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.

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.

Successful Retransplantation With Killer Cell Immunoglobulin-like Receptor Ligand-mismatched Cord Blood in Infant Acute Lymphoblastic Leukemia That Relapsed After Transplantation.

The prognosis of children with KMT2A -rearranged ( KMT2A -r) acute lymphoblastic leukemia (ALL) remains dismal. This report describes the successful retransplantation of a patient with infant ALL who relapsed both bone marrow and central nervous system. The patient received HLA-matched cord blood transplantation (CBT) and relapsed 18 months later. After achieving the second remission, the patient received a killer cell immunoglobulin-like receptor ligand-mismatched CBT with a reduced-intensity conditioning regimen and has been in remission for 52 months. Thus, killer cell immunoglobulin-like receptor ligand-mismatched CBT with reduced-intensity conditioning might be a treatment option for patients with KMT2A- r ALL who relapsed after transplantation, even with extramedullary relapse.

Catastrophic antiphospholipid syndrome with Epstein-Barr virus-associated hemophagocytosis: A clinicopathological conference.

Catastrophic antiphospholipid syndrome (CAPS) is a severe variant of antiphospholipid syndrome associated with multiorgan thrombosis in a short term. We present the case of a 14-year-old immunocompetent girl who developed renal, intestinal, and pulmonary infarction; thrombocytopenia; and hemolytic anemia within 1 week. She was diagnosed with thrombotic microangiopathy. Hence, plasma exchange and corticosteroid therapy were initiated, which improved thrombocytopenia. However, the patient's platelet count decreased. Her general condition gradually worsened with eventual death. An autopsy revealed multiple infarctions in the kidneys bilaterally, jejunum, ileum, and pulmonary parenchyma. Microthrombi were not detected. Massive hemophagocytosis was observed in the splenic pulp, lymph nodes, and bone marrow. Several Epstein-Barr viruses (EBVs)-encoded small ribonucleic acid (RNA)-positive lymphocytes were also found in the bone marrow. The presence of antibodies to both viral capsid antigen-immunoglobulin G and EBV nuclear antigen indicated past infection. Antiphospholipid antibody was positive after her death. The patient was finally diagnosed with CAPS and EBV-associated hemophagocytosis, possibly due to EBV reactivation. Establishing a clinical diagnosis of CAPS was relatively difficult because two different causes of thrombocytopenia, CAPS and hemophagocytosis, led to a difficulty in understanding this case's pathogenesis.

Maternal Chronic Disease and Congenital Anomalies of the Kidney and Urinary Tract in Offspring: A Japanese Cohort Study.

RATIONALE & OBJECTIVE: Several maternal chronic diseases have been reported as risk factors for congenital anomalies of the kidney and urinary tract (CAKUT) in offspring. However, these investigations used case-control designs, and cases with isolated genitourinary CAKUT were not distinguished from cases in which CAKUT were present with extrarenal congenital anomalies (complicated CAKUT). We examined the association of maternal diseases with isolated and complicated CAKUT in offspring using data from a prospective cohort study. STUDY DESIGN: A nationwide prospective birth cohort study. SETTING & PARTICIPANTS: 100,239 children enrolled in the Japan Environment and Children's Study between January 2011 and March 2014 at 15 research centers. Physicians' diagnoses in mothers and children were collected from medical record transcripts and questionnaires. EXPOSURES: Medical histories of maternal noncommunicable diseases, including obesity, hypertension, diabetes mellitus, kidney disease, hyperthyroidism, hypothyroidism, psychiatric disease, epilepsy, cancer, and autoimmune disease. OUTCOMES: CAKUT diagnosed during the first 3 years of life, classified as isolated or complicated. ANALYTICAL APPROACH: Multivariable Poisson regression with generalized estimating equations accounting for clustering by clinical center. RESULTS: Among the 100,239 children, 560 (0.6%) had CAKUT, comprising 454 (81%) isolated and 106 (19%) complicated forms. The risk of isolated CAKUT was increased in children of mothers who experienced kidney disease (adjusted risk ratio [RR], 1.80 [95% CI, 1.12-2.91]) or cancer (RR, 2.11 [95% CI, 1.15-3.86]). Furthermore, the risk of complicated CAKUT was increased in children of mothers with diabetes mellitus (RR, 3.04 [95% CI, 1.64-5.61]). LIMITATIONS: Lack of standardization or prespecification of clinical definitions, diagnostic criteria, measurements, and testing. Genetic testing was not performed. CONCLUSIONS: Isolated CAKUTs and complicated CAKUTs were associated with different maternal diseases. The results may inform clinical management of pregnancy and highlight potential differences in the genesis of isolated and complicated forms of CAKUT.

Hemophilic pseudotumor of the maxillary sinus in an inhibitor-positive patient with hemophilia A receiving emicizumab: a case report.

