Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jpeds.2020.11.041

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Background: The limits of viability in extremely premature infants are challenging for any neonatologists in developed countries. On the other hand, tThe neurological development and growth of extremely preterm infants have come to be the emerging issue in the next stage of following the management of in NICU.
Objective: To assess potential associations between changes in practice and survival/neurodevelopmental outcome, and clinical outcomes of extremely preterm infants born at the limit of viability were studied in a tertiary center.　　
Study design: A retrospective study enrolled 51 infants who had no congenital disorders, and were born at 22-24 weeks of gestational age (GA) in 2000-2009 in our single institution. Clinical variables and interventions were studied with regard to one-year survival and developmental quotient (DQ) at 3 years of age.　　
Results: The one-year survival rate of 24 preterm infants born in 2005-2009 (79%) was higher than that of the 27 those infants born in 2000-2004 (52%) (p=0.04). The iInfants born at or post-2005 underwent less and more frequently tocolysis (54% vs. 94%, p<0.01) and more frequently antenatal steroid therapy (32% vs. 6%, p=0.01) than those born at pre-20045, respectively. The post-2005 survivors (n=19) received more frequently indomethacin therapy (89% vs. 50%, p=0.03) and early parenteral nutrition (95% vs. 36%, p<0.01) than the pre-20045 survivors (n=14). There were no differences in the proportion of infants who attained a DQ of >50 at 3-years of age between pre-20045 (n=9/13=69%) and post-2005 groups (n=10/17=59%) (30% vs. 33%). Multivariate analysis indicated that extremely premature birth ity born at GA<24w was the sole critical factor for the development status with the a DQ of >50 in survivors.　　
Conclusions: The perinatal care after 2005 could improved the overall survival rate, but not, the neurological outcomes of preterm survivors at the limit of viability. Neurodevelopmental impairments were associated with the extremely premature birth ity born at GA<24w.

DOI： 10.1159/000355818

Language：English   Publisher：Neonatology  

Introduction: Infants born extremely preterm are at high risk for neurodevelopmental problems. However, their neurodevelopment exhibits a variety of trajectories. This study aimed to investigate the association between changes in neurodevelopmental outcomes and clinical characteristics among extremely preterm infants. Methods: This is a retrospective study of surviving children born at gestational age 22-28weeks in Kyushu University Hospital between 2010 and 2020. We collected perinatal and post-discharge data and investigated the association between clinical characteristics and changes in developmental quotient (DQ) scores between 1.5 and 3 years of corrected age. Results: Out of the 179 eligible extremely preterm infants, 115 (64%) underwent neurological evaluations at 1.5 and 3 years of corrected age. Among them, 33 (29%) showed improvement in their DQ scores (+10 or more), 62 (54%) showed no change (-9 to +9), and 20 (17%) showed a decline (-10 or less). Gestational age, birth weight, and perinatal complications during the NICU stay did not affect individual changes in DQ scores. Multivariable analysis revealed that greater growth in height until age 3 years was a significant predictor of increasing DQ scores, while male sex and having siblings had a negative effect on changes in the DQ scores. Conclusion: We first demonstrate clinical data conceptualizing that growth in height, sex, and sibling status, rather than perinatal complications, are biologically linked with favorable or unfavorable neurodevelopmental changes of extremely preterm infants during the first 3 years of life.

DOI： 10.1159/000541129

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PubMed

Publisher：金原出版  

DOI： 10.18888/sh.0000003140

CiNii Research

Language：English   Publisher：Japanese Journal of Ophthalmology  

Purpose: To assess the safety and efficacy of ripasudil for retinopathy of prematurity (ROP). Study design: Phase 1/2, multicenter, open-label, single-arm, 12-week clinical trial. Methods: Infants born with gestational age (GA) of ≤ 32 weeks or weight of ≤ 1500 g with zone I or II, ≥ stage 1, ROP in both eyes were enrolled. Ripasudil eye drops were administered to patients in both eyes. Phase 1 was a dose-escalation study (once daily for 1 week, then twice daily for 2 weeks); an additional dosing up to 9 weeks was allowed if no safety issues occurred. In phase 2, ripasudil was administered twice daily for up to 12 weeks. Adverse events were assessed. The proportion of patients with type 1 ROP progression, number of days for type 1 ROP progression, and progression to the most advanced ROP stage were estimated. Results: Twenty-four infants were enrolled (phase 1, n = 3; phase 2, n = 21). Nineteen and four patients experienced systemic and ocular adverse events, respectively. Efficacy endpoints were not different between the ripasudil and historical control groups. However, in the GA ≤ 27 weeks subgroup, fewer patients progressed to type 1 ROP in the ripasudil than in the historical control group (P = 0.09). In the GA ≤ 27 weeks subgroups, the 25th percentile for the number of days for type 1 ROP progression was 22 days in the historical control group and 44 days in the ripasudil group. Conclusion: Ripasudil was safe and inhibited/delayed type 1 ROP progression, especially in infants with short GA.

DOI： 10.1007/s10384-024-01100-3

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PubMed

Language：English   Publisher：シュプリンガー・ジャパン(株)  

Language：English   Publisher：Scientific Reports  

To examine whether patterns, such as the timings of onset or recovery from sleep disturbance, are associated with later developmental problems, including autism spectrum disorder (ASD). Mothers participating in the Japan Environment and Children’s Study with a child aged 3 years were included in the analyses. Children were assessed for short sleep and frequent awakenings at 1 month, 6 months, and 1 year of age. Developmental problems were evaluated at 3 years of age based on ASD diagnosis and developmental delay, using the Japanese translation of the Ages and Stages Questionnaire (ASQ) 3rd edition. Sleep disturbance patterns were classified by onset age, and developmental problem risks were examined based on onset/recovery ages. Among 63,418 mother-infant dyads, 0.4% of infants were later diagnosed with ASD, and 14.4% had abnormal scores on any ASQ domains. The later the onset of short sleep, the lower the risk of abnormal ASQ scores (RR of short sleep onset at 1 year: 1.41; 6 months: 1.52; 1 month: 1.57). The earlier the infants recovered from short sleep persistence, the lower the risk of developmental delay (RR of remittance of sleep problems identified at 1 month by 6 months: 1.07; 1 year: 1.31; not before 1 year: 1.57). Although not all patterns were significant, later short sleep onset and earlier recovery were associated with lower ASD risk. These findings may have significant implications for future interventions in infant development.

DOI： 10.1038/s41598-024-68672-5

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Lifelong health is dependent on prenatal growth and development, influenced by the placental intrauterine environment. Charged with dual functions--exchange of oxygen and nutrients as well as a barrier against toxins--the placenta itself is susceptible to environmental exposure to heavy metals. OBJECTIVE: To examine the use of placenta weight as a biomarker for heavy metal exposure using a large Japanese cohort of pregnant women. METHODS: The placenta weight, as a biomarker of exposure to heavy metals (cadmium, lead, and mercury), was investigated using data from the Japan Environment and Children's Study (2011-2014). Selenium and manganese were included as factors directly affecting fetal growth or heavy metal toxicity. Maternal blood samples collected in the second or third trimester were used to measure heavy metal concentrations. The association between maternal blood metal concentrations and placenta weight was explored by applying Z scores and multivariable logistic regression analysis and classifying participants into quartiles (Q1, Q2, Q3, and Q4) according to metal concentrations. RESULTS: This study included a total of 73,005 singleton pregnant women who delivered via live births and met the inclusion criteria. The median heavy metal concentrations in the maternal whole blood were 0.662?ng/g cadmium, 5.85?ng/g lead, 3.61?ng/g mercury, 168?ng/g selenium, and 15.3?ng/g manganese. Regression analysis revealed a significant correlation between placenta weight Z scores and maternal blood metal concentrations: cadmium, 0.0660 (standard error?=?0.0074, p?<?0.001); selenium, -0.3137 (standard error?=?0.0276, p?<?0.001); and manganese, 0.1483 (standard error?=?0.0110, p?<?0.001). CONCLUSION: This study provides a robust examination of the association between heavy metal exposure and placenta weight. Cadmium and manganese showed a positive correlation with significant differences, whereas selenium showed a negative correlation. Essential elements notably affect placenta weight differently. No significant association was noted between lead or mercury and placenta weight.

DOI： 10.1016/j.envint.2024.108725

Publisher：東京医学社  

DOI： 10.24479/peri.0000001482

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: CHARGE syndrome is a congenital malformation syndrome caused by heterozygous mutations in the CHD7 gene. Severe combined immunodeficiency (SCID) arises from congenital athymia called CHARGE/complete DiGeorge syndrome. While cultured thymus tissue implantation (CTTI) provides an immunological cure, hematopoietic cell transplantation (HCT) is an alternative option for immuno-reconstitution of affected infants. We aimed to clarify the clinical outcomes of patients with athymic CHARGE syndrome after HCT. METHODS: We studied the immunological reconstitution and outcomes of four patients who received non-conditioned unrelated donor cord blood transplantation (CBT) at Kyushu University Hospital from 2007 to 2022. The posttransplant outcomes were compared with the outcomes of eight reported patients. RESULTS: Four index cases received CBT 70-144?days after birth and had no higher than grade II acute graft-versus-host disease. One infant was the first newborn-screened athymic case in Japan. They achieved more than 500/μL na?ve T cells with balanced repertoire 1?month post transplant, and survived more than 12?months with home care. Twelve patients including the index cases received HCT at a median 106?days after birth (range: 70-195?days). One-year overall survival rate was significantly higher in patients who underwent non-conditioned HCT than in those who received conditioned HCT (100% vs. 37.5%, p?=?.02). Nine patients died, and the major cause of death was cardiopulmonary failure. CONCLUSIONS: Athymic infants achieved a prompt reconstitution of non-skewing na?ve T cells after non-conditioned CBT that led to home care in infancy without significant infections. Non-conditioned CBT is a useful bridging therapy for newborn-screened cases toward an immunological cure by CTTI.

DOI： 10.1002/pbc.30809

Language：English   Publisher：European Journal of Medical Genetics  

Introduction: NGLY1-associated congenital disorder of deglycosylation (CDDG1: OMIM #615273) is a rare autosomal recessive disorder caused by a functional impairment of endoplasmic reticulum in degradation of glycoproteins. Neurocognitive dysfunctions have been documented in patients with CDDG1; however, deteriorating phenotypes of affected individuals remain elusive. Case presentation: A Japanese boy with delayed psychomotor development showed ataxic movements from age 5 years and myoclonic seizures from age 12 years. Appetite loss, motor and cognitive decline became evident at age 12 years. Electrophysiological studies identified paroxysmal discharges on myoclonic seizure and a giant somatosensory evoked potential. Perampanel was effective for controlling myoclonic seizures. Exome sequencing revealed that the patient carried compound heterozygous variants in NGLY1, NM_018297.4: c.857G > A and c.-17_12del, which were inherited from mother and father, respectively. A literature review confirmed that myoclonic seizures were observed in 28.5% of patients with epilepsy. No other patients had progressive myoclonic epilepsy or cognitive decline in association with loss-of-function variations in NGLY1. Conclusion: Our data provides evidence that a group of patients with CDDG1 manifest slowly progressive myoclonic epilepsy and cognitive decline during the long-term clinical course.

