TAM. Methods: Among 60 newborn infants with DS consecutively admitted to our institutions from 2003 to 2016, 41 infants with or without TAM were enrolled for the study. Twenty-two TAM-patients were classified into “progression group” (n = 7) that required any therapy and “spontaneous resolution group” (n = 15). Serum concentrations of chemokines (CXCL8, CXCL9, CXCL10, CCL2 and CCL5) and transforming growth factor (TGF)-β1 were measured at diagnosis of TAM for assessing the outcome of progressive disease. Results: Three patients developed leukemia during the study period (median, 1147 days; range, 33–3753). Three died of hepatic failure. All patients in the progression group were preterm birth <37 weeks of gestational age and were earlier than those in the spontaneous resolution group (median, 34.7 vs. 37.0 weeks, p < 0.01). The leukocyte counts and CXCL8 and CCL2 levels at diagnosis in the progression group were higher than those in the spontaneous resolution group (leukocyte: median, 81.60 vs. 27.30 × 10
/L, p = 0.01; CXCL8: 173.8 vs. 34.3 pg/ml, p < 0.01; CCL2: 790.3 vs. 209.8 pg/mL, p < 0.01). Multivariate analyses indicated that an increased CCL2 value was independently associated with the progression and CXCL8 with the death of liver failure, respectively (CCL2: standardized coefficient [sc], 0.43, p < 0.01; CXCL8: sc = −0.46, p = 0.02). Conclusion: High levels of circulating CXCL8 and CCL2 at diagnosis of TAM may predict progressive hepatic failure in DS infants..
16. Hirosuke Inoue, Masayuki Ochiai, Yasunari Sakai, Kazuaki Yasuoka, Koichi Tanaka, Masako Ichiyama, Hiroaki Kurata, Junko Fujiyoshi, Yuki Matsushita, Satoshi Honjo, Kazuaki Nonaka, Tomoaki Taguchi, Kiyoko Kato, Shoichi Ohga, Neurodevelopmental outcomes in infants with birth weight ≤500 g at 3 years of age, Pediatrics, 10.1542/peds.2017-4286, 142, 6, 2018.12, OBJECTIVES: To determine neurodevelopmental outcomes at 3 years of age in children born with a birth weight (BW) of ≤500 g. METHODS: Infants who were born with a BW of ≤500 g from 2003 to 2012 in the Neonatal Research Network of Japan and survived to discharge from the NICU were eligible in this study. The study population consisted of 460 children (56.7% of 811 surviving infants) who were evaluated at 36 to 42 months of age. Neurodevelopmental impairment (NDI) was defined as having cerebral palsy, visual impairment, hearing impairment, or a developmental quotient score of <70. RESULTS: The overall proportion of NDI was 59.1% (95% confidence interval [CI]: 54.6%-63.5%). The trend revealed no significant change during the study period. In a multivariate modified Poisson regression analysis, NDI was associated with severe intraventricular hemorrhage (adjusted risk ratio [RR]: 1.42; 95% CI: 1.19-1.68; P <.01), cystic periventricular leukomalacia (adjusted RR: 1.40; 95% CI: 1.13-1.73; P <.01), severe necrotizing enterocolitis (adjusted RR: 1.31; 95% CI: 1.07-1.60; P <.01), surgical ligation for patent ductus arteriosus (adjusted RR: 1.29; 95% CI: 1.09-1.54; P <.01), and male sex (adjusted RR: 1.19; 95% CI: 1.01-2.40; P =.04). CONCLUSIONS: This cohort showed that neurodevelopmental outcomes of infants with a BW of ≤500 g have not improved from 2003 to 2012. Multivariate analysis revealed that severe intracranial hemorrhage and cystic periventricular leukomalacia were the strongest risk factors for NDIs. Our data suggested that measures aimed at reducing neurologic morbidities will be important for improving outcomes of infants with a BW of ≤500 g..