A 14-year-old inhibitor-positive male patient with severe hemophilia A and severe psychomotor disability was admitted due to left buccal swelling and impaired downward movement of the left eye. He had been on noninvasive positive-pressure ventilation (NPPV) through a nasal mask for upper airway obstruction. The patient began to have repeated epistaxis 16 months after initiation of treatment with 6 mg/kg Q4W of emicizumab, and was thus administered a bypassing agent. Left buccal swelling and impaired downward movement of the left eye appeared during the subsequent month. Imaging examination revealed a mass in the left maxillary sinus and bone destruction. Endoscopic tumor resection and tracheostomy were performed using recombinant activated factor VII. NPPV was discontinued thereafter. Pathological examination revealed that the mass was a hemophilic pseudotumor (HP). After discharge the emicizumab-regimen dose was changed to 3 mg/kg, Q2W to increase serum emicizumab levels. No recurrent HP or bleeding requiring treatment was observed. Pressure applied to the damaged nasal mucosa by NPPV was suspected as the main cause of HP development. If a mass is observed in a patient with hemophilia, HP should be considered as a possible diagnosis even if the patient is receiving emicizumab.

Association of Maternal Total Cholesterol With SGA or LGA Birth at Term: the Japan Environment and Children's Study.

CONTEXT: Maternal cholesterol is important for fetal development. Whether maternal serum total cholesterol (maternal TC) levels in midpregnancy are associated with small (SGA) or large (LGA) for gestational age independent of prepregnancy body mass index (BMI) and weight gain during pregnancy is inconclusive. OBJECTIVE: This work aimed to prospectively investigate the association between maternal TC in midpregnancy and SGA or LGA. METHODS: The Japan Environment and Children's Study is a nationwide prospective birth cohort study in Japan. Participants in this study included 37 449 nondiabetic, nonhypertensive mothers with singleton birth at term without congenital abnormalities. Birth weight for gestational age less than the 10th percentile and greater than or equal to the 90th percentile were respectively defined as SGA and LGA by the Japanese neonatal anthropometric charts. RESULTS: The mean gestational age at blood sampling was 22.7 ±â€…4.0 weeks. After adjustment for maternal age, sex of child, parity, weight gain during pregnancy, prepregnancy BMI, smoking, alcohol drinking, blood glucose levels, household income, and study areas, 1-SD decrement of maternal TC was linearly associated with SGA (odds ratio [OR]: 1.20; 95% CI, 1.15-1.25). In contrast, 1-SD increment of maternal TC was linearly associated with LGA (OR: 1.13; 95% CI, 1.09-1.16). Associations did not differ according to prepregnancy BMI and gestational weight gain (P for interaction > .20). CONCLUSION: Maternal TC levels in midpregnancy were associated with SGA or LGA in a Japanese cohort. It may help to predict SGA and LGA. Favorable maternal lipid profiles for fetal development must be explored.

Infantile neuroblastoma and maternal occupational exposure to medical agents.

BACKGROUND: Healthcare workers are often exposed to hazardous agents and are at risk for adverse health consequences that affect not only themselves but also their infants. This study aimed to examine whether such occupational exposure increased the risk of childhood cancer in offspring. METHODS: We used the dataset of the Japan Environment and Children's Study, a nationwide birth cohort involving over 100,000 mother-child pairs. Information was obtained via successive questionnaires that were completed until the child turned 1 year of age. The parents were asked whether they occupationally handled medical agents during pregnancy. RESULTS: A total of 26 infants developed neoplasms: neuroblastoma, leukemia, and brain tumor. The incidence of neuroblastoma was significantly higher in infants whose mothers were exposed to radiation (3/2142: 140.1 per 100,000 population) than in those who were not (12/90,384: 13.3 per 100,000 population). Multivariable regression analyses revealed a close association between maternal irradiation and the development of neuroblastoma (adjusted incident rate ratio: 10.68 [95% confidence interval: 2.98‒38.27]). CONCLUSIONS: The present study demonstrated, for the first time, a potential association between maternal occupational exposure and the occurrence of neuroblastoma in offspring. Further studies involving the large pediatric cancer registries are needed to confirm these preliminary results. IMPACT: Healthcare workers are often exposed to hazardous agents and are at risk for adverse health consequences that affect not only themselves but also their infants. This study examined the association between such occupational exposure and offspring's cancers that developed until the age of 1 year. Maternal exposure to ionizing radiation was associated with infantile neuroblastoma in offspring. Further studies involving the large pediatric cancer registries are needed to confirm these preliminary results.

Case Report: Japanese Siblings of Cystic Fibrosis With a Novel Large Heterozygous Deletion in the CFTR Gene.