DOI： 10.1016/j.ejmg.2023.104895

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Language：Japanese   Publisher：(公社)日本小児科学会  

小児科領域専門研修プログラム(研修プログラム)を有する基幹施設187施設のプログラム統括責任者を対象に、専攻医のNICU研修に関するアンケート調査を行い、前回調査(2019年度研修プログラム)と比較した。155施設から得られた回答を集計した結果、新生児蘇生法講習会(NCPR)受講は140施設(90.3%)が何らかの形で行っており、154施設ではNICUにおける研修を行っていた。NICU研修対象は全員が139施設(89.7%)、希望者が11施設(7.1%)で、ほとんどの基幹施設が自施設でNICU研修を実施しており、4～6ヵ月間の研修で40～59症例を経験できる施設が多かった。望ましいNICU研修期間は6ヵ月と回答した施設が多く、研修プログラムに6ヵ月以上のNICU研修を明記することは、新生児研修の標準化につながると考えられた。

DOI： 10.1111/ped.15870

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Occupational exposure to medical agents and ionizing radiation has been suggested as a possible risk factor for childhood cancer. However, the relationship between such exposure and pediatric malignancies has not yet been comprehensively studied. This cohort study aimed to investigate the association between parental occupational exposure to hazardous medical agents or ionizing radiation and the risk of childhood cancer in offspring. Data from a large birth cohort in Japan, which included 104,062 fetuses, were analyzed. The primary outcome was the development of leukemia or brain tumors diagnosed by community physicians during the first three years after birth. Exposure factors were medical agents, including anticancer agents, ionizing radiation, and anesthetics, handled by mothers during pregnancy or by fathers for three months prior to conception. The incidence of leukemia, but not of brain tumors, was higher in mothers exposed to anticancer drugs. Multivariable regression analysis showed that maternal exposure to anticancer drugs was associated with an increased risk of leukemia in offspring over one year of age (adjusted relative risk: 7.99 [95% confidence interval: 1.98-32.3]). Detailed information obtained from medical certificates of patients with identified leukemia revealed no infant leukemia but acute lymphoblastic leukemias in the exposed group. Our findings suggest that maternal occupational exposure to anticancer drugs may be a potential risk factor for acute lymphoblastic leukemia in offspring over one year of age. Effective prevention methods may be necessary to prevent maternal exposure to anticancer drugs and to reduce the risk of childhood malignancies.

DOI： 10.1182/blood.2023021008

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Neonatal disseminated intravascular coagulation (DIC) is a rare disease with a poor outcome. However, data on the incidence, treatment, and outcome of neonatal DIC are scarce. Thus, this study investigated the status of neonatal DIC in Japan. METHODS: We sent a retrospective questionnaire-based survey regarding the status of diagnosis and treatment of neonatal DIC from January 1, 2016, to December 31, 2018, to 30 hospitals in Kyushu with a neonatal-perinatal medicine division. The data collected by the questionnaire survey included information about the patients diagnosed with neonatal DIC. RESULTS: Among the 13,582 neonates surveyed, 120 (0.9?%) were diagnosed with DIC. Of them, clinical data were available for 105 cases. There were 11 deaths (mortality rate: 10.4?%), with the most common underlying condition being infection (n?=?9), followed by neonatal asphyxia and hematologic disease (both, n?=?1). Compared with the survival group, the death group had more infections, as well as a higher rate of bleeding symptoms and organ dysfunction. CONCLUSIONS: Neonatal DIC associated with infectious diseases has a poor outcome. Therefore, it is necessary to formulate diagnostic and treatment guidelines for early intervention in such cases.

DOI： 10.1016/j.pedneo.2023.04.020

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1543209120

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Numerous studies suggest that sex steroids might play a role in sex disparity observed in allergic diseases in adults. However, whether sex hormones influence allergic diseases in children remains unclear. The aim of the present study was to examine the association of sex steroid hormones with allergic disease in Japanese children. METHODS: The present cross-sectional study included 145 6-year-old children participating in a pilot birth cohort study in the Japan Environment and Children's Study. Data on allergic diseases were obtained from questionnaires, and serum levels of sex steroid hormones and allergen-specific IgE were measured. Logistic regression was performed to evaluate the association of sex hormones with allergic diseases. RESULTS: After adjusted sex, amount of body fat at 6?years, parental history of allergic disease, and exposure to tobacco smoke, serum dehydroepiandrosterone sulfate level was significantly associated with reduced odds of any allergic disease (adjusted odds ratio, 0.58; 95% confidence interval, 0.36-0.93; P?=?0.024) and serum follicle-stimulating hormone level was significantly associated with increased odds of any allergic disease (adjusted odds ratio, 2.04; 95% confidence interval, 1.01-4.11, P?=?0.046). Dehydroepiandrosterone sulfate level showed a significant association with number of allergic diseases. CONCLUSIONS: The current study findings suggest that sex hormones may play an important role in the development of allergic diseases in prepubertal children.

DOI： 10.1186/s12887-023-04302-9

Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: To establish actionable neonatal screening during the first month of life, we investigated critical diseases in seemingly healthy newborns discharged from birth hospitals. METHODS: This retrospective study enrolled previously healthy full-term infants who visited our hospital, a tertiary hospital in Japan, from home between 5 and 28?days after birth from 2009 to 2018. Infants with known perinatal or congenital diseases, positive newborn screening results, or accidental injuries were excluded. Data were collected from electronic medical records, including principal diagnosis, clinical details, and prognosis at 18?months of age. RESULTS: Ninety-seven (58?%) of 168 eligible neonates were admitted to the hospital, and 71 (42?%) were not. The median admission rate in patients with disease onset at ?14?days after birth (80?%) was significantly higher than that in patients with disease onset at ?15?days (42?%). Among 45 patients who received intensive medical care, 5 died and 10 developed neurodevelopmental sequelae. Four of 5 patients died by 100?days. Among 25 diseases treated in intensive care unit, 17 (68?%) diseases had a prevalence of <1 per 2000 live births. The commonly used diagnostic methods were imaging (n?=?58, 35?%) and physical examination (n?=?34, 20?%). CONCLUSION: Critical diseases due to rare and heterogeneous causes in ostensibly healthy newborns occurred predominantly in the first two weeks of life. Optimal newborn screening and health check-up protocols may benefit from the wide spectrum of life-threatening diseases occurring in home after birth.

DOI： 10.1016/j.earlhumdev.2023.105869

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Advanced perinatal medicine has decreased the mortality rate of preterm infants. Long-term neurodevelopmental outcomes of very-low-birth-weight infants (VLBWIs) remain to be investigated. METHODS: Participants were 124 VLBWIs who had in-hospital birth from 2007 to 2015. Perinatal information, developmental or intelligence quotient (DQ/IQ), and neurological comorbidities at ages 3 and 6 years were analyzed. RESULTS: Fifty-eight (47%) VLBWIs received neurodevelopmental assessments at ages 3 and 6 years. Among them, 15 (26%) showed DQ/IQ <75 at age 6 years. From age 3 to 6 years, 21 (36%) patients showed a decrease (?-10), while 5 (9%) showed an increase (?+10) in DQ/IQ scores. Eight (17%) with autism spectrum disorder or attention-deficit hyperactivity disorder (ASD/ADHD) showed split courses of DQ/IQ, including two with ?-10 and one with +31 to their scores. On the other hand, all 7 VLBWIs with cerebral palsy showed DQ ?35 at these ages. Magnetic resonance imaging detected severe brain lesions in 7 (47%) of those with DQ <75 and 1 (18%) with ASD/ADHD. CONCLUSIONS: VLBWIs show a broad spectrum of neurodevelopmental outcomes after 6 years. These divergent profiles also indicate that different risks contribute to the development of ASD/ADHD from those of cerebral palsy and epilepsy in VLBWIs. IMPACT: Very-low-birth-weight infants (VLBWIs) show divergent neurodevelopmental outcomes from age 3 to 6 years. A deep longitudinal study depicts the dynamic change in neurodevelopmental profiles of VLBWIs from age 3 to 6 years. Perinatal brain injury is associated with developmental delay, cerebral palsy and epilepsy, but not with ASD or ADHD at age 6 years.

DOI： 10.1038/s41390-023-02778-w

Publisher：東京医学社  

DOI： 10.24479/peri.0000001017

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Sleep problems and irritable temperaments are common among infants with autism spectrum disorder (ASD). The prospective association between such sleep problems and irritable temperaments and ASDs needs to be determined for elucidating the mechanism and exploring the future intervention study. Thus, in this study, we investigated whether sleep quality and temperament in 1-month-old infants are associated with the onset of ASD in 3-year-old children. We also assessed its sex-stratified associations. METHODS: We conducted a longitudinal study using data from 69,751 mothers and infants from a large-cohort study, the Japan Environment and Children's Study. We examined the prospective association between infant sleep quality and temperament at 1 month of age and ASD diagnosis by 3 years of age. RESULTS: Here we show infants with longer daytime sleep have a higher risk of later ASD than those with shorter daytime sleep (risk ratio [RR]: 1.33, 95% confidence interval [CI]: 1.01-1.75). Infants who experienced intense crying have a higher risk of ASD than those who did not (RR: 1.31, 95% CI: 1.00-1.72). There is a difference in sex in the association between a bad mood and later ASD. In particular, female infants experiencing bad moods have a higher risk of ASD than others (RR: 3.59, 95% CI: 1.91-6.75). CONCLUSIONS: The study findings provide important information for future intervention to reduce the risk of future ASD.

DOI： 10.1038/s43856-023-00314-9

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Prenatal exposure to metal elements has been reported as a potential risk factor for congenital malformation. However, studies on the relationship with congenital anomalies of the kidney and urinary tract (CAKUT) are very scarce. METHODS: Participants of a prospective cohort from the Japan Environment and Children's Study, conducted at 15 research centers, were recruited between January 2011 and March 2014. The exposure factors were concentrations of lead (Pb), cadmium (Cd), mercury (Hg), selenium (Se), and manganese (Mn) measured from maternal whole blood in the second or third trimester. The primary outcome was CAKUT diagnosed during the first three years of life, which was classified into isolated cases and complicated cases accompanied by extrarenal congenital defects. To conduct a nested case-control design within the cohort, we selected 351 isolated cases with 1404 matched controls, and 79 complicated cases with 316 matched controls. RESULTS: A logistic regression model was used to examine the associations between individual metal concentrations and each subtype of CAKUT. A higher level of Se was associated with an increased risk of isolated CAKUT (adjusted odds ratio [95?% confidence interval]: 3.22 [1.33-7.77]). Meanwhile, higher levels of Pb and Mn were associated with a reduced risk of the complicated subtype (0.46 [0.24-0.90] and 0.33 [0.15-0.73], respectively). A Bayesian kernel machine regression model accounting for mixed effects of multiple metals further demonstrated that a higher level of Mn alone was significantly associated with a reduced occurrence of the complicated subtype. CONCLUSIONS: Using a stringent statistical approach, the present study demonstrated that a higher Mn concentration in the maternal blood was associated with a lower risk of complicated CAKUT in offspring. Further cohort and experimental studies are needed to verify the clinical impact of this finding.

