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Previous epidemiological studies have reported an increased risk of anemia in people with allergic disorders. However, previous studies have followed a cross-sectional design. The aim of this study was to investigate the association between the two conditions with a cohort dataset. We used data of 80,943 children in the Japan Environment and Children’s Study, the largest birth cohort in Japan. The association between anemia and allergic disorders was evaluated with a logistic regression model and propensity score analysis. After adjusting for potential confounders, children with asthma (odds ratio [OR], 1.85; 95% confidence interval [CI], 1.32–2.60), atopic dermatitis (OR, 2.18; 95% CI, 1.66–2.85), allergic rhinitis (OR, 1.35; 95% CI, 1.05–1.74), allergic rhinoconjunctivitis (OR, 2.95; 95% CI, 1.91–4.54), and food allergies (OR, 1.92; 95% CI, 1.44–2.56) at 2 years of age predicted high odds of developing anemia in the next year. Any allergy at 2 years of age was associated with an increased risk of anemia at the age of 3 years (OR, 1.80; 95% CI, 1.41–2.29). The findings remained stable in the propensity score analysis. Results suggest that allergic diseases were related to caregiver-reported anemia in children.

This study aimed to describe the distribution of pregnancies with medical and obstetric complications based on the Japan Environment and Children's Study (JECS). We evaluated the distribution of the history of obstetric/gynaecological diseases, the history of obstetric labour complications, pregnancy with medical and surgical complications, and obstetric labour complications in participants in the JECS. Of 100,818 pregnant women with medical record entries after delivery, 15,305 (15.2%) had medical and surgical complications in pregnancy and 46,756 (46.4%) experienced obstetric labour complications. The proportion of pregnancies with heart disease, kidney disease and hepatitis was 0.3%, 0.3% and 0.1%, respectively. Gestational diabetes was diagnosed in 2715 (2.7%) women. The proportion of women with mild and severe gestational hypertension was 2.3% and 1%, respectively. The JECS is the largest birth cohort in Japan. These data will provide useful, basic information for perinatal care in Japan.IMPACT STATEMENTWhat is already known on this subject? Epidemiological studies have suggested that pre-existing diseases and complications of pregnancy, such as heart disease in pregnancy, gestational hypertension and gestational diabetes, may have implications for pregnancy outcomes, as well as for children's health and development.What the results of this study add? We evaluated the distribution of the history of obstetric/gynaecological diseases, the history of obstetric labour complications, medical and surgical complications in pregnancy, and obstetric labour complications using data from the Japan Environment and Children's Study (JECS).What the implications are of these findings for clinical practice and/or further research? The JECS is the largest birth cohort in Japan. Our data will provide useful, basic information for perinatal care in Japan.

Background This study assessed the psychometric profile of 10 questionnaires (every 6 months, from 6 to 60 months) from the Japanese translation of the Ages and Stages Questionnaires, third edition (J‐ASQ‐3). Methods Data from 439 children in a birth cohort were used to identify the J‐ASQ‐3 score distribution, establish cut‐off scores, and calculate the instrument's internal consistency. Data were also collected from 491 outpatients to examine J‐ASQ‐3 test–retest reliability and concurrent validity, which was examined using the Kyoto Scale of Psychological Development (KSPD) and the Japanese version of the Denver Developmental Screening Test II (J‐Denver II). Both the original and the alternative screening criteria of the ASQ‐3 were used (failure in at least one and at least two domains, respectively). Results Cronbach's alpha for each J‐ASQ‐3 subscale on each questionnaire ranged from 0.45 to 0.89. Test–retest reliability was >0.75 for the subscales on almost all questionnaires. Concurrent validity was also adequate. In comparison with the screening results of the KSPD, the overall sensitivity and specificity were 96.0% and 48.8%, respectively, when the ASQ‐3 original criterion was used, and 92.1% and 74.9%, respectively, when the alternative criterion was used. In comparison with the screening results of the J‐Denver II, the overall sensitivity and specificity were 75.6% and 74.7%, respectively, when the ASQ‐3 original criterion was used, and 56.3% and 93.0%, respectively, when the alternative criterion was used. Conclusions This study quantified the psychometric profiles of the Japanese translations of 10 ASQ‐3 questionnaires. We demonstrated the validity of the J‐ASQ‐3 and determined new cut‐off scores. Further studies with larger samples from a greater range of locations are required to clarify the suitability of this tool for all Japanese children.