17. Hiroaki Kurata, Masayuki Ochiai, Hirosuke Inoue, Masako Ichiyama, Kazuaki Yasuoka, Junko Fujiyoshi, Yuki Matsushita, Satoshi Honjo, Yasunari Sakai, Shoichi Ohga, A nationwide survey on tracheostomy for very-low-birth-weight infants in Japan, Pediatric Pulmonology, 10.1002/ppul.24200, 54, 1, 53-60, 2019.01, Objectives: Tracheostomy is indicated for very-low-birth-weight infants (VLBWIs) with prolonged respiratory problems during the perinatal period. The objective of this study is to clarify the epidemiology and risk factors in VLBWIs with tracheostomy after birth in Japan. Methods: A total of 40 806 VLBWIs were registered in the Neonatal Research Network of Japan database from 2003 to 2012. Among them, 34 674 infants (85%) survived over 28 days after birth and were subjected to this study. The clinical variables at birth, outcomes at hospital discharge and associated factors for tracheostomy were examined. Results: The proportion of VLBWIs with tracheostomy did not increase during the study period (mean 36 cases per year, 0.93%). The rate of in-hospital death over 28 days after birth did not differ between tracheostomized and non-tracheostomized infants (2/324, 0.6% vs 314/34 350, 0.9%). Tracheostomized infants more frequently had severe or moderate bronchopulmonary dysplasia (BPD) (75.5% vs 26.0%, P < 0.01) and longer hospitalization (229 days vs 83 days, P < 0.01) than non-tracheostomized infants. Tracheostomized patients showed higher comorbidities with hypoxic ischemic encephalopathy (odds ratio [OR] 10.98, P < 0.01), muscular disease (OR 10.95, P < 0.01), severe or moderate BPD (OR 7.79, P < 0.01), chromosomal abnormality (OR 4.43, P < 0.01) or sepsis (OR 1.78, P < 0.05) at hospital discharge than non-tracheostomized patients. Conclusion: We demonstrated the non-increasing rate in tracheostomy for VLBWIs and such cases were associated with an excellent survival in Japan. These data provide evidence that more attentive care must be practiced in order to reduce the pulmonary and neuromuscular burdens of VLBWIs at birth..
18. Masako Ichiyama, Hirosuke Inoue, Masayuki Ochiai, masataka ishimura, Akira Shiraishi, Junko Fujiyoshi, Hironori Yamashita, Kazuo Sato, Shinya Matsumoto, Taeko Hotta, Takeshi Uchiumi, Dongchon Kang, Shoichi Ohga, Diagnostic challenge of the newborn patients with heritable protein C deficiency, Journal of Perinatology, 10.1038/s41372-018-0262-0, 39, 2, 212-219, 2019.02, Objective: The diagnosis of neonatal-onset protein C (PC) deficiency is challenging. This study aimed to establish the neonatal screening of heritable PC deficiency in Japan. Study design: We determined the changes in plasma activity levels of PC and protein S (PS) in healthy neonates, and studied newborn patients with PROC mutation in the Japanese registry. Result: Physiological PC and PS levels increased with wide range. The PC/PS-activity ratios converged after birth. The PC/PS-activity ratios of 19 patients with biallelic mutations, but not, 9 with monoallelic mutation, were lower than those of 13 without mutation. The logistic regression analyses established a formula including two significant variables of PC activity (cut-off < 10%, odds ratio = 30.0) and PC/PS-activity ratio (cut-off < 0.35, odds ratio = 22.7), with 93% sensitivity and 44% specificity for determining patients with mutation(s). Conclusion: The PC/PS-activity ratio is an effective parameter for the genetic screening of neonatal-onset PC-deficiency in Japanese population..