DOI： 10.1016/j.scitotenv.2023.164356

Language：English   Publisher：Pediatrics and Neonatology  

Background: The Edinburgh postnatal depression scale (EPDS) is commonly used in screening for major postpartum depression (PPD). We explored the clinical factors associated with score changes. Methods: Mothers (n=1,287) who delivered a single live-born infant in Kokura Medical Center in Japan during 2018–2019 were analyzed. The EPDS-Japanese version was conducted at the first and fourth weeks after childbirth. Scores of ≥9 were considered to indicate an increased risk of PPD. Results: The scores improved during the four-week period (5.03±0.12 to 3.79±0.10). Primiparity, Cesarean section (CS), and a low Apgar score were identified as initial risk factors, however, primiparity remained in the multivariate analysis (aOR 2.02, 95% CI 1.37–2.97). Age ≥35 years was associated with worsened scores (aOR 1.88, 95%CI 1.01–3.51), but CS improved (aOR 0.38, 95%CI 0.21–0.70). Primiparity, CS, and neonatal respiratory support were the initial risk factors, while infant anomaly was a late risk factor in mothers whose infants were admitted to the neonatal intensive care unit (NICU) (aOR 3.35, 95%CI 1.31–8.56). In mothers of infants with an NICU stay of ≥4 weeks, infant anomaly was associated with worsened scores (aOR 6.61, 95%CI 1.11–39.3), while respiratory support was associated with improved scores (aOR 0.09, 95%CI 0.01–0.65). Twenty-six mothrs with worsened scores received psychiatric support; three developed PPD. Two of the three were ≥35 years of age, neither of their infants had anomalies. Conclusion: Maternal aging and infant anomaly were risk factors for PPD. PPD occurred in mothers with worsened EPDS scores after mental care. Puerperants with worsening risk factors should be targeted to control PPD.

DOI： 10.1016/j.pedneo.2022.09.013

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Language：Japanese   Publisher：(公社)日本小児科学会  

第2回(2022年度)小児科専門医試験【日本専門医機構認定プログラム制】受験者を対象に、新生児研修内容や専攻医の新生児研修に関する意識についてアンケート調査を行い、176名(28.7%)から回答を得た。新生児蘇生法講習会(NCPR)を受講率は90.3%であり、小児科専門研修プログラムにNCPR講習は組み入れられていない基幹施設も少なくないと考えられるが、ほとんどの専攻医がNCPRは小児科研修に必要と考えていること、分娩のある施設の小児科に勤務する可能性もあることから、研修プログラムにNCPRを加えることが望ましいと考えられた。94.3%が"新生児集中治療管理室(NICU)研修がある"、74.6%が"6ヵ月以上1年未満のNICU研修期間が望ましい"と答えており、最低6ヵ月間のNICU研修を行うという小児科研修プラグラムが望ましいと考えられた。

Publisher：診断と治療社  

DOI： 10.34433/pp.0000000421

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/pbc.30047

Language：Japanese   Publisher：(公社)日本小児科学会  

2022年7月～9月に、小児科標榜2502施設を対象にSARS-CoV-2感染妊婦(感染妊婦)から出生した新生児の診療の現状や管理方法、社会的影響に関する調査を行い894施設から回答を得られた。感染妊婦の新生児の受入れは410施設で、2020年2月～2022年6月に241施設で感染妊婦2373人が出産した新生児2373人のうち29人が陽性であった。感染妊婦の新生児に対するSARS-CoV-2検査は404/410施設で行い、検査回数は2回が最も多く、検査日齢は日齢0と2が最も多かった。第1、2波と第6波時点で管理上に大きな変更が無い施設が最も多く、SARS-CoV-2陽性の職員や面会者から新生児への水平感染は非常に少なく、約60%の施設でオンライン面会ができ、NICUやGCUでは90%が面会制限していた。乳児院へ行った例で「愛着形成が困難であった」「母親が濃厚接触者となり隔離期間が長かった」という理由を認めた。

Publisher：東京医学社  

DOI： 10.24479/peri.0000000761

CiNii Research

Language：Japanese   Publisher：The Japanese Society of Hematology  

<p>The number of reports on genetic predisposition to pediatric thrombosis is increasing. The risk of thrombosis in childhood varies according to patient age, and the contribution of genetic predisposition also differs. The term early-onset thrombophilia, which occurs until the age of 20 years in patients with genetic diagnosis, was defined. Then, the registry in Japan was established. Further, publications were reviewed comprehensively, and results revealed the genetic and clinical characteristics of patients. Less than 60% of patients presented with protein C (PC) deficiency, and over half of them had PC-gene monoallelic variants. The number of patients with protein S or antithrombin deficiency increased with age. None of them were aged between 6 and 8 years. PC-Tottori and protein S-Tokushima, which are high-frequency and low-risk variants in Japanese, contributed to the development of thrombosis. However, PC-Tottori did not affect the development of severe PC deficiency. One exceptional <i>de novo</i> PC-deficient variant was identified in 32 EOT families, and thrombosis developed concurrently in three pairs of mothers-newborns. Appropriate EOT screening tests targeting PC deficiency are required to prevent maternal and neonatal thromboses.</p>

DOI： 10.11406/rinketsu.64.1131

PubMed

CiNii Research

Language：Japanese   Publisher：The Japanese Society of Pediatric Hematology / Oncology  

<p>Idiopathic thrombosis developing in childhood has increased in incidence because of advances in medical technology and improved disease recognition. The genetic predisposition of pediatric thrombosis (thrombophilia) primarily consists of protein C, protein S, and antithrombin deficiencies. Evidence of thrombolysis, specific replacement, or anticoagulant therapy for these disorders does not exist. Moreover, trials for direct oral anticoagulants and specific replacement therapy for non-hereditary idiopathic thrombosis have also not proceeded. Hereditary thrombosis occurring in childhood leads to poor outcomes. Repetitive purpura fulminans require life-long anticoagulant therapy; however, a specific treatment strategy does not exist. Pregnancy and delivery of unaffected carriers could trigger maternal and infant thrombosis. Herein, we established a research project, “Establishment of a clinical algorithm for idiopathic thrombosis that develops from neonates to adults,” supported by the Japan Agency for Medical Research and Development in 2020–2022. This study proposed thrombosis underlying genetic predispositions as early-onset thrombosis/thrombophilia (EOT) and aimed to present a clinical guideline for EOT. In this symposium, we showed the progress of the EOT registry and the guideline.</p>

DOI： 10.11412/jspho.60.234

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Pulmonary agenesis is a complete absence of the pulmonary parenchyma, airways, and vasculature unilaterally or bilaterally. Although bilateral cases are lethal, the outcome of unilateral cases remains not well described. We performed a comprehensive literature review to assess the clinical features of pulmonary agenesis. METHODS: Four database sources were searched on October 10, 2021 and two cases were included from our institution. Studies related to the clinical impact of comorbidity and intervention on the survival outcome in pulmonary agenesis were included for full-text review. RESULTS: We identified 259 patients-with right-sided (59%), left-sided (34%), and bilateral agenesis (7%)-among 195 articles and our two cases. Additional anomalies included cardiovascular (40%), skeletal (30%), gastrointestinal (20%), tracheal (20%: all stenoses), and genitourinary (14%) anomalies. Fifty-seven (24%) individuals in unilateral pulmonary agenesis had isolated disease. Outcomes related to survival were not uniformly reported, but the 2-year overall survival rate of unilateral agenesis was 62% and no subsequent death was reported until 13 years of age. The right-sided agenesis was more frequently associated with tracheal stenosis (27% vs. 11%, p?=?0.003) than the left-sided disease. A multivariable analysis indicated that tracheal stenosis (hazard ratio [HR]:?2.2, 95% confidence interval [CI]: 1.3-4.1, p?=?0.003) and gastrointestinal anomalies (HR: 2.0, 95% CI: 1.1-3.3, p?=?0.010) were prognostic factors for mortality. CONCLUSIONS: The poor prognostic factors were tracheal stenosis, right agenesis, and gastrointestinal anomalies. Treatment for these comorbidities is a key point for improving the survival of unilateral pulmonary agenesis.

DOI： 10.1002/ppul.26135

Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Infants with congenital diaphragmatic hernia (CDH) are at risk of neurodevelopmental disabilities. This study aimed to investigate the association between lung to thorax transverse area ratio (LTR) and neurodevelopmental outcomes at 3?years of age in fetuses with CDH. METHODS: We performed a retrospective study of infants with prenatally diagnosed isolated left-sided CDH born in Kyushu University Hospital between 2008 and 2016. We examined the association between prenatal ultrasound findings including LTR and development quotient (DQ) at 36 to 42?months of chronological age. RESULTS: We identified 34 live-born fetuses with isolated left-sided CDH, of which 30 survived and four died before discharge. The median LTR in the survivors was higher than in the non-survivors (p?<?0.01). Among the survivors, 26 had available data on LTR (median 0.12, range 0.08-0.18) and overall DQ at 3?years of age (93, 61-112). Their median gestational age and birth weight were 37.6 (range 34.4-39.1) weeks and 2716 (2.256-3494) grams, respectively. There was no significant difference in overall DQ scores between the two groups divided according to the median LTR values (p?=?0.62). LTR values were not associated with overall DQ scores after adjusting for gestational age (p?=?0.39). In addition, no association was observed between LTR values and any subscale DQ scores. CONCLUSION: In fetuses with isolated left-sided CDH, prenatal LTR predicts the mortality but not neurodevelopmental outcomes at 3?years of age.

DOI： 10.1016/j.earlhumdev.2022.105598

Publisher：東京医学社  

DOI： 10.24479/peri.0000000139

CiNii Research

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

Trisomy 18 (T18) is one of the most commonly diagnosed aneuploidies leading to poor survival outcome. However, little is known about the dual risk of T18 and very low birth weight (VLBW, weighing <1500?g at birth). We aimed to investigate the survival and clinical features of VLBW infants with T18. In this observational cohort study, infants with T18 admitted to the neonatal intensive care unit in Kyushu University Hospital from 2000 to 2019 were eligible. Among 30 infants with T18 who were enrolled as study participants, 11 (37%) were born with VLBW. VLBW infants had lower gestational age (34.4 vs. 39.4?weeks, p?<?0.01) and a higher incidence of esophageal atresia (64% vs. 11%, p?<?0.01) than non-VLBW infants. The proportions of patients who underwent any surgery (55% vs. 5%, p?<?0.01) and positive pressure ventilation (82% vs. 32%, p?=?0.02) were higher in VLBW than non-VLBW infants. One-year overall survival rate (45% vs. 26%, p?=?0.32 by log-rank test) did not differ between the two groups. In conclusion, being born at VLBW may not be fatal for infants with T18 undergoing active interventions.

DOI： 10.1002/ajmg.a.62466

Language：English   Publishing type：Research paper (scientific journal)  

ObjectivesTo determine the neurodevelopmental outcomes of very-low-birth-weight infants (VLBWIs, birth weight <1,500 g) after 9 years of follow-up.MethodsThis study prospectively recruited 224 VLBWIs born from 2003 to 2009 in Kyushu University Hospital, Japan. Comorbidities of neurocognitive impairment, epilepsy, and autism spectrum disorder or attention-deficit hyperactivity disorder (ASD/ADHD) were assessed at age 3, 6, and 9 years.ResultsNeurodevelopmental profiles were obtained from 185 (83%), 150 (67%), and 119 (53%) participants at age 3, 6, and 9 years, respectively. At age 9 years, 25 (21%) VLBWIs showed intelligence quotient (IQ) <70, 11 (9%) developed epilepsy, and 14 (12%) had a diagnosis of ASD/ADHD. The prevalence of epilepsy was higher in children with an IQ <70 at age 9 years than in those with an IQ >= 70 (44% vs 0%). In contrast, ASD/ADHD appeared at similar frequencies in children with an IQ <70 (16%) and >= 70 (11%). Perinatal complications and severe brain lesions on MRI were considered common perinatal risks for developmental delay and epilepsy but not for ASD/ADHD. Male sex was identified as a unique risk factor for ASD/ADHD.ConclusionThese data suggest that VLBWIs showed a higher prevalence of developmental delay, epilepsy, and ASD/ADHD at age 9 years than the general population. Distinct mechanisms might be involved in the pathogenic process of ASD/ADHD from those of developmental delay and epilepsy.