Few studies have investigated the risky health behaviors and psychosocial characteristics of teenage mothers in countries with a low teenage birth rate, like Japan. We examined the differences in maternal prenatal risky health behaviors and psychosocial characteristics, and birth weight of infants between teenage and adult mothers. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: We identified 1159 teenage (age younger than 20 years) and 73,547 adult mothers (20-34 years) who participated a nationwide birth cohort study between 2011 and 2014. Behavioral and psychosocial characteristics were ascertained using questionnaires during pregnancy. Birth weight of infants was verified through medical records. Univariate and multivariable logistic regression were used to assess the association of teenage motherhood and birth weight of infants with parity, marital status, household income, maternal education, job status, preconception body mass index, gestational weight gain, psychological distress, and smoking status.Teenage mothers were significantly more likely to smoke and have psychological distress and less likely to use alcohol than adult mothers (9.9% vs 4.6%, P .001; 8.9% vs 3.4%, P .001; 1.3% vs 2.5%, P .001, respectively). No association was found between teenage motherhood and low birth weight in infants (odds ratio 0.99; 95% confidence interval, 0.73-1.32). Further, no association was found after adjusting for covariates.A substantially greater number of Japanese teenage mothers smoked and experienced severe psychological distress than adult mothers. Our findings will be useful for future research and for developing effective policies and programs for teenage mothers and their children.

Tobacco smoke exposure is known to lower serum 25-hydroxyvitamin D (25(OH)D) concentrations. This study evaluated the association between passive smoking and vitamin D deficiency (VDD) in young children using data from the Japan Environment and Children’s Study (JECS), the largest birth cohort study in Japan. Information on parental smoking status was extracted from a survey of JECS for children aged 1.5 years and data for serum 25(OH)D concentrations were obtained from blood tests in the Sub-Cohort Study of JECS performed at age 2 years. Logistic regression and linear models were fitted to evaluate the association between these variables. Data were analyzed for 4593 children. After adjusting for covariates, smoke exposure was significantly associated with increased incidence of VDD (OR 1.35; 95% CI, 1.14–1.59) according to the logistic model. The linear model indicated that passive smoking negatively predicted de-seasonalized serum 25(OH)D concentrations (β −0.5; 95% CI −0.95 to −0.08) in children aged 2 years. The results suggest that smoke exposure is a risk factor for VDD in children. Given that VD plays a crucial role in bone metabolism and the immune system, our findings are significant for clinical and public health.

Background Hypertensive disorders of pregnancy (HDP) are one of the most common medical conditions that women encounter during pregnancy. Whether or not hypertensive disorders of pregnancy (HDP) are associated with allergic conditions in the offspring is unclear. This study used data from a large Japanese birth cohort to investigate whether HDP contributes to the development of allergic conditions in the offspring at 3 years. We also assessed the effect of blood pressure at different pregnancy trimesters on children's allergies. Methods We obtained data from the Japan Environment and Children's Study (JECS), which included 104 062 fetal records. After data selection, we analyzed 77 505 mother–child pairs, using logistic regression models to examine the relationships between HDP or the mother's blood pressure and their children's allergic conditions. In addition, we also evaluated the effect of HDP during pregnancy on allergies with a propensity score matched dataset, using a logistic regression model that predicts the conditional probability of whether a mother belonged to the HDP or non-HDP group. Results Among the 77 505 mothers eligible for analysis, 2334 (3.0%) had HDP. Percentages of women with hypertension were 1.7% in early gestation, 1.0% in mid-gestation, and 1.6% in late gestation. After adjusting for multiple potential confounders, HDP contributed nothing to allergy development in offspring. Children born to women with hypertension were no more likely than those without to have allergic conditions at 3 years of age. The propensity score matched dataset showed similar findings. Conclusion HDP and high blood pressure during pregnancy are apparently not risk factors for developing allergy in offspring. This information may help clinicians in counseling women who suffered HDP during pregnancy.