19. Hirosuke Inoue, Jun Muneuchi, Takuro Ohno, Aiko Arikawa, Tatsuro Ishibashi, Toshiro Hara, Central retinal artery occlusion following transcatheter balloon aortic valvuloplasty in an adolescent with aortic valvular stenosis, Pediatric Cardiology, 10.1007/s00246-007-9181-0, 29, 4, 830-833, 2008.07, A 12-year-old girl with aortic valvular stenosis underwent transcatheter balloon aortic valvuloplasty (BAV) using a femoral artery approach. Anticoagulation with heparin during the procedure was used. The patient noted sudden onset of concentric constriction of the visual field in the right eye 40 min after BAV. Brain magnetic resonance imaging and cervical ultrasound revealed no abnormality. Funduscopic examination showed white swelling around the macular region, indicating ischemia, consistent with central retinal artery occlusion (CRAO). CRAO should be recognized as a rare and serious complication associated with BAV even among the pediatric population. This requires careful evaluation of anticoagulation during the left heart procedures..
20. Koichi Kusuhara, Takayuki Hoshina, Mitsumasa Saito, masataka ishimura, Hirosuke Inoue, Takahiko Horiuchi, Tetsuji Sato, Toshiro Hara, Successful treatment of a patient with tumor necrosis factor receptor-associated periodic syndrome using a half-dose of etanercept, Pediatrics International, 10.1111/j.1442-200X.2011.03525.x, 54, 4, 552-555, 2012.08, TNF receptor-associated periodic syndrome (TRAPS) is caused by mutations of TNFRSF1A gene and characterized by recurrent febrile episodes of prolonged duration and initial good response to steroids. Etanercept, a TNF blocker, has been used as a putative molecular-targeted agent for TRAPS, with some patients showing limited efficacy. Here, we report a patient with TRAPS who recovered from steroid dependency by etanercept and kept remission with a reduced dose of etanercept. The pathophysiology of TRAPS still remains to be elucidated and several hypotheses have been proposed. In the most recent hypothesis, the concerted action of wild-type and mutant TNF receptors plays an important role in provoking enhanced inflammation in TRAPS. The excellent response to etanercept in our patient suggested that there is heterogeneity in TRAPS patients in terms of the contribution of normal TNF signaling to autoinflammation..
21. Hirosuke Inoue, Shoichi Ohga, Takeshi Kusuda, Junko Kitajima, Tadamune Kinjo, Masayuki Ochiai, Yasushi Takahata, Satoshi Honjo, Toshiro Hara, Serum neutrophil gelatinase-associated lipocalin as a predictor of the development of bronchopulmonary dysplasia in preterm infants, Early Human Development, 10.1016/j.earlhumdev.2012.12.011, 89, 6, 425-429, 2013.06, Background: Bronchopulmonary dysplasia (BPD) is a chronic lung disease mostly occurring in preterm infants. The pathogenesis of BPD involves early inflammation and remodeling of the premature lung. Aim: To search for the novel predictive marker of BPD development, we studied serum levels of neutrophil gelatinase-associated lipocalin (NGAL), an innate immune mediator, in preterm infants. Methods: Serum NGAL concentrations at birth were measured by enzyme-linked immunosorbent assay. The reference levels were determined in 52 infants having no anomalies or inherited diseases. The levels and clinical variables were assessed in association with BPD. Results: Geometric means (95%CI) of serum NGAL levels at birth of infants having no underlying diseases were 32.4 (22.1-47.5), 58.6 (47.9-71.8), and 126.2 (99.0-168.7) ng/mL for <. 31, 31-36 and >. 36 gestational weeks (GW), respectively (p. <. 0.001). These levels positively correlated with neutrophil (p. <. 0.0001) or monocyte counts (p. <. 0.0001). The median NGAL levels (307.8. ng/mL) and neutrophil counts (4141/μL) at birth of 16 preterm infants (<. 31. GW) who developed BPD were higher than those (42.9. ng/mL and 1357/μL) of 20 infants (<. 31. GW) who did not (p. <. 0.0001 and p=0.012), respectively. In multivariable analysis for 36 infants born less than 31. GW, higher NGAL levels (≥. 82. ng/mL) but not neutrophil counts at birth had a significant association with developing BPD (gestational-age adjusted odds ratio [OR]=37.45 [3.08-455.49], p. <. 0.01). Conclusions: High serum levels of NGAL at birth could be an early sensitive marker for BPD in preterm infants, because their levels were physiologically low..