DOI： 10.1212/CPJ.0000000000000920

Language：English   Publishing type：Research paper (scientific journal)  

Differences in low birth weight rate depending on maternal socioeconomic characteristics have not yet been demonstrated using the Vital Statistics in Japan; therefore, this study aimed to investigate these differences according to maternal occupations. "Report of Vital Statistics: Occupational and Industrial Aspects" and the Vital Statistics in Japan were used every five years from 1995 to 2015. Nine types of occupations were compared. The low birth weight rate was calculated according to maternal occupations and year. Also, the standardized low birth weight ratio was obtained by dividing the number of low-birth-weight infants for each maternal occupation by an expected number of low birth weight infants. The standardized low birth weight ratio for manual workers was the highest among all occupations from 2000 to 2015, and it was significantly higher than one throughout the years. The ratio for clerical workers was also significantly higher than one from 1995 to 2010. Whereas, the ratio for farmers was significantly lower than one in most of the years. It was suggested that health guidance and prenatal care are particularly needed for manual workers, and a study investigating the differences in prenatal characteristics among maternal occupations is necessary for finding a reason for disparity.

DOI： 10.3390/ijerph18158040

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The association between a slower physical growth and poorer neurodevelopment has been established in infants born preterm or small for gestational age. However, this association is inconsistent in term-born infants, and detailed investigations in infancy, when intervention is most beneficial for improving outcomes, are lacking. We therefore examined this association separately by sex during the first year of life in term-born infants. METHODS: Using data collected until children reached 12 months old in an ongoing prospective cohort of the Japan Environment and Children's Study, we analyzed 44,264 boys and 42,541 girls with singleton term-birth. The exposure variables were conditional variables that disentangle linear growth from weight gain relative to linear growth, calculated from the length and weight at birth and 4, 7 and 10 months old. Neurodevelopmental delay was identified using the Japanese-translated version of Ages & Stages Questionnaires, third edition. RESULTS: A reduced risk of neurodevelopmental delay at 6 months old was observed in children with a higher birth weight (adjusted relative risks [aRRs]: 0.91 and 0.93, 95?% confidence intervals [95?% CIs]: 0.87-0.96 and 0.88-0.98 in boys and girls, respectively) and increased linear growth between 0 and 4 months old (aRRs: 0.85 and 0.87, 95?% CIs: 0.82-0.88 and 0.83-0.91 in boys and girls, respectively). A reduced risk at 12 months was found in children with an increased linear growth between 0 and 4 months (aRRs: 0.92 and 0.90, 95?% CIs: 0.87-0.98 and 0.84-0.96 in boys and girls, respectively), boys with an increased relative weight gain between 0 and 4 months (aRR: 0.90, 95?% CI: 0.84-0.97), and girls with a higher birth weight (aRR: 0.89, 95?% CI: 0.83-0.96). CONCLUSIONS: These results suggest that a slow physical growth by four months old may be a predictor of neurodevelopmental delay during infancy.

DOI： 10.1186/s12887-021-02815-9

Language：English   Publishing type：Research paper (scientific journal)  

Introduction Retinopathy of prematurity (ROP) is a vascular proliferative disorder that occurs in preterm infants. Existing treatments are only indicated in severe ROP cases due to the high invasiveness and the potential risk of irreversible side effects. We previously elucidated that ripasudil, a selective inhibitor of the Rho-associated protein kinase, has the ability to inhibit abnormal retinal neovascularisation in animal models. In addition, ripasudil eye drops (Glanatec ophthalmic solution 0.4%) have been already used for the treatment of glaucoma. Since eye drop therapy is less invasive, early intervention for ROP is possible. The purpose of this phase I/II trial is to evaluate the safety and efficacy of ripasudil eye drops for preterm infants with ROP. Methods and analysis This is a multicentre, open-label, single-arm phase I/II trial. To evaluate the safety and efficacy of ripasudil as much as possible, ripasudil will be administered to all enrolled preterm infants with zone I/II, stage 1, or worse ROP. The safety and efficacy of ripasudil in treated patients will be assessed in comparison to a historical control group. Because this is the first trial of ripasudil in preterm infants, a dose-escalation study (once daily for 1 week, then two times per day for 2 weeks) will be conducted in phase I. After obtaining approval from the independent data and safety monitoring board to continue the trial after the completion of phase I, phase II will be conducted. In phase II, ripasudil eye drops will be administered two times per day for 12 weeks. The primary endpoint in phase II is also safety. Efficacy and pharmacokinetics will be evaluated as secondary endpoints. Ethics and dissemination This study protocol was approved by the institutional review board at each of the participating centres. Data will be presented at international conferences and published in peer-reviewed journals. Trial registration numbers NCT04621136 and jRCT2071200047.

DOI： 10.1136/bmjopen-2020-047003

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1111/dmcn.14403

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1111/ped.14107

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12185-019-02738-3

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1371/journal.pone.0230678

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1038/s41372-019-0494-7

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1016/j.pedneo.2018.11.007

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1016/j.jpeds.2019.05.033

Language：English   Publishing type：Research paper (scientific journal)  

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 × 10⁹/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.

DOI： 10.1016/j.pedneo.2018.09.005

Language：English   Publishing type：Research paper (scientific journal)  

c-Jun-amino-terminal kinase-interacting protein 3 (JIP3), encoded by MAPK8IP3, is an adaptor protein of the kinesin-1 complex and essential for axonal transport in neurons. However, an association between MAPK8IP3 variants and human disease has not been established. We identified 5 individuals from four families with recurrent de novo variants c.1732C>T (p.Arg578Cys) and c.3436C>T (p.Arg1146Cys) in MAPK8IP3. The core phenotype includes spastic diplegia, intellectual disability, cerebral atrophy, and corpus callosum hypoplasia. Zebrafish embryos overexpressing human mutant JIP3 showed axon varicosities of the posterior lateral line nerve, suggesting an adverse effect on the developing axons. Our results suggest that MAPK8IP3 variants cause a neurodevelopmental disease. ANN NEUROL 2019;85:927–933.

DOI： 10.1002/ana.25481

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1038/s41372-018-0262-0

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1002/ppul.24200

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/ped.13945

Language：English   Publishing type：Research paper (scientific journal)  

Background: Thrombotic microangiopathies (TMA) are microvascular occlusive disorders characterized by systemic or intrarenal platelet aggregation, thrombocytopenia, and red cell fragmentation. Post-operative TMA mostly occurs in adult patients with cardiovascular surgery, with the distinct pathophysiology from classical thrombotic thrombocytopenic purpura (TTP) although the exact pathophysiology remains unclear. Case presentation: A one-month-old infant developed TMA after the initial surgery of double outlet right ventricle. ADAM metallopeptidase with thrombospondin type 1 motif 13 (ADAMTS13) activity was sustained (64%) with the undetectable inhibitor. Von Willebrand factor (VWF) multimer analyses showed absent high-molecular weight multimers. Echocardiography disclosed severe mitral regurgitation. The mitral valve repair 32 days after the initial valvuloplasty led to prompt resolution of TMA. These suggested that TMA occurred in association with valvulopathy-triggered turbulent shear flow, mechanical hemolysis and endothelial damage. The consumption of large VWF multimers might account for the vascular high shear stress shown in Heyde syndrome. Conclusion: The youngest case of post-operative TMA underscores the critical coagulopathy after the first surgical intervention for congenital heart disease.

DOI： 10.1016/j.pedneo.2018.02.002

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1542/peds.2017-4286

Language：English   Publishing type：Research paper (scientific journal)  

Right aortic arch with aberrant left subclavian artery (RAA/aLSCA) is a rare aortic arch anomaly. The clinical association of aLSCA stenosis with RAA/aLSCA has not yet been fully elucidated. The aim of this study was to investigate the diagnosis, incidence, management and outcome of aLSCA stenosis in infants with prenatally diagnosed RAA/aLSCA. Ten fetuses who were diagnosed as having RAA/aLSCA in Kyushu University Hospital between January 2011 and December 2014 were enrolled. The maternal and child medical records were reviewed to investigate sex, gestational age at the fetal diagnosis, gestational age and body weight at birth, the findings of computed tomography (CT), Doppler ultrasonography of the vertebral artery and angiography, and the complications and outcomes of aLSCA stenosis. In 8 of 10 patients, aLSCA stenosis was identified on the first CT examination after birth. No patients had dysphagia or respiratory distress. The stenosis spontaneously resolved in 3 patients. In 4 of the 5 remaining patients, aLSCA stenosis progressed, including one case in which complete occlusion occurred—the case was associated with retrograde flow from the left vertebral artery supplying the distal LSCA. Balloon angioplasty was successfully used to treat stenosis in two cases. The subclavian steal phenomenon and developmental problems were not observed in any patients. aLSCA stenosis was identified in 80% of patients with RAA/aLSCA after birth. The early detection and elective treatment of stenotic lesions may be required to prevent complete occlusion during the development of the cardiovascular and cerebrovascular systems.

DOI： 10.1007/s00380-017-1056-6

Language：English   Publishing type：Research paper (scientific journal)  

Children born small for gestational age (SGA) are at a higher risk for metabolic disorders later in life. In this study, we aimed to characterize young SGA children without catch-up growth and evaluate the effects of GH treatment on endocrinological, metabolic, and immunological parameters. Study design is a one-year single hospital-based study included prospective observation of SGA patients during 12 months of GH treatment. Clinical and laboratory profiles of SGA children at baseline were compared with controls born appropriate size for age. Twenty-six SGA children (median age, 3.4 years) and 26 control children (median age, 3.8 years) were enrolled. Anthropometric, hematologic, biochemical, immunological, and endocrinological parameters were assessed at baseline and 1, 3, 6, 9, and 12 months after the start of GH treatment. As a result, median height SD score (SDS) of SGA children increased by +0.42 with 12-month GH treatment. Body mass index SDS was lower in SGA children than in controls. Serum apolipoprotein A1 increased, whereas apolipoprotein B decreased during GH treatment. Serum leptin and resistin levels, which were lower in SGA children than in controls at baseline, did not change remarkably with GH treatment. Monocyte counts, which were lower in SGA patients at baseline, increased after GH treatment. Neutrophil counts significantly increased after GH treatment. Natural killer cell ratios, which were higher in SGA patients, decreased after GH treatment. In conclusion, there was no evidence suggesting metabolic abnormalities in SGA children. Serum apolipoprotein changes might predict the beneficial role of GH treatment in lowering cardiometabolic risk.

DOI： 10.1507/endocrj.EJ17-0485

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1016/j.jpeds.2017.05.017

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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.