Introduction: Previous studies have reported that maternal asthma increases the risk of preterm birth. We hypothesized that inflammatory reactions caused by allergic diseases might affect the uterine environment and, subsequently, perinatal outcomes. The objective of this study was to examine the associations between allergic features among mothers and preterm pregnancy outcomes in a nationwide birth cohort. Methods: We analyzed data from pregnant women obtained from the Japanese Environment and Children’s Study (JECS), a nationwide general birth cohort study. We used binomial and multinomial logistic regression models to examine the associations between maternal allergic features and preterm birth, threatened preterm labor (TPL), and preterm premature rupture of the membrane (PPROM). Results: A total of 97,683 pregnant women were included. Prevalence of preterm birth, TPL, and PPROM was 4.7, 19.6, and 1.2%, respectively. Maternal history of allergic diseases (asthma, allergic rhinitis, allergic conjunctivitis, food allergy, drug allergy, and contact dermatitis) increased the risk of TPL(adjusted odds ratio [aOR] = 1.11 [95% CI: 1.06–1.17], aOR = 1.12 [1.08–1.16], aOR = 1.10 [1.04–1.16], aOR = 1.17 [1.09–1.26], aOR = 1.35 [1.23–1.48], and aOR = 1.34 [1.20–1.49], respectively). Although some maternal allergic features showed a negative association with preterm birth, the variables affecting preterm birth differed according to the gestational age of the fetus (22–33 weeks vs. 34–36 weeks). There were no significant associations between maternal allergic features and PPROM. Conclusion: Maternal allergic disease, except atopic dermatitis, may increase the risk of TPL. Comorbidity of maternal allergic disorders and perinatal adverse outcomes require further investigation.

Background Capturing epidemiological signatures is essential to document burdens of disease and to design health care services, including prevention measures, clinical interventions, and policies. There are large geographical and ethnic variations in the epidemiology of allergic and immunological diseases. Various data are available from North America and Europe, but the epidemiology of allergic and immunological diseases in Asia is not well documented. Objective To characterize epidemiological signatures of allergic and immunological disease in young children in Japan. Methods This was a national, multicenter, prospective birth cohort study: Japan Environment and Children's Study (JECS). A general population of 103,060 women was enrolled during pregnancy. Allergic and immunological outcomes were assessed among young children using questionnaire data. Results The prevalence of caregiver-reported immediate food allergy was 7.6%, 6.7%, and 4.9% at age 1, 2, and 3 years, respectively. Hen egg allergy was most common (5.4% prevalence at age 1 year) followed by allergies to cow milk and wheat. Several patterns of allergic symptom clusters were identified. Physician diagnosed, as reported by the caregiver, non-IgE mediated gastrointestinal food allergy affected 0.5% of infants. By contrast, caregiver-reported gastrointestinal food allergies affected 1.4% of children. Kawasaki disease affected 0.3% and 0.4% children, respectively, at age 1 and 3 years. Primary immunodeficiency disorders affected 0.005% children at age 3 years. Conclusion These data provide important epidemiological signatures of allergy and immunology in young Japanese children including the age-specific prevalence of allergic disease, Kawasaki disease, and primary immune deficiency.

The present study established a nomogram of fetal thyroid circumference (FTC) and the appearance timing of fetal distal femoral and proximal tibial ossification to assess fetal thyroid function in Japan. Between April 2015 and July 2019, normal pregnant women at our hospital were recruited for the study. FTC was measured by the automatic ellipse outline and plotted against gestational age (GA). Fetal distal femoral and proximal tibial ossification measurements were obtained with standard electronic calipers from outer-to-outer margins (> 1 mm as the presence of ossification). A total of 199 pregnant women were examined. FTC increased logarithmically to GA. A nomogram of FTC was expressed by a logarithmic formula: $${\ln}\left( {{\text{FTC}}} \right)\, = \,{\exp}\left( {{4}.{679}0{-}{3}0.{3961}/{\text{GA}}} \right)$$ . The respective 5–95th percentiles of FTC at each GA were 20.2–36.2 mm at 22 weeks, 25.0–44.8 mm at 26 weeks, 29.2–52.3 mm at 30 weeks, and 32.9–59.0 mm at 34 weeks. The fetal distal femoral epiphysis was not visualized before 30 weeks, but was visualized in 100% of fetuses after 35 weeks of gestation. The fetal proximal tibial epiphysis was not visualized before 33 weeks, but was visualized in 73.7% of fetuses at 37 weeks of gestation. We generated a GA-dependent FTC nomogram for Japanese fetuses. We also confirmed the appearance timing of fetal distal femoral and proximal tibial ossification to assess bone maturation. These assessments may be very useful for evaluating fetal thyroid function in Japan.