22. Arisa Fujiwara, Kotaro Fukushima, Hirosuke Inoue, Takeshi Takashima, Hiromasa Nakahara, Shoji Satoh, Masayuki Ochiai, Toshiro Hara, Mototsugu Shimokawa, Kiyoko Kato, Perinatal management of preterm premature ruptured membranes affects neonatal prognosis, Journal of Perinatal Medicine, 10.1515/jpm-2013-0192, 42, 4, 499-505, 2014.01, Aim: To determine the factors affecting neonatal prognosis in preterm premature rupture of membranes (PPROM). Method: We conducted a case-control study involving 92 women between the years 2000 and 2010 diagnosed with PPROM between 25 and 31 weeks' gestation, who received antenatal steroids, and delivered between 26 and 31 weeks' gestation; a retrospective cohort study was conducted based on the results. We used data from four tertiary centers and compared the frequencies of neonatal neurologic deficits and neonatal deaths. Results: There was a difference between the two groups; specifically, the ND group (n = 18) consisted of patients whose infants had neurologic deficits and/or neonatal deaths and the neurologically normal (NN) group (n = 74) included NN neonates amongst the patients who had expectant management (94% vs. 73%, respectively). Multivariable analysis revealed that expectant management was independently associated with an increased risk for neonatal neurologic deficits and neonatal deaths (odds ratio, 16.14). All neonates with poor prognosis in the expectantmanagement group delivered within 14 days after PPROM. Conclusions: Expectant management within 14 days after PPROM is associated with poor neonatal outcomes. Decisions regarding an expectant strategy should be made carefully. An immediate, planned delivery after steroid administration should be considered to improve neonatal prognosis in patients who have PPROM after 26 weeks' gestation..
23. Kazuhiro Okubo, Yasunari Sakai, Hirosuke Inoue, Satoshi Akamine, Yoshito Ishizaki, Yuki Matsushita, Masafumi Sanefuji, Hiroyuki Torisu, Kenji Ihara, Marco Sardiello, Toshiro Hara, Moyamoya disease susceptibility gene RNF213 links inflammatory and angiogenic signals in endothelial cells, Scientific Reports, 10.1038/srep13191, 5, 2015.08, Moyamoya disease (MMD) is a cerebrovascular disorder characterized by occlusive lesions of the circle of Willis. To date, both environmental and genetic factors have been implicated for pathogenesis of MMD. Allelic variations in RNF213 are known to confer the risk of MMD; however, functional roles of RNF213 remain to be largely elusive. We herein report that pro-inflammatory cytokines, IFNG and TNFA, synergistically activated transcription of RNF213 both in vitro and in vivo. Using various chemical inhibitors, we found that AKT and PKR pathways contributed to the transcriptional activation of RNF213. Transcriptome-wide analysis and subsequent validation with quantitative PCR supported that endogenous expression of cell cycle-promoting genes were significantly decreased with knockdown of RNF213 in cultured endothelial cells. Consistently, these cells showed less proliferative and less angiogenic profiles. Chemical inhibitors for AKT (LY294002) and PKR (C16) disrupted their angiogenic potentials, suggesting that RNF213 and its upstream pathways cooperatively organize the process of angiogenesis. Furthermore, RNF213 down-regulated expressions of matrix metalloproteases in endothelial cells, but not in fibroblasts or other cell types. Altogether, our data illustrate that RNF213 plays unique roles in endothelial cells for proper gene expressions in response to inflammatory signals from environments..