DOI： 10.1159/000474930

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Beckwith–Wiedemann syndrome (BWS) is a congenital overgrowth syndrome that is occasionally associated with hyperinsulinemic hypoglycemia (HH) in the neonatal period. Sotos syndrome (SS) and Kabuki syndrome (KS) are other malformation syndromes that may be complicated with HH, however, the detailed clinical characteristics of HH accompanied with these syndromes remain unclear. We herein conducted a nationwide questionnaire survey in Japan. We sent a primary questionnaire concerning the clinical experience for these syndromes to 347 perinatal care institutions. As a result, 222 departments or hospitals returned the questionnaires and the total numbers of BWS, SS, and KS patients were 113, 88, and 51, respectively. We sent a secondary questionnaire to 31 institutions where patients with these syndromes presented with HH during infancy. The secondary questionnaires were returned from the institutions and the numbers of patients were 16 for BWS, 9 for SS, and 3 for KS, respectively. Then, we compared the clinical characteristics of infants suffering from transient HH with and without these dysmorphic syndromes. As a result, BWS, SS, and KS patients showed significantly larger body size, lower Apgar scores, higher insulin levels at HH, and shorter durations of HH than non-dysmorphic infants with transient HH. We propose that a careful observation for the signs of HH, even if not specific to the syndromes, is important for the diagnosis of patients with BWS, SS, and KS in the postnatal period.

DOI： 10.1002/ajmg.a.38011

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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.

DOI： 10.1159/000447991

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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 SDR_BW and SDR_GA, 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 SDR_GA and SDR_BW 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.

DOI： 10.1371/journal.pone.0161439

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Purpose: To document long-term morphological changes of Chiari type II malformation (CM-II) following closure of spina bifida manifesta (SBM). Methods: We retrospectively evaluated postnatal magnetic resonance images of the CM-II and posterior fossa (PF) in 28 consecutive cases. We measured changes in vertebral level and length of the cerebellar peg (CP), cerebrospinal fluid (CSF) spaces anterior and posterior to the cerebrospinal junction, PF area, and the anteroposterior diameters of the foramen magnum (FM) and C1 vertebra. We examined the morphological differences between the cases with and without ventriculoperitoneal (VP) shunting and derived predicted means by nonlinear mixed-effect modeling. Results: At birth, there were significant differences in CP length, PF area, and FM and C1 diameters between those who underwent VP shunting and those who did not. In cases with a CP below C1, VP shunting was required in every case but one. In those with visible CSF space at birth, VP shunts were not required. In 17 of 18 cases with a CP below C1, the vertebral level ascended by mean two vertebral levels (range 0–5 levels) within 4–6 months of delivery. In the remaining case, slowly progressive hydrocephalus and delayed CP descent required VP shunting at 8 months. Predicted mean CP length and FM and C1 diameters were greater in those who underwent VP shunting, but there was no difference in predicted mean PF area. Conclusion: The morphology of CM-II and the presence of hydrocephalus influence each other in children who have undergone postnatal SBM repair.

DOI： 10.1007/s00381-016-3041-2

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.4049/jimmunol.1500295

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Language：English   Publishing type：Research paper (scientific journal)  

Severe protein C-deficiency is a rare heritable thrombophilia of the newborn. Infants with biallelic PROC mutations present purpura fulminans and intracranial thromboembolism, while the prenatal onset of mutated heterozygotes remains unclear. We herewith present the first case of fetal ventriculomegaly and neonatal stroke associated with heterozygous PROC mutation. The infant was born to a healthy mother at 38 gestational weeks. The fetal growth had been normal, but the routine ultrasound screening had indicated mild hydrocephalus at 28. weeks of gestation. He developed convulsions two days after birth. Computed tomography of the brain revealed multiple hemorrhagic infarctions and ventriculomegaly. Dissociated levels of the plasma activity between protein C (21%) and protein S (42%) reached to determine the heterozygote of PROC c.574_576delAAG, a common thrombophilic predisposition in Asian ancestries. PC-mutant heterozygotes may have a limited high risk of cerebral thromboembolism during the perinatal course.

DOI： 10.1016/j.braindev.2015.07.004

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X-linked agammaglobulinemia (XLA) is one of the most common humoral immunodeficiencies, which is caused by mutations in Bruton's tyrosine kinase (BTK) gene. To examine the possibility of using gene therapy for XLA, we constructed a helper-dependent adenovirus/adeno-associated virus BTK targeting vector (HD-Ad.AAV BTK vector) composed of a genomic sequence containing BTK exons 6-19 and a green fluorescence protein-hygromycin cassette driven by a cytomegalovirus promoter. We first used NALM-6, a human male pre-B acute lymphoblastic leukemia cell line, as a recipient to measure the efficiency of gene targeting by homologous recombination. We identified 10 clones with the homologous recombination of the BTK gene among 107 hygromycin-resistant stable clones isolated from two independent experiments. We next used cord blood CD34⁺ cells as the recipient cells for the gene targeting. We isolated colonies grown in medium containing cytokines and hygromycin. We found that the targeting of the BTK gene occurred in four of the 755 hygromycin-resistant colonies. Importantly, the gene targeting was also observed in CD19⁺ lymphoid progenitor cells that were differentiated from the homologous recombinant CD34⁺ cells during growth in selection media. Our study shows the potential for the BTK gene therapy using the HD-Ad.AAV BTK vector via homologous recombination in hematopoietic stem cells.

DOI： 10.1038/gt.2015.91

Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/pr.2015.180

Language：English   Publishing type：Research paper (scientific journal)  

SUMMARY: In developed countries,the infection related-mortality rates in children hospitalized in tertiary medical facilities,where many patients with underlying disease are also hospitalized,are uncertain. We investigated the characteristics of infectious diseases-related fatal cases in the pediatric ward of a Japanese tertiary medical facility. A total of 188 patients who died in the pediatric ward or intensive care unit at Kyushu University Hospital from 2002 to 2011 were enrolled. The patient characteristics were investigated based on their medical records. A total of 35 patients died of infections,31 of whom had underlying diseases. Most patients died of sepsis or pneumonia (n ＝ 27). All 9 patients who died within 7 days of birth were premature. Nine of the 13 patients with malignancy or hematological disorders died of hematopoietic stem cell transplantation (HSCT)-associated infections. The ratio of infectious disease-related fatal cases to the total cases decreased in the latter half of the study period. In particular,the proportion of preterm infants who died of infections was significantly lower in the latter 5 years (p ＝ 0.02). Many of the infectious disease-related fatal cases were in premature infants and HSCT or post-HSCT patients. However,the mortality due to infectious diseases decreased in these patient groups.

DOI： 10.7883/yoken.JJID.2015.591

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Objective To compare rates of a composite outcome of mortality or major morbidity in very-preterm/very low birth weight infants between 8 members of the International Network for Evaluating Outcomes. Study design We included 58 004 infants born weighing <1500 g at 24⁰–31⁶ weeks' gestation from databases in Australia/New Zealand, Canada, Israel, Japan, Spain, Sweden, Switzerland, and the United Kingdom. We compared a composite outcome (mortality or any of grade ≥3 peri-intraventricular hemorrhage, periventricular echodensity/echolucency, bronchopulmonary dysplasia, or treated retinopathy of prematurity) between each country and all others by using standardized ratios and pairwise using logistic regression analyses. Results Despite differences in population coverage, included neonates were similar at baseline. Composite outcome rates varied from 26% to 42%. The overall mortality rate before discharge was 10% (range: 5% [Japan]-17% [Spain]). The standardized ratio (99% CIs) estimates for the composite outcome were significantly greater for Spain 1.09 (1.04-1.14) and the United Kingdom 1.16 (1.11-1.21), lower for Australia/New Zealand 0.93 (0.89-0.97), Japan 0.89 (0.86-0.93), Sweden 0.81 (0.73-0.90), and Switzerland 0.77 (0.69-0.87), and nonsignificant for Canada 1.04 (0.99-1.09) and Israel 1.00 (0.93-1.07). The adjusted odds of the composite outcome varied significantly in pairwise comparisons. Conclusions We identified marked variations in neonatal outcomes between countries. Further collaboration and exploration is needed to reduce variations in population coverage, data collection, and case definitions. The goal would be to identify care practices and health care organizational factors, which has the potential to improve neonatal outcomes.

DOI： 10.1016/j.jpeds.2016.04.083

Language：English   Publishing type：Research paper (scientific journal)  

Purpose: To compare the utility and limitations of prenatal magnetic resonance (MR) imaging using half-Fourier acquisition single-shot turbo spin-echo (HASTE) with postnatal heavily T2-weighted imaging (hT2WI) for the evaluation of central nervous system abnormalities associated with myelomeningocele (MMC). Methods: Sixteen patients with MMC who had undergone pre- and postnatal MR imaging were included in this study. MR imaging, including HASTE, was undertaken in the 3rd trimester, and hT2WI was performed immediately after delivery. The precision with which each could distinguish MMC, hindbrain herniation and ventriculomegaly was compared retrospectively. Results: The skin defects and MMC sacs were clearly visible on prenatal HASTE images, although it was difficult to identify precisely the level of MMC compared with postnatal hT2WI, in which the detailed anatomical relationships of the spinal cord, neural placode and ventral nerve roots were evident in every case. Hindbrain herniation could be visualized on prenatal HASTE images, although its severity was difficult to evaluate because of the small size of the structures and neck flexion; again, the resolution was superior on postnatal hT2WI. For hydrocephalus, there were no significant differences in the diagnostic precision and ability to grade the severity between pre- and postnatal imaging. Conclusion: Prenatal HASTE imaging permits the diagnosis and understanding of the gross anatomy of MMC and associated hindbrain herniation and ventriculomegaly, but postnatal hT2WI is superior for evaluating detailed anatomy.

DOI： 10.1159/000381746

Language：English   Publishing type：Research paper (scientific journal)  

Large placental chorioangioma is a rare but serious complication of pregnancy. To our knowledge, this case is the first reported diagnosis of consumption coagulopathy in a fetus using fetal blood sampling (FBS) during pregnancy complicated by placental chorioangioma. A 25-year-old woman, primigravida, was referred to our hospital at 29 weeks of gestation for placental chorioangioma. At 34+1 gestation, polyhydramnios and hyperdynamic circulation were observed in the fetus. FBS demonstrated microangiopathic hemolytic anemia and the presence of consumption coagulopathy. Cesarean section was performed at 34+4 gestation because fetal maturation was expected. A female infant weighing 2158 g was born, with Apgar scores of 6 and 8 at 1 and 5 min, respectively. Neonatal blood sampling results were similar to those of FBS. The infant was treated for hyperdynamic cardiac function, hemolytic anemia, and consumption coagulopathy on mechanical ventilation in the neonatal intensive care unit and recovered fully. When fetal anemia is suspected in a case of large placental chorioangioma, the possibility of developing consumption coagulopathy during the fetal period should be considered.

Language：English   Publishing type：Research paper (scientific journal)  

A 36-year-old primigravida woman with a normal pregnancy course presented with fetal unilateral focal ventriculomegaly on routine ultrasonography performed at 28 weeks of gestation. Periventricular venous infarction (PVI) in utero was diagnosed with fetal magnetic resonance imaging (MRI). The neonate was born at term uneventfully and in utero PVI was confirmed by MRI after birth. The neonate was diagnosed with hereditary protein C deficiency after coagulation laboratory studies. At 10 months of age, the infant presented with mild retardation of motor development. This is the first report about prenatally diagnosed PVI in utero by fetal MRI. When focal, unilateral enlargement of the ventricles is detected in utero by prenatal ultrasonography, it is important to consider PVI and perform confirmatory fetal MRI.