Nutritional requirements increase during pregnancy. However, relatively few studies have examined longitudinal changes in dietary intake from periconception to pregnancy. Here, we investigated changes in the intake of food and nutrients, and compliance with dietary reference intakes (DRIs) in pregnant women. The Japan Environment and Children’s Study, a nationwide multicenter prospective cohort study, included 30,373 pregnant women who answered a validated food frequency questionnaire repeatedly to assess changes in dietary intake in periconception and pregnancy. Energy-adjusted intakes of food groups and nutrients were described using the density method. The percentage of women not meeting DRIs was calculated. Of all foods groups examined, intake of food significantly increased from periconception to pregnancy for dairy products (mean difference 23.5 g/1000 kcal, 95% confidence interval [CI] 22.0–25.0 g/1000 kcal), confectionaries (2.0 g/1000 kcal, 1.8–2.2 g/1000 kcal), and soft drinks (1.3 g/1000 kcal, 0.3–2.3 g/1000 kcal). Of all nutrients examined, intake was significantly increased for calcium (mean difference 27 mg/1000 kcal, 95% CI 25–29 mg/1000 kcal), vitamin A (15 μgRE/1000 kcal, 13–18 g/1000 kcal), and saturated fat (0.4% energy, 0.4–0.4% energy). The percentage of women not meeting DRIs increased for vitamin B group, vitamin C, saturated fat and salt. We found that energy-adjusted intakes of calcium, vitamin A, and saturated fat increased from periconception to pregnancy, while intake of other nutrients did not increase. The percentage of women not meeting DRIs increased for water-soluble vitamins, saturated fat, and salt.

Pregnant women have more sleep problems compared to non-pregnant women. Our objective was to investigate the differences in sleep patterns by age among Japanese women enrolled in the Japan Environment and Children’s Study during preconception and pregnancy. Questionnaires on sleep status were administered to pregnant women twice in the first, second and/or third trimesters. Wake-up time, bedtime, sleep duration and quality of sleep were analyzed in 103,099 respondents. Women younger than 20 years of age awoke and slept the latest in comparison to all other age groups during preconception and pregnancy. Sleep time of women younger than 20 years of age was the longest in comparison to other age groups. The wake-up time and bedtime of teenage mothers were delayed from preconception to second or third trimester, but they did not display any statistically significant changes in other age groups. Moreover, the younger the pregnant women were the more sleep trouble they had despite reportedly being tired, and felt more sleep-deprived despite having had enough sleep time in both second and third trimesters. The sleep state of pregnant women differed by age, with younger women experiencing more sleep trouble and feeling less rested compared to other groups. In future studies, the influences of sleep during pregnancy on the health and development of the children of these pregnant women will be clarified.

We examined the socio-demographic and behavioral factors associated with alcohol consumption before and after pregnancy awareness in pregnant women. This cross-sectional study included 91,828 pregnant women in a nationwide Japanese birth cohort study from 2011 to 2014. Alcohol consumption before and after pregnancy awareness, and sociodemographic behavioral characteristics were assessed through self-reported questionnaires. Determinants of alcohol consumption were investigated using logistic regression. Prevalence of alcohol consumption before and after pregnancy awareness was 50.0% and 2.8%, respectively. Most women consumed low to moderate levels of alcohol. Before pregnancy awareness, high educational level (odds ratios [OR] 1.11, 95% confidence interval [CI] 1.07 to 1.15), high household income (OR 1.16, 95% CI 1.09 to 1.24), and smoking (OR 1.77, 95% CI 1.65 to 1.90) were significantly associated with increased odds of alcohol consumption. After pregnancy awareness, older age (OR 1.73, 95% CI 1.54 to 1.94) and smoking (OR 5.57, 95% CI 4.88 to 6.37) were significantly associated with increased odds of alcohol consumption, and high education level (OR 0.72, 95% CI 0.64 to 0.81) and high household income (OR 0.75, 95% CI 0.63 to 0.89) were significantly associated with decreased odds of alcohol consumption. A half of women consumed alcohol before pregnancy awareness. Guidelines recommend abstinence from alcohol consumption in pregnant women for precaution, although influence of low to moderate levels of prenatal alcohol exposure on the fetus is inconclusive. Social-demographic characteristics differed between women who consumed alcohol before pregnancy awareness and women who continued alcohol after pregnancy awareness.