24. Toshinori Nakashima, Hirosuke Inoue, Junko Fujiyoshi, Naoko Matsumoto, Longitudinal analysis of serum cystatin C for estimating the glomerular filtration rate in preterm infants, Pediatric Nephrology, 10.1007/s00467-015-3309-x, 31, 6, 983-989, 2016.01, Background: Cystatin C (Cys-C) is a more sensitive marker of renal function than creatinine (Cre) in pediatric and adult populations. However, the reference values of serum Cys-C for estimating glomerular filtration rates (eGFRs) in premature infants during the first year of life have not been sufficiently studied. Methods: In this prospective study, 481 blood samples were collected from 261 preterm infants with uncomplicated clinical courses during their first year of life. Infants were divided into three groups according to gestational age at birth: 27- 30 weeks, 31-33 weeks, and 34-36 weeks. Serum Cys-C and Cre levels were measured at 6-30 days, 3-5 months, 7- 9 months, and 12-14 months after birth and the eGFR was calculated using two previously published equations. Results: The median serum Cys-C levels were 1.776, 1.248, 1.037, and 0.960 mg/L at the first, second, third, and fourth measurement time-point, respectively, with the value significantly decreasing with age up to 12-14 months. Cys-C levels were independent of gestational age and gender. In contrast to Cys-C, serum Cre values declined rapidly up to 3-5 months, then remained constant up to 12-14 months. Using the Cys-C-based equation, the eGFR significantly increased with increasing age until approximately 1 year after birth; however, no such trend was noted using the equation based on Cys-C + Cre. Conclusions: Reference ranges for Cys-C in premature infants decline gradually over the first year after birth. Cys-C appears to be a more reliable marker than Cre for estimating GFR in preterm infants..
25. Masako Ichiyama, Shoichi Ohga, Masayuki Ochiai, Koichi Tanaka, Yuka Matsunaga, Takeshi Kusuda, Hirosuke Inoue, masataka ishimura, Tomohito Takimoto, Yui Koga, Taeko Hotta, Dongchon Kang, Toshiro Hara, Age-specific onset and distribution of the natural anticoagulant deficiency in pediatric thromboembolism, Pediatric Research, 10.1038/pr.2015.180, 79, 1, 81-86, 2016.01, Background:The early diagnosis of inherited thrombophilia in children is challenging because of the rarity and hemostatic maturation.Methods:We explored protein C (PC), protein S (PS), and antithrombin (AT) deficiencies in 306 thromboembolic patients aged ≤20 y using the screening of plasma activity and genetic analysis.Results:Reduced activities were determined in 122 patients (40%). Low PC patients were most frequently found in the lowest age group (0-2 y, 45%), while low PS or low AT patients were found in the highest age group (16-20 y; PS: 30% and AT: 20%). Genetic study was completed in 62 patients having no other causes of thromboembolism. Mutations were determined in 18 patients (8 PC, 8 PS, and 2 AT genes). Six of eight patients with PC gene mutation were found in age 0-2 y (75%), while six of eight patients with PS gene mutation were in 7-20 y. Two AT gene-mutated patients were older than 4 y. Four PC-deficient and two PS-deficient patients carried compound heterozygous mutations. All but one PC gene-mutated patient suffered from intracranial thromboembolism, while PS/AT gene-mutated patients mostly developed extracranial venous thromboembolism.Conclusion:Stroke in low PC infants and deep vein thrombosis in low PS/AT school age children could be targeted for genetic screening of pediatric thrombophilias..
26. Hirosuke Inoue, Hisanori Nishio, Hidetoshi Takada, Yasunari Sakai, Etsuro Nanishi, Masayuki Ochiai, Mitsuho Onimaru, Si Jing Chen, Toshiro Matsui, Toshiro Hara, Activation of Nod1 signaling induces fetal growth restriction and death through fetal and maternal vasculopathy, Journal of Immunology, 10.4049/jimmunol.1500295, 196, 6, 2779-2787, 2016.03, Intrauterine fetal growth restriction (IUGR) and death (IUFD) are both serious problems in the perinatal medicine. Fetal vasculopathy is currently considered to account for a pathogenic mechanism of IUGR and IUFD. We previously demonstrated that an innate immune receptor, the nucleotide-binding oligomerization domain-1 (Nod1), contributed to the development of vascular inflammations in mice at postnatal stages. However, little is known about the deleterious effects of activated Nod1 signaling on embryonic growth and development. We report that administration of FK565, one of the Nod1 ligands, to pregnant C57BL/6 mice induced IUGR and IUFD. Mass spectrometry analysis revealed that maternally injected FK565 was distributed to the fetal tissues across placenta. In addition, maternal injection of FK565 induced robust increases in the amounts of CCL2, IL-6, and TNF proteins as well as NO in maternal, placental and fetal tissues. Nod1 was highly expressed in fetal vascular tissues, where significantly higher levels of CCL2 and IL-6 mRNAs were induced with maternal injection of FK565 than those in other tissues. Using Nod1-knockout mice, we verified that both maternal and fetal tissues were involved in the development of IUGR and IUFD. Furthermore, FK565 induced upregulation of genes associated with immune response, inflammation, and apoptosis in fetal vascular tissues. Our data thus provided new evidence for the pathogenic role of Nod1 in the development of IUGR and IUFD at the maternal-fetal interface..