Cystic fibrosis (CF) is a rare disease in the Japanese. The most common CFTR variant in Japanese CF patients is a large heterozygous deletion that can easily avoid detection by standard gene sequencing methods. We herein report a novel large heterozygous deletion in the CFTR gene in Japanese siblings with CF. A genetic analysis was performed in two patients (9-year-old boy and 5-month-old girl) who were clinically diagnosed with CF because of the positive result for the rapid fecal pancreatic elastase antigen test and the elevation of the sweat chloride concentration. In addition to conventional polymerase chain reaction (PCR) and direct sequencing, multiplex ligation-dependent probe amplification (MLPA) was performed to check for a large deletion and duplication of the CFTR gene. Based on MLPA findings, the breakpoint of heterozygous deletion was identified by real-time quantitative PCR followed by the sequence of the amplified junction fragment. In MLPA, the numbers of the fragments corresponding to exons 1, 16, 17a, and 17b and 234 nt and 747 nt upstream from the translation initiation codon of exon 1 in the CFTR gene and exon 3 in the ASZ1 gene were reduced by almost half. The c.2908+1085_3367+260del7201 variant (exon 16-17b deletion) was identified in one allele. The other allele had a large 137,567-bp deletion from g.117,361,112 (ASZ1 3' flanking region) to g.117,498,678 (CFTR intron 1) on chromosome 7. Since the deletion variant lacked the entire promoter region of CFTR, CFTR mRNA would not be transcribed from the allele, indicating it to be a novel pathogenic variant causing CF. As large mutations are frequently detected in Japanese CF patients, MPLA can be useful when searching for variants.

Measurement of the Estradiol Concentration in Cerebrospinal Fluid from Infants and Its Correlation with Serum Estradiol and Exosomal MicroRNA-126-5p.

Estradiol has an important role in the brain, such as in neuronal development and protection, but estradiol levels in the human brain have not been well investigated. In this study, we measured the estradiol concentration in the cerebrospinal fluid (CSF) of infants to reveal the relationships between the estradiol concentrations in the serum and the CSF and further determined exosomal microRNAs in serum. Estradiol in the CSF was strongly correlated with serum estradiol and moderately correlated with miR-126-5p in the serum exosomes. This report is the first to determine the estradiol concentration in CSF from infants and showed that the levels of miR-126-5p as well as serum estradiol can be candidates to predict brain estrogen status.

Impaired B-Cell Differentiation in a Patient With STAT1 Gain-of-Function Mutation.

Hypogammaglobulinemia is a rare complication of STAT1 gain-of-function (GOF) mutations. We report an adult patient diagnosed with hypogammaglobulinemia caused by B-cell depletion during the treatment of disseminated cryptococcosis. The patient carried the STAT1 GOF mutation (c.820C>T, p.R274W). The flow cytometric analysis of his bone marrow revealed that B-cell differentiation was blocked in the stages between pre-B1b and pre-B2 cells. On the other hand, his brother who carried the same mutation displayed normal B-cell counts, thereby indicating that the unrecognized variants in same or other gene might be associated with abnormal B-cell differentiation in the patients. In conclusion, impaired B-cell differentiation in the bone marrow can cause hypogammaglobulinemia in patients with STAT1 GOF mutations.

Perioperative safety and haematostatic efficacy of a new bypassing agent pd-FVIIa/FX (Byclot) in haemophilia patients with high-responding type inhibitors.

: The novel agent pd-FVIIa/FX is a 1 : 10 protein weight mixture of activated factor VII (FVIIa) and factor X (FX) derived from donated blood plasma. A phase III clinical trial of pd-FVIIa/FX revealed high efficacy for bleeding episodes in haemophilia patients with inhibitors. However, up to now, only one case of this new agent being used for surgery had been reported. The objective of this study is to evaluate the perioperative haemostatic efficacy and safety of pd-FVIIa/FX in haemophilia patients with inhibitors. We retrospectively reviewed 25 operation charts from 14 haemophilia patients with high-responding inhibitors using pd-FVIIa/FX during the perioperative period. Efficacy was evaluated by attending physicians and results divided into four groups (excellent, good, fair, and poor). The operation chart was provided by nine Japanese medical institutes with expertise in haemophilia management. Out of the total of 25 surgical procedures, 44% (11/25) were classified as major surgery and the remainders were minor surgeries. In all of the surgeries but one, rFVIIa and/or APCC were administered in combination or sequential method. In all cases except one, the haemostatic efficiency rate was judged as excellent or good by treating physicians for an overall efficacy rate of 96%. No thrombotic adverse effects were reported. This study's results suggest that both combination and sequential therapy of pd-FVIIa/FX and other bypassing agents are well tolerated and effective for the control of perioperative bleeding in haemophilia patients with high-responding inhibitors.