Vitamin D (VitD) may affect immune system modulation and result in the development of atopic dermatitis (AD). However, published findings have remained controversial. We investigated the association between early-life 25-hydroxyvitamin D (25(OH)D) levels and AD risk at childhood with a birth cohort. The data were obtained from “the Japan Environment and Children’s Study (JECS)” and “the Sub-Cohort study of JECS” performed with children aged 2 years. “Liquid chromatography-tandem mass spectrometry” was used to measure VitD. The information on AD was obtained from parents’ answers to a questionnaire when their children were aged 3 years. In order to explain the seasonal effects on VitD levels, a deseasonalized continuous variable was further calculated. The logistic regression models were fitted to evaluate the effect of VitD on childhood AD. The study included 4378 children with complete data on VitD and AD. The results from models indicated that low VitD at 2 years was not a risk factor for the development of AD at 3 years, after adjusting for potential confounders. Moreover, there was no U-shape relationship between deseasonalized VitD and childhood AD. Overall, early-life 25(OH)D levels were not link to the increased risk of developing childhood AD.

Background In recent years, a resurgence in the number of infants with vitamin D deficiency has been noted. In addition to seasonal differences in exposure to ultraviolet (UV) rays, regional differences in dietary habits and lifestyles may affect susceptibility to vitamin D deficiency. However, no studies have been conducted on infants in multiple regions of Japan to determine the extent of differences in vitamin D status. Methods The levels of 25-hydroxyvitamin D (25OHD) were measured by radioimmunoassay in 126 infants aged 2 to 4 years, who participated in the Pilot Study of the Japan Environment and Children's Study (JECS) by the Ministry of Environment of Japan. A multiple regression model with 25OHD level as the outcome variable, and season and region as explanatory variables was generated. Results A Wald test revealed that both region and season during which infants participated in this study significantly affected 25OHD levels (p-value = 0.0087 and

Objective Although environmental lead exposure has decreased, several studies have shown that low-level lead exposure can result in adverse psychological symptoms. However, few studies have examined lead neurotoxicity in pregnant women. We investigated the association between lead exposure and psychological symptoms in pregnant women, and between socio-economic status and blood lead levels. Methods Blood lead levels were measured in 17,267 pregnant women in the Japan Environment and Children’s Study. Odds ratios (ORs) for high blood lead levels were calculated using multinomial logistic regression. Psychological symptoms were assessed using the Kessler Psychological Distress Scale (K6). ORs for depression (K6 ≥ 13 or ≥5) were calculated using logistic regression with adjustment for potential confounders. Results The geometric mean of whole blood lead levels was 0.58 μg/dl (range 0.14–6.75 μg/dl). Higher blood lead levels were associated with older age (OR 1.79, 9 5% confidence interval [CI] 1.46–2.19), unmarried status (OR 1.75, 95 % CI 1.31–2.33), lower household income (OR 1.76, 95 % CI 1.38–2.24), and lower educational attainment (OR 1.34, 95 % CI 1.20–1.48). The percentage of women with K6 scores ≥13 and ≥5 was 3 % and 28.2 %, respectively. There was no significant association between lead exposure and K6 score (K6 ≥ 13: OR 1.00, 95 % CI 0.76–1.32; K6 ≥ 5: OR 0.98, 95 % CI 0.88–1.09). Conclusion Our results indicate a small but significant association between higher blood lead levels and lower socio-economic status in a population with low blood lead levels, but no association between low-level lead exposure and psychological symptoms.