27. Satoshi Narumi, Naoko Amano, Tomohiro Ishii, Noriyuki Katsumata, Koji Muroya, Masanori Adachi, Katsuaki Toyoshima, Yukichi Tanaka, Ryuji Fukuzawa, Kenichi Miyako, Saori Kinjo, Shoichi Ohga, Kenji Ihara, Hirosuke Inoue, Tadamune Kinjo, Toshiro Hara, Miyuki Kohno, Shiro Yamada, Hironaka Urano, Yosuke Kitagawa, Koji Tsugawa, Asumi Higa, Masakazu Miyawaki, Takahiro Okutani, Zenro Kizaki, Hiroyuki Hamada, Minako Kihara, Kentaro Shiga, Tetsuya Yamaguchi, Manabu Kenmochi, Hiroyuki Kitajima, Maki Fukami, Atsushi Shimizu, Jun Kudoh, Shinsuke Shibata, Hideyuki Okano, Noriko Miyake, Naomichi Matsumoto, Tomonobu Hasegawa, SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7, Nature Genetics, 10.1038/ng.3569, 48, 7, 792-797, 2016.07, Adrenal hypoplasia is a rare, life-threatening congenital disorder. Here we define a new form of syndromic adrenal hypoplasia, which we propose to term MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) syndrome. By exome sequencing and follow-up studies, we identified 11 patients with adrenal hypoplasia and common extra-adrenal features harboring mutations in SAMD9. Expression of the wild-type SAMD9 protein, a facilitator of endosome fusion, caused mild growth restriction in cultured cells, whereas expression of mutants caused profound growth inhibition. Patient-derived fibroblasts had restricted growth, decreased plasma membrane EGFR expression, increased size of early endosomes, and intracellular accumulation of giant vesicles carrying a late endosome marker. Of interest, two patients developed myelodysplasitc syndrome (MDS) that was accompanied by loss of the chromosome 7 carrying the SAMD9 mutation. Considering the potent growth-restricting activity of the SAMD9 mutants, the loss of chromosome 7 presumably occurred as an adaptation to the growth-restricting condition..
28. Masayuki Ochiai, Yuki Matsushita, Hirosuke Inoue, Takeshi Kusuda, Dongchon Kang, Kiyoshi Ichihara, Naoki Nakashima, Kenji Ihara, Shoichi Ohga, Toshiro Hara, Blood reference intervals for preterm low-birth-weight infants A multicenter cohort study in Japan, PLoS One, 10.1371/journal.pone.0161439, 11, 8, 2016.08, Preterm low-birth-weight infants remain difficult to manage based on adequate laboratory tests. The aim of this study was to establish blood reference intervals (RIs) in those newborns who were admitted to and survived in the neonatal intensive care unit (NICU). A multicenter prospective study was conducted among all infants admitted to 11 affiliated NICUs from 2010 to 2013. The clinical information and laboratory data were registered in a network database designed for this study. The RIs for 26 items were derived using the parametric method after applying the latent abnormal values exclusion method. The influence of birth weight (BW) and gestational age (GA) on the test results was expressed in terms of the standard deviation ratio (SDR), as SDRBW and SDRGA, respectively. A total of 3189 infants were admitted during the study period; 246 were excluded due to a lack of blood sampling data, and 234 were excluded for chromosomal abnormalities (n = 108), congenital anomalies requiring treatment with surgical procedures (n = 76), and death or transfer to another hospital (n = 50). As a result, 2709 infants were enrolled in this study. Both the SDRGA and SDRBW were above 0.4 in the test results for total protein (TP), albumin (ALB), alanine aminotransferase (ALT), and red blood cells (RBC); their values increased in proportion to the BW and GA. We derived 26 blood RIs for infants who were admitted to NICUs. These RIs should help in the performance of proper clinical assessments and research in the field of perinatal-neonatal medicine..