Language：English   Publishing type：Research paper (scientific journal)  

Introduction This study aimed to assess whether weight growth velocity (WGV) predicts neurodevelopmental outcomes in extremely low birth weight infants (ELBWIs). Methods Subjects were infants who weighed 501-1000 g at birth and were included in the cohort of the Neonatal Research Network of Japan (2003-2007). Patel's exponential model (EM) method was used to calculate WGV between birth and discharge. Assessment of predictions of death or neurodevelopmental impairment (NDI) was performed at 3 years of age based on the WGV score, which was categorized by per one increase in WGV. Multivariate logistic regression analysis was used to calculate adjusted odds ratios and their 95% confidence intervals (95%CI). Results In the 2961 ELBWIs assessed, the median WGV was 10.5 g/kg/day (interquartile, 9.4- 11.9). With the categorical approach, the adjusted odds ratios for death or NDI with WGV scores of 6 and 7 were 2.41 (95%CI, 1.60-3.62) and 1.81 (95%CI, 1.18-2.75), respectively, relative to the reference WGV score of 10. WGV scores ≥8 did not predict death or NDI. Conclusions WGV scores <8 were significant predictors suggesting that values of WGV during hospitalization in a NICU are associated with neurodevelopmental outcomes. Further investigations is necessary to determine whether additional nutritional support may improve low WGV in ELBWIs.

DOI： 10.1371/journal.pone.0139014

Language：English   Publishing type：Research paper (scientific journal)  

Background: Increasing attention has been given to neuro-developmental problems of very low birth weight infants (VLBWIs) at school age. However, it remains unknown whether their neuro-cognitive function and psychiatric symptoms are mutually associated. Aim: The aim of this study was to investigate the characteristics of neuro-cognitive functions in VLBWIs and their relationship with psychiatric symptoms. Methods: A total of 160 VLBWIs who were born at our institute between 2001 and 2005 were recruited consecutively and followed up until nine years of age. The developmental profiles were obtained from 77 children (45 males and 32 females) at six to nine years of age using the ADHD Rating Scale-Fourth edition (ADHD-RS), Autism Screening Questionnaire-Japanese version (ASQ-J) and the Wechsler Intelligence Scale for Children-Third edition (WISC-III). Results: The full-scale intelligence quotient did not significantly differ between the male and female VLBWIs (median: 91 vs. 99, p = 0.17). The males had higher total scores (median: 13 vs. 4, p. <. 0.01) and higher scores on the subscales of Inattention (8 vs. 2, p < 0.01) and Hyperactivity-Impulsivity (5 vs. 1, p < 0.01) of the ADHD-RS compared with the females. The Verbal Comprehension Index (VCI) of the WISC-III was inversely correlated with the total scores of the ASQ-J for all VLBWIs (n = 77, rc: - 0.32, 95% CI: - 0.19 to - 0.01, p = 0.04). We also observed that the Freedom from Distractibility Index (FDI) of the WISC-III was significantly correlated with the Inattentive scores of the ADHD-RS (n = 45, rc: - 0.18, 95% CI: - 0.35 to - 0.02, p = 0.03) in male, but not female VLBWIs. Conclusions: We herein report that the VCI and FDI of the WISC-III were correlated with the autism spectrum disorder and attention deficit hyperactivity disorder symptoms, respectively, in male VLBWIs.

DOI： 10.1016/j.earlhumdev.2015.09.005

Language：English   Publishing type：Research paper (scientific journal)  

Background: Correlations among Chiari type II malformation (CMII) morphological findings, the proportion of fetal heart rate patterns corresponding to the quiet phase (QP), and neurological outcomes have yet to be investigated. Findings: The correlations among the morphological findings (i.e., the degree of ventriculomegaly, myelomeningocele levels, and degree of cerebellar herniation), proportion of time spent in QP, and developmental quotients (DQs) were analyzed in 22 children. The proportion of time spent in QP was compared between children with poor neurological outcomes (n = 9) and those with good outcomes (n = 13). Pearson's correlations and the Mann-Whitney U-test were used to assess for statistical significance; P < 0.05 was considered statistically significant. No significant differences were observed between the DQs and morphological findings, but the DQs and the proportion of time spent in QP were significantly correlated (r = 0.287, P = 0.01). The proportion of time spent in QP was significantly different between children with poor outcomes and those with good outcomes (median, 11% [range, 0-32%] vs. 28% [range, 2-55%]; P = 0.006). Conclusions: The proportion of fetal heart rate patterns corresponding to the QP might be a useful predictor of neurological outcomes in 2-year-old children with CMII.

DOI： 10.1186/s13104-015-1014-2

Language：English  

DOI： 10.1016/j.ijantimicag.2014.07.005

Language：Japanese  

DOI： 10.1515/jpm-2013-0192

Language：English   Publishing type：Research paper (scientific journal)  

Introduction: Whether parenteral nutrition benefits growth of very low birth weight (VLBW) preterm infants in the setting of rapid enteral feeding advancement is unclear. Our aim was to examine this issue using data from Japan, where enteral feeding typically advances at a rapid rate. Methods: We studied 4005 hospitalized VLBW, very preterm (23-32 weeks' gestation) infants who reached full enteral feeding (100 ml/kg/day) by day 14, from 75 institutions in the Neonatal Research Network Japan (2003-2007). Main outcomes were weight gain, head growth, and extra-uterine growth restriction (EUGR, measurement <10^th percentile for postmenstrual age) at discharge. Results: 40% of infants received parenteral nutrition. Adjusting for maternal, infant, and institutional characteristics, infants who received parenteral nutrition had greater weight gain [0.09 standard deviation (SD), 95% CI: 0.02, 0.16] and head growth (0.16 SD, 95% CI: 0.05, 0.28); lower odds of EUGR by head circumference (OR 0.66, 95% CI: 0.49, 0.88). No statistically significant difference was seen in the proportion of infants with EUGR at discharge. SGA infants and infants who took more than a week until full feeding had larger estimates. Discussion: Even in infants who are able to establish enteral nutrition within 2 weeks, deprivation of parenteral nutrition in the first weeks of life could lead to under nutrition, but infants who reached full feeding within one week benefit least. It is important to predict which infants are likely or not likely to advance on enteral feedings within a week and balance enteral and parenteral nutrition for these infants.

DOI： 10.1371/journal.pone.0088392

Language：English  

DOI： 10.1016/j.earlhumdev.2012.12.011

Language：English  

DOI： 10.1111/hae.12097

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Inherited or acquired protein C (PC) deficiency leads to thromboembolic events. Plasma PC activity in infancy is physiologically lower than in adults. We describe a case of neonatal asphyxia and acute renal failure associated with isolated PC deficiency. A full-term male infant was born to a healthy mother by caesarean section because of fetal distress. The small-for-gestational age infant showed 2 and 7 of Apgar scores at 1 and 5 minutes, respectively. Hypercoagulability required repeated infusions of fresh frozen plasma. Coagulation study revealed PC activity, 6%, protein S activity, 61%, and high D-dimer levels, along with normal factor VII activity and absent vitamin K deficiency. Anticoagulant and activated PC therapy improved coagulopathy and nephropathy. Imaging analyses indicated no visceral infarctions. Renal function and PC activity have been slowly normalized until 6 months of age. He had no PROC mutation or PC-deficient parents. Selective PC deficiency may occur as an acquired cause of hypercoagulable crisis in the stressed newborn.

DOI： 10.1038/jp.2012.55

Language：English  

DOI： 10.1002/ajmg.a.35657

Language：English  

DOI： 10.1016/j.braindev.2012.01.007

Language：English   Publishing type：Research paper (scientific journal)  

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

DOI： 10.1542/peds.2012-0336

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1111/j.1442-200X.2011.03510.x

Language：English  

DOI： 10.2350/11-05-1034-CR.1

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Despite advances in diagnosis and management, non-immune hydrops fetalis (NIHF) has a high mortality rate. Perinatal survival depends on the underlying disorder and the gestational age at diagnosis. As prognostic information is limited, this study acquired data regarding the neurological development of perinatal survivors.We performed a retrospective chart review of 214 cases in which NIHF was diagnosed antenatally. We recorded maternal demographic characteristics and interventions and their effectiveness, as well as the short-term outcome (survival) and long-term outcome including developmental quotients. Among the affected fetuses, 91 (42.5%) survived the perinatal period. Fetuses with chylothorax, chyloascites, or meconium peritonitis, and those in whom therapy was effective, had high survival rates irrespective of the type of intrauterine intervention. The subsequent intact survival rate was 28/56 (50.0%), with intact defined as ratio of the number of infants with normal development to the number of all infants followed. In contrast to the perinatal survival rate, the intact survival rate decreased as gestational age at diagnosis advanced. These findings suggest that the long-term intact survival rate depends on the underlying cause of NIHF. Additionally, while survival was improved with intensive perinatal care during the perinatal period, aggressive perinatal intervention was not a prognostic factor for neurological outcome.

DOI： 10.1016/j.earlhumdev.2011.04.015

Language：English   Publishing type：Research paper (scientific journal)  

Background: Cytokines and chemokines during perinatal period may involve the neurological development of newborns. Aims: We investigated the association of circulating chemokines during neonatal period with the outcome of premature infants. Study design: The prospective study enrolled 29 very low birth weight (< 1500. g) and appropriate-for-date infants having no underlying diseases. Serum concentrations of chemokines (CXCL8, CXCL9, CXCL10 and CCL2) and cytokines at birth and 4. weeks postnatal age were measured. Developmental quotients (DQ) at 3. years of age by the Kyoto Scale of Psychological Development were studied for the association with chemokine/cytokine levels and clinical variables including chorioamnionitis, Apgar scores, ventilator treatment and supplemental oxygen. Results: CXCL8 levels at birth and days of ventilator treatment were negatively, CCL2 levels at 4. weeks after birth and 5-minute Apgar scores were positively correlated with the DQ of postural-motor [P-M] area at 3. years of age, respectively (CXCL8: correlation coefficient [CC] = -0.394, p = 0.037, ventilation: CC = -0.518, p = 0.006, CCL2: CC = 0.528, p = 0.013, and Apgar score: CC = 0.521, p = 0.005). Infants showing both ≥ 50. pg/ml of CXCL8 at birth and < 250. pg/ml of CCL2 4. weeks after birth had lower DQ of P-M than those who did not (p < 0.001). Multivariate analyses indicated that CCL2 levels at 4. weeks of age were higher in infants who attained normal DQ of P-M (≤ 85) (adjusted mean, 338.4 [95% confidence interval, 225.5-507.8]) than in those who did not (< 85) (159.0, [108.2-233.7]) (p = 0.019). Conclusion: Circulating patterns of CXCL8 (IL-8) and CCL2 (MCP-1) during the neonatal period might affect the neurological development of preterm infants.

DOI： 10.1016/j.earlhumdev.2011.03.006

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Objective: The aim of this study was to assess the genetic effects of the vascular endothelial growth factor (VEGF) pathway on retinopathy of prematurity (ROP). Study Design: A prospective study from a tertiary center that enrolled 204 Japanese infants (<35 weeks of gestational age (GA)) having no anomalies. ROP developed in 127, but not in 77 infants. The relative severity was defined as non-severe, moderate and severe ROP for GA, based on the staging criteria. VEGF (g.-634G>C, g.+13553C>T) and VEGF-receptor (KDR g.+4422(AC)11 to 14, Flt-1 c.+6724(TG)13 to 23) gene polymorphisms and clinical variables were assessed by uni/multivariate analyses. Result: The frequency of polymorphisms did not differ between ROP and non-ROP patients. The TT genotype of g.+13553 showed a higher odds ratio for non-severe ROP than CC genotype (P=0.006). Multivariate analyses indicated that low birth weight, blood transfusion and respiratory distress syndrome, but not polymorphisms, were the risk factors of advanced ROP (≥stage 3). Conclusion: A genotype of the VEGF pathway weakly affects the severity of ROP compared with other clinical factors.

