Association of placental weight at birth with maternal whole blood concentration of heavy metals (cadmium, lead, mercury, selenium, and manganese): The Japan Environment and Children's Study (JECS).

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.

Non-conditioned cord blood transplantation for infection control in athymic CHARGE syndrome.

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 naïve 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 naïve 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.

Pediatric leukemia and maternal occupational exposure to anticancer drugs: the Japan Environment and Children's Study.

ABSTRACT: 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 malignant neoplasms 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 3 years after birth. Exposure factors were medical agents, including anticancer agents, ionizing radiation, and anesthetics, handled by mothers during pregnancy or by fathers for 3 months before 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 older than 1 year (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 older than 1 year. Effective prevention methods may be necessary to prevent maternal exposure to anticancer drugs and to reduce the risk of childhood malignant neoplasms.

The clinical and genetic landscape of early-onset thrombophilia in Japan.

OBJECTIVES: To determine the optimal management for early-onset thrombophilia (EOT), the genetic and clinical features of protein C (PC)-, protein S (PS)-, or antithrombin (AT)-deficient patients of ≤20 years of age were studied in Japan. METHODS/RESULTS: Clinical and genetic information of all genetically diagnosed cases was collected through the prospective, retrospective study, and literature review. One-hundred-one patients had PC (n = 55), PS (n = 29), or AT deficiency (n = 18). One overlapping case had PC- and PS-monoallelic variant. Fifty-five PC-deficient patients (54%) had 26 monoallelic or 29 biallelic variant(s), and 29 (29%) PS-deficient patients had 20 monoallelic or nine biallelic variant(s). None of the patients had AT-biallelic variants. The frequent low-risk allele p.K193del (PC-Tottori) was found in five patients with monoallelic (19%) but not 29 with biallelic variant(s). The most common low-risk allele p.K196E (PS-Tokushima) was found in five with monoallelic (25%) and six with biallelic variant(s) (67%). One exceptional de novo PC variant was found in 32 families with EOT. Only five parents had a history of thromboembolism. Thrombosis concurrently developed in three mother-newborn pairs (two PC deficiency and one AT deficiency). The prospective cohort revealed the outcomes of 35 patients: three deaths with PC deficiency and 20 complication-free survivors. Neurological complications were more frequently found in patients with PC-biallelic variants than those with PC-, PS-, or AT-monoallelic variants (73% vs. 24%, p = .019). CONCLUSIONS: We demonstrate the need for elective screening for EOT targeting PC deficiency in Japan. Early prenatal diagnosis of PC deficiency in mother-infant pairs may prevent perinatal thrombosis in them.

Sex steroid hormones and allergic diseases in children: a pilot birth cohort study in the Japan Environment and Children's Study cohort.

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.

Serum erythroferrone levels during the first month of life in premature infants.

OBJECTIVE: To examine erythroferrone (ERFE)-hepcidin iron regulation in premature infants under intensive care at risk of iron metabolic disorders. STUDY DESIGN: A retrospective cohort recruited 31 infants with a birth weight of <1500 g hospitalized in a tertiary center. Their hematological status was measured at birth and 2 and 4 weeks of life. RESULTS: ERFE was positively correlated with the reticulocyte hemoglobin content at 2 (r2 = 0.2374) and 4 weeks (r2 = 0.6005). An assumed negative correlation between ERFE and hepcidin was not determined during the neonatal period. Hepcidin was positively correlated with the leukocyte count (r2 = 0.3089) and ferritin (r2 = 0.7476) at birth and C-reactive protein (r2 = 0.3591) at 2 weeks and negatively correlated with the reticulocyte count (r2 = 0.2887) at 4 weeks. CONCLUSION: The vulnerability of the ERFE-hepcidin pathway within 4 weeks may contribute to iron imbalance in premature infants.

Survival outcomes of very low birth weight infants with trisomy 18.

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.

Trends in Bronchopulmonary Dysplasia Among Extremely Preterm Infants in Japan, 2003-2016.