29. Masayuki Ochiai, Hiroaki Kurata, Hirosuke Inoue, Koichi Tanaka, Yuki Matsushita, Junko Fujiyoshi, Yoshifumi Wakata, Kiyoko Kato, Tomoaki Taguchi, Hidetoshi Takada, An Elevation of Serum Ferritin Level Might Increase Clinical Risk for the Persistence of Patent Ductus Arteriosus, Sepsis and Bronchopulmonary Dysplasia in Erythropoietin-Treated Very-Low-Birth-Weight Infants, Neonatology, 10.1159/000447991, 111, 1, 68-75, 2016.12, Background: The substantial risk of iron overload is not routinely monitored in most of the neonatal intensive care units (NICUs) in Japan; however, blood transfusion is an essential strategy for successfully treating preterm low-birth-weight infants. Objective: The aim of this study was to investigate the iron status and clinical features of infants with a birth weight of <1,500 g, i.e. very-low-birth-weight infants (VLBWIs). Methods: This prospective observational study enrolled 176 (82.6%) patients from a total of 213 VLBWIs admitted to our NICU from 2009 to 2014. Clinical information was collected including maternal records and infant morbidity and treatment. Management strategies including enteral iron supplementation, erythropoietin administration and blood transfusion were allowed according to the consensus in Japan. The hematological status was surveyed from birth to 12 postnatal weeks of age. The iron status was determined according to serum iron, unbound iron-binding capacity and serum ferritin. The definition of hyperferritinemia was set as a value of ≥500 ng/ml. Results: Twenty-four (13.6%) infants displayed hyperferritinemia. A multiple logistic analysis selected 3 associated factors of hyperferritinemia: surgical ligation for patent ductus arteriosus, sepsis and moderate or severe states of bronchopulmonary dysplasia. We also verified that the value of ferritin was significantly correlated with those of aspartate transaminase, creatine kinase and C-reactive protein according to a multilinear regression analysis. After excluding the ferritin data of these outliers, we did not observe any factors associated with hyperferritinemia. Conclusions: Hyperferritinemia might be associated with oxygen radical diseases and susceptibility to infection..
30. Kazuaki Yasuoka, Hirosuke Inoue, Koichi Tanaka, Junko Fujiyoshi, Yuki Matsushita, Masayuki Ochiai, Yuhki Koga, Toshiharu Matsuura, Tomoaki Taguchi, Shoichi Ohga, Successful liver transplantation for transient abnormal myelopoiesis-associated liver failure, Neonatology, 10.1159/000474930, 112, 2, 159-162, 2017.08, Infants with Down syndrome (DS) are at risk of developing a transient abnormal myelopoiesis (TAM). TAM occasionally involves liver fibrosis, which can be fatal. The management of liver disease in TAM has not yet been established and is mainly supportive. We report an infant with DS and TAM who developed end-stage liver failure. Liver dysfunction progressed even after blast cells disappeared from the circulation. He underwent a living-donor liver transplantation at 56 days of life without surgical complications. The explanted liver showed atrophy and severe fibrosis without leukemic cell infiltration. The posttransplant course was favorable with no hematological abnormality. He is doing well 8 months after transplantation. To the best of our knowledge, this report is the first showing that liver transplantation might be a treatment option for TAM-related liver failure..