DOI： 10.1038/jp.2010.111

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Background: Amnioreduction remains a treatment option for pregnancies with twin-to-twin transfusion syndrome (TTTS) not meeting criteria for laser surgery or those in which it is not feasible. Amnioreduction is a relatively simple treatment which does not require sophisticated technical equipment. Previous reports of conservative management have indicated that major neurodevelopmental impairment occurs in 14.3-26% of survivors. The purpose of this study was to investigate long-term neurodevelopmental outcome in conservatively treated TTTS.Methods: During the nine-year study period from January 1996 to December 2004, all pregnancies with TTTS who were admitted to our center were investigated. TTTS was diagnosed by using standard prenatal ultrasound criteria, and staged according to the criteria of Quintero et al. We reviewed gestational age at diagnosis, gestational age at delivery, the stage of TTTS at diagnosis, and diagnosis to delivery interval. Neonatal cranial ultrasound findings were reviewed and the neurodevelopmental outcomes were evaluated.Results: Twenty-one pregnancies with TTTS were included. Thirteen pregnancies (62%) were treated with serial amnioreduction. The mean gestational age at delivery was 28 weeks (22 - 34 weeks). The perinatal mortality rate was 42.9%. Twenty survivors were followed up until at least 3 years of age. The mean age at follow-up was 6.3 years (3 - 12 years). Six children (30%) had neurodevelopmental impairment. Four children (20%) had major neurodevelopmental impairment and two children (10%) had minor neurodevelopmental impairment. Children with neurodevelopmental impairment were delivered before 29 weeks of gestation.Conclusions: Our study showed a high rate of perinatal mortality and a high rate of major neurodevelopmental impairment in conservatively treated TTTS. The long-term outcomes for the survivors with TTTS were good when survivors were delivered after 29 weeks of gestation.

DOI： 10.1186/1471-2393-11-32

Language：Japanese   Publishing type：Research paper (scientific journal)  

Iron homeostasis and hepcidin in the neonates

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1038/jp.2010.143

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Background: Premature newborns are vulnerable to iron imbalance, although the iron homeostasis during the perinatal period remains unclear. To clarify the iron metabolism of premature infants, we measured serum prohepcidin concentrations of preterm infants, and analyzed the association with iron parameters.Methods: Seventy-one (61 preterm and 10 term) infants were enrolled for the study, that had no underlying diseases including asphyxia, bleedings, infection, and anomalies. Serum concentrations of prohepcidin at birth and 1 month after birth were determined by enzyme-linked immunosorbent assay.Results: Prohepcidin levels at birth but not 1 month postnatal age positively correlated with gestational age (correlation coefficient [CC]:0.334, P-=-0.005) and birth weight (CC: 0.367, P-=-0.002). The levels at birth of preterm infants (median: 29.93-ng/ml, range: 4.0-110.6) were lower than those of full-term infants, and increased thereafter. On the other hand, the levels in small-for-gestational age infants were not associated with gestational age or birth weight. Prohepcidin levels at birth correlated positively with red cell counts (CC-=-0.487, P-=-0.025), unsaturated iron binding capacity (CC-=-0.755, P-=-0.001), total protein (CC-=-0.624, P-=-0.005), and serum albumin levels (CC-=-0.500, P-=-0.025), and negatively with serum iron levels (CC-=--0.688, P-=-0.003), but not ferritin levels. Multivariate analyses indicated that prohepcidin levels at birth were lower in infants with pregnancy-induced hypertension (P-=-0.03) or premature rupture of membrane (P-=-0.01).Conclusions: Prohepcidin production was physiologically low at birth of preterm infants according to the gestational age, and the levels might be susceptible to the in utero stress. The postnatal increase might reflect the maturation and/or adaptation of iron homeostasis.

DOI： 10.1002/pbc.22773

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1007/s00431-009-1126-6

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Objectives: To assess risk factors for the growth and development of small-for-gestational age (SGA) infants whose birth weight was less than the 10^th percentile. Patients and methods: SGA infants who were admitted to the neonatal intensive care unit from 1995 to 1998 were enrolled in the study. Fifty-six SGA infants, having no chromosomal abnormalities, inherited diseases, TORCH infections, major anomaly and/or multiple birth, were divided into 34 asymmetrical and 22 symmetrical SGA infants by ≥ or <10 ^th percentile head circumference (HC) at birth. The physical growth including HC, and the developmental quotient (DQ) and intelligent quotient (IQ) scores were evaluated up to 6 years of age. Results: Symmetrical SGA infants had lower levels of weight, height and HC, but not of total DQ at 3 years or IQ scores at 6 years of age than asymmetrical SGA infants. The 21 SGA infants who had a HC less than the 10^th percentile at 1 year of age (non-catch-up group) showed lower total DQ (mean 96 vs. 105) and IQ (82 vs. 102) scores than 34 SGA infants who had not (catch-up group). Conclusions: These results suggested that psychomotor development of SGA infants depended on the HC at 1 year of age rather than that at birth.

DOI： 10.1515/JPM.2008.042

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Objective: To search a novel function of erythroid progenitor cells circulating as the major nucleated cell population in umbilical cord blood (CB) cells. Materials and Methods: Human CB-derived CD36⁺ erythroid progenitors were subjected to cDNA microarray. Gene expression and biological property of CB-erythroid progenitors and adult peripheral blood (PB)-erythroid progenitors were compared by using real-time polymerase chain reaction (PCR) and serum-free culture system with erythropoietin (EPO). Results: The microarray revealed 124-fold higher levels of insulin-like growth factor-II (IGF-II) gene expression in CB-CD36⁺ erythroid progenitors than in stimulated lymphocytes of adult PB. Real-time PCR verified that IGF-II mRNA levels were highest in CB-CD36⁺ erythroid progenitors compared to other CB- or adult PB-fractionated cells. When CB-CD36⁺ erythroid progenitors were cultured with EPO in serum-free medium, anti-IGF-II-antibody (Ab) reduced the number of erythroid colonies. When CB- and adult PB-derived erythroid colony-forming cells (ECFCs) were cultured with interleukin-3, stem cell factor, and EPO, mRNA levels per cells of IGF-II peaked on day 12, but those of type 1 and type 2 receptors did not increase with ECFCs maturation. The maturation rate by IGF-II was higher in CB-ECFCs than in adult PB-ECFCs. The majority of CB-ECFCs expressed IGF-II protein. Anti-IGF-II-Ab, but not anti-IGF-I-Ab, reduced the number of CB-ECFCs in liquid culture with EPO. Anti-IGF-II-Ab accelerated apoptosis of ECFCs, assessed by dimethylthiazole tetrazolium bromide, bromodeoxyuridine, and flow cytometric analyses. ECFCs failed to attain full maturity in the presence of anti-IGF-II-Ab. Conclusions: These results suggest that IGF-II is produced by erythroid progenitors themselves, and has a crucial role in fetal erythropoiesis by modulating apoptosis and maturation in an autocrine fashion.

DOI： 10.1016/j.exphem.2007.12.009

Language：English   Publishing type：Research paper (scientific journal)  

Objective: To develop a new scoring system for computed tomography (CT) of the chest for assessing the clinical status of patients with bronchopulmonary dysplasia (BPD) in comparison with a modified Edwards roentgenographic scoring system. Study design: Preterm infants diagnosed with BPD (n = 42) were assessed prospectively by chest CT scan at the time of discharge. Three radiologists classified the CT findings into 1 of 3 categories-hyperexpansion, emphysema, or fibrous/interstitial abnormalities-and developed a new scoring system. We assessed interobserver reproducibility and investigated whether this classification system reflected the severity of BPD in these patients. Results: The CT scores had acceptable reproducibility (coefficient of correlation [cc] = 0.721 to 0.839). The subgroup with a more severe form of BPD had a higher CT score. The CT score correlated with the clinical score at 36 weeks of postmenstrual age (cc = 0.367) and the duration of oxygen therapy (cc = 0.537). Patients who were discharged home on oxygen had higher CT scores than patients who were not. Conclusions: The new chest CT scoring system may have higher objectivity and accuracy in terms of predischarge assessment of clinical status as well as prediction of the prognosis of patients with BPD.

DOI： 10.1016/j.jpeds.2007.05.043

Language：English   Publishing type：Research paper (scientific journal)  

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DOI： 10.1055/s-2005-918892

Event date： 2016.11 - 2016.12

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：大阪市   Country：Japan  

Event date： 2016.2

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：大阪市   Country：Japan  

Event date： 2014.8

Language：English   Presentation type：Oral presentation (general)  

Venue：Fukuoka   Country：Japan  

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：Vancouver   Country：Canada  

Event date： 2020.2

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2020.2

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：神戸市   Country：Japan  

Event date： 2019.2

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：福岡市   Country：Japan  

Event date： 2019.2

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：鹿児島市   Country：Japan  

Event date： 2019.2

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Venue：福岡市   Country：Japan  

Event date： 2018.3

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Venue：東京都   Country：Japan  

Event date： 2018.2

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Venue：仙台市   Country：Japan  

Event date： 2018.2

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：東京都   Country：Japan  

Event date： 2018.2

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Venue：東京都   Country：Japan  

Event date： 2018.2

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2018.2

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡市   Country：Japan  

Event date： 2018.2

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Country：Japan  

Event date： 2017.2

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

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Event date： 2017.2

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Event date： 2016.2

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：大町市   Country：Japan  

Event date： 2016.2

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Venue：大阪市   Country：Japan  

Event date： 2014.5

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：Vancouver   Country：Canada  

Event date： 2013.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：横浜市   Country：Japan  

【背景と目的】本邦の周産期医療は世界トップレベルの救命率を誇るが、体が小さく未熟な新生児の特殊性ゆえに臨床研究が進みにくい。そこで、臨床研究や診療の評価の基礎となる、早産児・低出生体重児の入院時の血液検査基準値を設定する。
【方法】既存のネットワークをもとに多施設共同臨床研究を行うインフラを整備し、10の関連施設から年間1000例程度のハイリスク新生児をデータベースに登録した。対象は関連施設に入院した全ての新生児であり、死亡退院と先天異常例は除外した。測定項目は標準化サーベイランス27項目のうち入院時ルーティン項目を選択した。入院時（日齢0‐1）の血液検査所見を性別、在胎週数、出生体重別に層別化して、ノンパラメトリック法にて基準値と基準範囲（95%信頼区間）を設定した。本研究は当院（22-131）および関連施設のIRBの承認を受けており、UMIN-CTR（000083）臨床試験に登録している。
【結果と今後の方針】ほとんどの項目で性差はなく、在胎週数や出生体重に比例して増加する項目（総蛋白、アルブミン、クレアチニン等）と変化しない項目（尿素窒素、カルシウム、カリウム等）を認めた。今後は米国臨床検査標準委員会のガイドライン（CLCI Document C28-A3）に従い、充分な症例数の集積を進めて、信頼性の高い基準範囲を求める予定である。

Event date： 2013.5

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：Kuching, Sarawak   Country：Malaysia  

Objective: To establish the best practice for perinatal management, clinical outcomes of extremely preterm infants born at the limit of viability were studied in a tertiary center.
Study design: A retrospective study enrolled 51 infants who had no congenital disorders, and were born at 22-24 weeks of gestational age (GA) in 2000-2009 in our single institution. Clinical variables and interventions were studied with regard to one-year survival and developmental quotient (DQ) at 3 years of age.
Results: The one-year survival rate of 24 preterm infants born in 2005-2009 (79%) was higher than that of 27 those in 2000-2004 (52%) (p=0.04). The infants born at post-2005 underwent less and more frequently tocolysis (54% vs. 94%, p<0.01) and antenatal steroid therapy (32% vs. 6%, p=0.01) than those born at pre-2005, respectively. The post-2005 survivors (n=19) received more frequently indomethacin therapy (89% vs. 50%, p=0.03) and early parenteral nutrition (95% vs. 36%, p<0.01) than the pre-2005 survivors (n=14). There were no difference in the proportion of infants who attained DQ of >50 at 3-year of age between pre-2005 (n=9) and post-2005 groups (n=10) (30% vs. 33%). Multivariate analysis indicated that extremely prematurity born at GA<24w was the sole critical factor for the development status with the DQ of >50 in survivors.
Conclusions: The perinatal care after 2005 could improve the overall survival rate, but not, neurological outcomes of preterm survivors at the limit of viability. Neurodevelopmental impairments were associated with the extremely prematurity born at GA<24w.