Background: Although we recognise that immunization is indispensable to global elimination of various diseases, the adjuvants used in inactivated vaccines often upregulate type 2 immunity that is dominant in allergic diseases. On the other hand, BCG vaccine is known to induce type 1 immunity. We hypothesised that administration during infancy of a greater number of "initial" vaccines that contain adjuvants may influence the development of allergies later in life by changing the balance of type 1/type 2 immunity. Methods: We obtained information regarding vaccinations and allergic diseases by using questionnaires that were used in The Japan Environment and Children's Study (JECS), i.e., a nationwide, multicentre, prospective birth cohort study including 103,099 pregnant women and their children. We examined for associations between the history of vaccination before 6 months of age and symptoms related to allergies at 12 months of age. Findings: Our statistical analyses included 56,277 children. Physician-diagnosed asthma was associated with receiving 3 (aOR 1.395, 95% CI 1.028-1.893) or 4-5 different inactivated vaccines (aOR 1.544, 95% CI 1.149-2.075), compared with children who received only one inactivated vaccine. Similar results were found for two questionnaire-based symptoms, i.e., wheeze (aOR 1.238, 95% CI 1.094-1.401; 3 vaccines vs. a single vaccine) and eczema (aOR 1.144, 95% CI 1.007-1.299; 4 or 5 vaccines vs. a single vaccine). Interpretation: The prevalence of asthma, wheeze and eczema among children at 12 months of age was associated with having received a greater number of initial inactivated vaccines before 6 months of age. Although these results should be cautiously interpreted, we can at least postulate that development of better vaccines is needed to reduce the risk of later development of allergic diseases. Nevertheless, further studies should be conducted, and we are planning to extend the evaluation period until at least 13 years of age. Funding Statement: This study was funded and supported by the Ministry of the Environment, Japan. Declaration of Interests: All authors have no conflicts of interest related to this study. Ethics Approval Statement: The JECS protocol was reviewed and approved by the Ministry of the Environment’s Institutional Review Board on Epidemiological Studies and by the ethics committees of all participating institutions. Written informed consent was obtained from all participants (i.e. pregnant women or other caregivers). The JECS was conducted in accordance with the Helsinki Declaration and other nationally valid regulations and guidelines.

Objective The purpose of the study was to extend our understanding of the Kyoto Scale of Psychological Development (KSPD) by comparison with a parent-rated scale, the Kinder Infant Development Scale (KIDS). Methods The participants of this study were 229 children aged 0–4, who were referred to the Developmental Evaluation Center of the National Center for Child Health and Development, due to a suspected developmental disorder/delay. The participants were divided into subgroups, depending on age and overall DQ. For each group separately, correlation analyses were conducted between the Developmental Quotient (DQ) of each KSPD domain and DQ of each KIDS subscale. Results For high DQ group, in all ages, the KSPD Postural-Motor (P-M) domain DQ demonstrated a high correlation with the KIDS Physical–Motor DQ, and at young ages, it was also found to be moderately or strongly associated with the KIDS Manipulation DQ. For high DQ group, the KSPD Cognitive–Adaptive (C–A) domain DQ was most consistently related to the KIDS Manipulation DQ, and was also moderately correlated with the KIDS Physical–Motor DQ, Receptive Language DQ, Social Relationship with Adults DQ, Discipline DQ, and Feeding DQ, depending on age. For high DQ group, the KSPD Language–Social (L–S) DQ most consistently showed a moderate or high correlation with the KIDS Receptive Language DQ and the Manipulation DQ, and also related to Physical–Motor DQ, Expressive Language DQ, Language Conception DQ, Social Relationship with Adults DQ, and Social Relationship with Children DQ for some age groups. The low DQ group demonstrated stronger relationships on many of the pairs of the DQ of a KSPD subdomain and the DQ of a KIDS subscale, regardless of the type of subdomains and subscales. Conclusions For high DQ group, the KSPD P-M domain was consistently related to parent-reported physical/motor development, the C–A domain primarily reflected a child’s fine motor skills and his/her ability to understand and follow verbal instructions provided by adults, while the L–S domain was associated with parent-reported language ability. For low DQ group, the effect of global delay increased overall correlations between each domain and subscale. Further studies are necessary to replicate the findings in a larger sample including typical children.