31. Hirosuke Inoue, Masayuki Ochiai, Kazuaki Yasuoka, Koichi Tanaka, Hiroaki Kurata, Junko Fujiyoshi, Yuki Matsushita, Shutaro Suga, Kazuaki Nonaka, Tomoaki Taguchi, Kiyoko Kato, Shoichi Ohga, Early Mortality and Morbidity in Infants with Birth Weight of 500 Grams or Less in Japan, Journal of Pediatrics, 10.1016/j.jpeds.2017.05.017, 190, 112-117.e3, 2017.11, Objective To assess the short-term prognosis of Japanese infants with a birth weight (BW) of ≤500 g. Study design Demographic and clinical data were reviewed for 1473 live born infants with a BW ≤500 g at gestational age ≥22 weeks who were treated in the 204 affiliated hospitals of the Neonatal Research Network of Japan between 2003 and 2012. Results Survival to hospital discharge occurred in 811 of 1473 infants (55%; 95% CI 53%-58%). The survival rates of BW ≤300 g, 301-400 g, and 401-500 g were 18% (95% CI 10%-31%), 41% (95% CI 36%-47%), and 60% (95% CI 57%-63%), respectively. In a multivariable Cox proportional hazards analysis, antenatal corticosteroid use (adjusted hazard ratio: 0.68; 95% CI 0.58-0.81; P <.01), cesarean delivery (0.69; 95% CI 0.56-0.85; P <.01), advanced gestational age per week (0.94; 95% CI 0.89-0.99; P =.02), BW per 100-g increase (0.55; 95% CI 0.49-0.64; P <.01), Apgar score ≥4 at 5 minutes (0.51; 95% CI 0.43-0.61; P <.01), and no major congenital abnormalities (0.38; 95% CI 0.29-0.51; P <.01) were associated with survival to discharge. Despite the improved survival rate over the 10-year study period (from 40% in 2003 [95% CI 30%-51%] to 68% in 2012 [95% CI 61%-75%]), at least 1 severe morbidity was present in 81%-89% of the survivors. Conclusions Improvements in perinatal-neonatal medicine have improved the survival, but not the rate of major morbidities, of infants with a BW ≤500 g in Japan..
32. Hirosuke Inoue, Serum neutrophil gelatinase-associated lipocalin as a predictor of the development of bronchopulmonary dysplasia in preterm infants., 10.1016/j.earlhumdev.2012.12.011., 89(6):425-9., 2013.06.
33. Arisa Fujiwara, Hirosuke Inoue, Perinatal management of preterm premature ruptured membranes affects neonatal prognosis., 10.1515/jpm-2013-0192., 42(4):499-505. , 2014.07.
34. 大久保一宏, Hirosuke Inoue, Moyamoya disease susceptibility gene RNF213 links inflammatory and angiogenic signals in endothelial cells., 10.1038/srep13191., 17;5:13191. , 2015.08.
35. Ichiyama Masako, Hirosuke Inoue, Age-specific onset and distribution of the natural anticoagulant deficiency in pediatric thromboembolism., 10.1038/pr.2015.180., 79(1-1):81-6. , 2016.01.
36. Nakashima T, Hirosuke Inoue, Longitudinal analysis of serum cystatin C for estimating the glomerular filtration rate in preterm infants., 10.1007/s00467-015-3309-x., 31(6):983-9. , 2016.06.
37. Hirosuke Inoue, Activation of Nod1 Signaling Induces Fetal Growth Restriction and Death through Fetal and Maternal Vasculopathy., 10.4049/jimmunol.1500295., 196(6):2779-87., 2016.05.
38. Narumi S, Hirosuke Inoue, SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7., 10.1038/ng.3569., 48(7):792-7., 2016.07.
39. Masayuki Ochiai, Hirosuke Inoue, An Elevation of Serum Ferritin Level Might Increase Clinical Risk for the Persistence of Patent Ductus Arteriosus, Sepsis and Bronchopulmonary Dysplasia in Erythropoietin-Treated Very-Low-Birth-Weight Infants., 111(1):68-75., 2017.01.
40. Masayuki Ochiai, Hirosuke Inoue, Blood Reference Intervals for Preterm Low-Birth-Weight Infants: A Multicenter Cohort Study in Japan., 10.1371/journal.pone.0161439, 11(8):e0161439, 2016.08.