Event date： 2013.5

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：Kuching, Sarawak   Country：Malaysia  

Background: Follow up studies of very low birth weight infant (VLBWI) have documented the risks of autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD) increase at school age.
Objectives: This study aimed to evaluate the correlation between psychiatric symptoms and intelligent quotients (IQ) in VLBWI.
Study design: A cross sectional study recruited VLBWI born at our institute in 2001-2005. We examined seventy-seven children in ADHD-Rating Scale 4th (DuPaul, 1998), Autism Spectrum Questionnaire and Wechsler Intelligence Scale for Children (WISC-3rd) at 6-9 years of age.
Results: Male VLBWI (n=45) had significantly higher total ADHD, Inattentive (IA) and Hyperactivity-Impulsivity (HI) scales than female ones (n=32) respectively (p<0.01). Multivariate analysis revealed that Verbal Comprehension (VC) and Freedom from Distractibility (FD) of WISC-3rd were negatively correlated with ASQ (cc; -0.323, 95%CI; -0.186 to -0.006, p=0.04) and IA (cc; -0.625, 95%CI; -0.350 to -0.019, p=0.03), respectively.
Conclusions: To evaluate psychiatric symptoms of VLBWI at school age, VC and FD of WISC-3rd need to be considered for educational support in addition to IQ.

Event date： 2011.11

Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2011.11

Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2011.11

Country：Japan  

Event date： 2011.11

Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2011.11

Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2011.8

Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2011.7

Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2011.7

Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2011.7

Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2011.6

Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2011.6

Presentation type：Oral presentation (general)  

Venue：福岡市   Country：Japan  

Event date： 2011.5

Presentation type：Oral presentation (general)  

Venue：別府市   Country：Japan  

Event date： 2011.4 - 2011.5

Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2011.4

Presentation type：Oral presentation (general)  

Venue：福岡市   Country：Japan  

Event date： 2009.4

Presentation type：Oral presentation (general)  

Venue：奈良市   Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

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Country：Japan  

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Language：Japanese   Publisher：(株)東京医学社  

Language：English   Publisher：Pediatrics and Neonatology  

This article [2023;64(3):319–326] titled “Changing risk factors for postpartum depression in mothers admitted to a perinatal center”, published in this journal, has a mistake. In 2.1. Study population: Line 7, “Fifty-seven mothers” should be corrected to “Forty-eight mothers”. In 3.1. Clinical features: Line 9, “The mean and standard deviation (SD)EPDS-J scores were 5.03 ± 0.12 within the first week and 3.79 ± 0.10 at the fourth week.” should be corrected to “The mean and standard deviation (SD)EPDS-J scores were 5.03 ± 4.45 within the first week and 3.79 ± 3.75 at the fourth week.” The authors apologize for this oversight. The authors would like to apologize for any inconvenience caused.

DOI： 10.1016/j.pedneo.2024.08.002

Scopus

PubMed

Language：Japanese   Publisher：(一社)日本小児血液・がん学会  

小児期に発症する特発性血栓症は医療技術の進歩と疾患認識の拡がりから増加傾向にある.遺伝性血栓症は新生児期に発症するprotein C(PC)欠乏症と思春期に発症するPC,protein Sおよびantithrombin欠乏症が占める.一方で,これら異常症に対する血栓溶解,特異的補充や抗凝固療法のエビデンスは存在しない.また遺伝性以外の特発性血栓症においても直接経口抗凝固剤や特異的補充療法などのエビデンス集積が進んでいない.小児期発症の遺伝性性血栓症は予後不良である.電撃性紫斑に対して抗凝固療法が生涯必要となるがその具体的方法は確立していない.未発症保因者の妊娠出産は母子の血栓発症の誘因となる.日本医療研究開発機構(AMED)難治性疾患等政策研究事業「新生児から成人までに発症する特発性血栓症の診療アルゴリズムの確立」研究班(2020-22年度)では,新生児から成人までに発症する血栓症のうち遺伝性素因の関与が強いものを早発型遺伝性血栓症(early-onset thrombosis/thrombophilia,EOT)ととらえ診療指針を発信する.国内外の文献や診療ガイドラインなどを参考にし,患児とその家族を血栓症から守る治療管理に必要な情報を医療従事者に提供するための質問項目を設定し,各項目に回答する形式で「新生児から成人までに発症する特発性血栓症の診療ガイド(仮)」を作成中である.今回EOTレジストリならびに診療ガイドの進捗を報告する.(著者抄録)

Language：Japanese   Publisher：(一社)日本血液学会-東京事務局  

小児血栓症患者における遺伝素因の報告が増えている。小児期は年齢ごとに発症リスクが異なり,遺伝素因の寄与度も様々である。20歳までに発症する血栓症のうち遺伝素因が関与するものを"早発型遺伝性血栓症(early-onset thrombophilia,EOT)"として登録し,網羅的文献検索と併せて本邦患者の遺伝的背景と臨床経過を明らかにした。患者の60%以上をプロテインC(PC)欠乏症が占め,その半分以上が片アレル変異の保有者だった。年齢とともにプロテインS(PS)およびアンチトロンビン欠乏症が増加して主体となった。6～8歳の発症はなかった。日本人高頻度・低リスクバリアントのPC-TottoriとPS-Tokushimaも確認されたが,前者は重症PC欠乏症の発症に寄与していなかった。解析した32家系中de novo発症は1家系のみで,周産期の同時発症母子例が3家系あった。PC欠乏症を標的に適切なEOTスクリーニングを行って周産期血栓症から母子を守ることが期待される。(著者抄録)

Language：Japanese   Publisher：(株)日本臨床社  

Language：Japanese   Publisher：(公社)福岡県医師会  

Language：Japanese   Publisher：(株)医学書院  

Language：Japanese   Publisher：(株)メディカ出版  

Language：Japanese   Publisher：(株)東京医学社  

Language：Japanese   Publisher：(公社)日本新生児成育医学会  

チーム医療では医療情報を言語化して共有する。チーム以外に情報を共有するために診療録や症例要約等へ記録する。医療で生じる課題は無限大である。課題を論理的・科学的に検証する作業が研究となる。研究成果は学会報告だけでは記録に残らない。第三者による厳粛な検証を受けて論文として記録に残される。簡潔な英文で論文を記載すれば,世界中の人々に読んでもらうことができる。私たちの論文が未来の人類に活かされるかもしれない。(著者抄録)

Language：Japanese   Publisher：(株)診断と治療社  

＜文献概要＞早産児の貧血は症状に乏しいこともあり,血液ガスで測定される血球計測値を用いる.ヘモグロビン12g/dLが治療の目安である.退院後も栄養法に基づき貧血の評価を継続する.エビデンス構築が課題である.

Language：Japanese   Publisher：日本産婦人科・新生児血液学会  

新生児期の血栓症は希少な事例と考えられてきたが、医療の高度化と疾患認識の広がりにより報告数が増加している。さらに、日本人小児の血栓性素因における遺伝性プロテインC欠乏症の重要性が示されてきた。今回私たちは新生児血栓症の全国調査を行い、遺伝性プロテインC欠乏症の遺伝学的効果と、遺伝学的検査の悉皆性を示すことができた。今後は調査対象を小児から成人に達するまでに拡大し、小児患者とその家族を血栓症から守る個別化医療の確立を目指す。(著者抄録)

Language：Japanese   Publisher：(株)東京医学社  

Language：Japanese   Publisher：(株)先端医学社  

Language：Japanese   Publisher：(株)メディカ出版  

Language：Japanese   Publisher：(株)総合医学社  

＜ここがポイント!＞▼DICの基本的病態は、新生児・小児と成人とは相違ない。▼新生児・小児の凝固線溶機能は、生理的成熟過程においてDICの感受性が変化する。▼新生児期および小児期におけるDICの契機となる要因は成人と異なる。▼わが国では新生児DICのための診断・治療指針が策定されている。▼新生児と小児の早期かつ正確な診断には、採血方法や検査項目の選択が重要である。▼進行が速い新生児DICに適切に対応するため、治療戦略の標準化が課題である。(著者抄録)

Language：Japanese   Publisher：(株)東京医学社  

Language：Japanese   Publisher：日本産婦人科・新生児血液学会  

新生児単純ヘルペスウイルス(HSV)感染症は、主に垂直感染によって発症する重要な周産期感染症の一つである。臨床病型は表在型(SEM;skin, eye, and mouth)、中枢神経型(CNS;central nervous system)および全身型(Disseminated)の3つに分類され、それぞれ異なる症状と臨床経過を示す。1970年代以降、抗ウイルス薬の登場、またHSV-DNAを検出するPCR法の開発により、早期診断・治療が可能となり飛躍的に治療成績は改善した。しかし新生児医療が高度化した現代においても、全身型の新生児死亡率は29%、中枢神経型は65%以上に神経学的後遺症を残し、依然として予後不良の疾患である。本稿では新生児HSV感染症に対する治療指針と現在の課題について提示する。また新生児ヘルペス脳炎や新生児HSV関連血球貪食性リンパ組織球症といった重症例のリスク因子や治療戦略についても概説する。(著者抄録)

Language：Japanese   Publisher：日本産婦人科・新生児血液学会  

新生児血栓症はまれと考えられてきたが、医療の進歩に伴い診断例は増加傾向にある。血栓症の原因として、心疾患や感染症などのほか、凝固因子・抗凝固因子に関する遺伝性疾患を基礎にもつ可能性がある。日本人に多い遺血栓性素因はプロテインC(PC)、プロテインS、アンチトロンビン(AT)欠乏症、およびADAMTS13欠乏症だが、新生児ではPC欠乏症がほとんどである。私たちは、小児血栓症の診断と治療の向上のため日本人小児の遺伝性血栓症の分子疫学と臨床像をまとめ、早期診断のための活性基準値および診断予測式を作成した。2020年より遺伝子検査が保険適応となり、より早く正確な診断が可能となった。血栓症治療においてもPC製剤、AT製剤などの補充療法に加え、2021年より新生児に対しても直接経口抗凝固薬も使用可能となった。重症PC欠乏症に対する根治療法としての肝移植も報告され、治療選択も拡大している。(著者抄録)

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Type：Competition, symposium, etc. 

Number of participants：80

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Number of participants：80

Type：Competition, symposium, etc. 

Number of participants：80

Type：Competition, symposium, etc. 

Number of participants：80

Type：Competition, symposium, etc. 

Number of participants：80

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Seminar, workshop

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Seminar, workshop