Background In our prior randomized trial on preventing influenza, asthma attacks as a secondary outcome occurred less often in the vitamin D group than in the placebo group. We aimed to clarify whether low-dose, short-term vitamin D supplementation, in addition to standard treatments, improves control of childhood asthma. Methods We conducted a randomized, double-blind, placebo-controlled trial comparing vitamin D3 supplements (800 IU/day) with placebo for 2 months in schoolchildren with asthma. The primary outcomes were frequency and severity of asthma judging from changes in asthma control levels defined by the Global Initiative for Asthma (GINA) by collaborating doctors at 2 and 6 months. Results Japanese schoolchildren with asthma (n = 89) were randomly assigned to receive vitamin D (n = 54) or placebo (n = 35). At 2 months, GINA asthma control was significantly more improved in the vitamin D group compared with the placebo group (P = 0.015). Childhood asthma control test (CACT) scores, a secondary outcome, were also significantly (P = 0.004) improved in the vitamin D group compared with the placebo group at 2 months, and differences remained significant (P = 0.012) at 6 months. The proportion of patients with a peak expiratory flow rate

Because vitamin D may have beneficial effects on glucose metabolism in pregnant women with gestational diabetes mellitus, we explored whether maternal 25-hydroxyvitamin D (25OHD) levels in normal pregnancy have association with diabetes-related hormone levels and glycated albumin (GA). A prospective cohort study was performed to collect serum samples from 612 pairs of pregnant women and cord blood of their offspring. Levels of 25OHD and GA in maternal and cord blood were measured by radioimmunoassay and enzyme assay, respectively. Using cord serum, 12 diabetes-related hormones were assayed. Spearman’s rank correlation coefficient was used to quantify the strength of association between biomarkers. A prominent association between maternal and cord 25OHD levels (r = 0.76, 95% confidence intervals (CIs): 0.73–0.79, P < 0.0001) and weak association between maternal and cord GA (r = 0.22, 95% CIs: 0.14–0.30, P < 0.0001) were shown. Among the 12 diabetes-related hormones, both maternal and cord 25OHD levels showed prominent negative associations with glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These results suggest that decreased maternal 25OHD may be associated with decreased cord 25OHD and increased cord GLP-1 and GIP levels, which may be involved with the transfer of maternal glucose to the fetus.

Importance Children with food allergies may develop asthma or recurrent wheeze. Objective To evaluate whether asthma or recurrent wheeze among children were changed by avoiding supplementing breastfeeding (BF) with cow’s milk formula (CMF) in the first 3 days of life. Design, Setting, and Participants This randomized, unmasked, clinical trial was conducted at 1 university hospital in Japan beginning October 2013 with follow-up examinations occurring until January 2020. A total of 312 newborns at risk for atopy were randomized and assigned to either BF with or without amino acid–based elemental formula (EF) or BF with CMF, with follow-up examinations for participants showing signs of atopy conducted at 24 months. Follow-up examinations ran through January 2020. Interventions Immediately after birth, newborns were randomly assigned (1:1 ratio) to either breastfeeding with or without amino acid–based elemental formula for at least the first 3 days of life (no CMF group) or breastfeeding supplemented with CMF (≥5 mL/d) from the first day of life to 5 months of age (CMF group). Main Outcomes and Measures Asthma or recurrent wheeze diagnosed by the pediatric allergy specialists of this trial; subgroups were stratified by serum levels of 25-hydroxyvitamin D and IgE. Results Of 312 infants (156 [50.0%] randomized to the no CMF group), 302 (96.8%) were followed up at their second birthday: 77 of 151 (51.0%) in the no CMF group and 81 of 151 (53.6%) in the CMF group underwent extended follow-up because of having atopic conditions. Asthma or recurrent wheeze developed in 15 (9.9%) of the children in the no CMF group, significantly less than the children in the CMF group (27 [17.9%]; risk difference, −0.079; 95% CI, −0.157 to −0.002). In participants with vitamin D levels above the median at 5 months of age, asthma or recurrent wheeze developled in 5 (6.4%) children in the no CMF group, significantly less than in the children in the CMF group (17 [24.6%]; risk difference, −0.182; 95% CI, −0.298 to −0.067;P for interaction = .04). In the highest quartile group of total IgE at age 24 months, asthma or recurrent wheeze developed in 2 children (5.3%) in the no CMF group, significantly less than the children in the CMF group (14 [43.8%]; risk difference, −0.385; 95% CI, −0.571 to −0.199;Pfor interaction = .004). Conclusions and Relevance The findings of this study suggest that avoiding CMF supplementation in the first 3 days of life has the potential to reduce the risk of asthma or recurrent wheeze in young children, especially among those with high vitamin D or high IgE levels. Trial Registration umin.ac.jp/ctr Identifier:UMIN000011577