OBJECTIVE: To investigate recent trends in bronchopulmonary dysplasia (BPD) and its risk factors among extremely preterm infants. STUDY DESIGN: Demographic and clinical data were reviewed for 19 370 infants born at 22-27 weeks of gestation registered in the affiliated hospitals of the Neonatal Research Network of Japan between 2003 and 2016. We investigated the overall survival and prevalence of bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age and risk factors for developing BPD among the survivors. RESULTS: Among 19 370 infants, 2244 (11.6%) died by 36 weeks' postmenstrual age. The mortality rate decreased from 19.0% (99% CI, 15.7%-22.8%) in 2003 to 8.0% (99% CI, 6.2%-10.3%) in 2016. Among 17 126 survivors, BPD developed in 7792 (45.5%) infants, and its proportion significantly increased from 41.4% (99% CI, 36.5%-46.4%) in 2003 to 52.0% (99% CI, 48.2%-55.9%) in 2016. A multivariable analysis of the survivors showed a positive association of BPD with ≥4 weeks' supplemental oxygen or invasive ventilation, birth weight <750 g, small for gestational age, ≥4 weeks' noninvasive positive pressure ventilation, chorioamnionitis, <26 weeks' gestational age, <20 cases per year of center patient volume, or treated patent ductus arteriosus. Although the median duration of invasive ventilation was shortened, the proportions of factors associated adversely with BPD generally showed increasing trends over time. CONCLUSIONS: The mortality rate of extremely preterm infants has decreased, but the rate of BPD has increased in survivors between 2003 and 2016. Despite the decreasing duration of invasive ventilation over time, increasing rates of BPD suggest that differences in the patient population or other management strategies influence the development of BPD.

[Diagnosis and management of early-onset thrombophilia/thrombosis: a review].

Evidence of the molecular epidemiology of thrombophilia is growing, and the clinical management of adult thromboembolism patients has recently made significant progress. On the other hand, there is little or no evidence concerning the genetic variation, treatment, and prophylaxis of thromboembolism development in the early life stage. The clinical presentation of early-onset thrombosis/thrombophilia, which mostly occurs in newborns and adolescents, differs from that in cases of adult-onset. Recurrent purpura fulminans and/or intracranial hemorrhage/infarction leads to dangerous lifelong complications. As in the setting of cancer genomic medicine, germline variants require determination for the individualized control of early-onset thrombophilia. The genetic predisposition to thrombosis varies among ethnicities. In the Japanese population, the protein S variant (PS-Tokushima, K196E) has attracted attention as the cause of a common and low-risk prothrombotic predisposition in adults, while protein C deficiency greatly impacts the onset of pediatric thrombosis. In 2020, 3 years after the registration of idiopathic thrombosis as a designated intractable disease, genetic tests have been promulgated for health insurance portability. Disease-specific therapy for early-onset thrombophilia is crucial. Here, we review the genetic heterogeneity, prophylaxis, and treatment strategy of the rare subgroups of severe heritable thrombosis conditions in Japan.

Neurodevelopmental outcomes following intravitreal bevacizumab injection in Japanese preterm infants with type 1 retinopathy of prematurity.

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.

Prognostic factors for survival of herpes simplex virus-associated hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) occurs in neonates with disseminated infection of herpes simplex virus (HSV). Little has been reported on the control of rapid HLH progression. We studied the cytokine profile and genetic basis of two index cases with divergent outcomes after early treatment of type 2 HSV infection. One survivor had fever and elevated serum levels of tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), interferon (IFN)-ß, and IFN-γ at diagnosis. The other neonate had no fever or TNF-α production, but significant IL-6 or IFN responses during the treatment course, and died 19 days after birth. Among 16 reported cases of neonatal HSV-HLH including index cases, eight deceased neonates experienced significantly less fever at presentation (p = 0.028), lower platelet counts (p = 0.019), and lower ratios of soluble IL-2 receptor (sIL-2R) to ferritin levels (p = 0.044) than eight survivors. The 100-day overall survival rates were significantly higher in patients with fever (p = 0.004), > 100 × 109/L of platelet counts (p = 0.035) or > 20 of sIL-2R/ferritin ratio at diagnosis (p = 0.004). The first febrile and cytokine responses to HSV infection predict the early outcome of neonatal HSV-HLH.

Transcutaneous blood gas monitoring among neonatal intensive care units in Japan.

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.

Association of perinatal factors of epilepsy in very low birth weight infants, using a nationwide database in Japan.

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.

Inflammation in the neonatal period and intrauterine growth restriction aggravate bronchopulmonary dysplasia.

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.

Chemokine levels predict progressive liver disease in Down syndrome patients with transient abnormal myelopoiesis.

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)-ß1 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.

A nationwide survey on tracheostomy for very-low-birth-weight infants in Japan.

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.

Neurodevelopmental Outcomes in Infants With Birth Weight ≤500 g at 3 Years of Age.

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.

Thrombotic microangiopathy in a very young infant with mitral valvuloplasty.

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.