Objectives: No previous study has used repeated measures data to examine the associations of dog/cat ownership with wheezing and asthma prevalence among children. This prospective study used repeated measurers analysis to determine whether dog/cat ownership in childhood is an independent risk factor for wheezing and asthma, after adjustment for gestational, socio-economical, and demographical confounders confounders, in Japan. Methods: We conducted a multicenter pilot study of the Japan Environment and Children's Study (JECS) during 2009-2010. Among 440 newborn infants enrolled, 410 (52.8% males) were evaluated for dog/cat ownership in the home and history of wheezing and asthma in five follow-up questionnaire surveys (until age 6 years). Dog/cat ownership during follow-up period was categorized into four groups: 7.6% were long-term dog/cat owners, 5.9% were toddler-age owners, 5.9% were preschool-age owners, and 80.7% were never owners. Results: The prevalence of wheezing during follow-up period increased from 20.8% to 35.4% and the prevalence of asthma increased from 1.3% to 16.3%. A fitted logistic generalized estimating equation models including important confounders showed no significant associations of the interaction between dog and/or cat ownership and follow-up time with the risks of wheezing and asthma. However, the risks of wheezing and asthma were slightly lower for long-term and toddler-age dog/cat owners than for preschool-age and never owners. Conclusions: The present findings suggest that dog and cat ownership from toddler-age does not increase the risks of wheezing and asthma compared with never owners among Japanese children.

Importance Cow’s milk formula (CMF) is used to supplement breastfeeding (BF) at birth without clear clinical evidence to support the practice. Objective To determine whether avoiding supplementation with CMF at birth can decrease risks of sensitization to cow’s milk protein and/or clinical food allergy, including cow’s milk allergy (CMA), overall and in subgroups stratified by 25-hydroxyvitamin D (25[OH]D) levels. Design, Setting, and Participants The Atopy Induced by Breastfeeding or Cow’s Milk Formula (ABC) trial, a randomized, nonblinded clinical trial, began enrollment October 1, 2013, and completed follow-up May 31, 2018, at a single university hospital in Japan. Participants included 330 newborns at risk for atopy; of these, 312 were included in the analysis. Data were analyzed from September 1 through October 31, 2018. Interventions Immediately after birth, newborns were randomized (1:1 ratio) to BF with or without amino acid–based elemental formula (EF) for at least the first 3 days of life (BF/EF group) or BF supplemented with CMF (≥5 mL/d) from the first day of life to 5 months of age (BF plus CMF group). Main Outcomes and Measures The primary outcome was sensitization to cow’s milk (IgE level, ≥0.35 allergen units [UA]/mL) at the infant’s second birthday. Secondary outcomes were immediate and anaphylactic types of food allergy, including CMA, diagnosed by oral food challenge test or triggered by food ingestion, with food-specific IgE levels of at least 0.35 UA/mL. Subgroup analysis was prespecified by tertiles of serum 25(OH)D levels at 5 months of age. Results Of the 312 infants included in the analysis (160 female [51.3%] and 152 male [48.7%]), 151 of 156 (96.8%) in the BF/EF and BF plus CMF groups were followed up until their second birthday. The primary outcome occurred in 24 infants (16.8%) in the BF/EF group, which was significantly fewer than the 46 infants (32.2%) in the BF plus CMF group (relative risk [RR], 0.52; 95% CI, 0.34-0.81). The middle tertile of the 25(OH)D subgroup, but not the low and high tertiles, had a significant interaction with the intervention (RR, 0.19; 95% CI, 0.07-0.50;P = .02). The prevalence of food allergy at the second birthday was significantly lower in the BF/EF than in the BF plus CMF groups for immediate (4 [2.6%] vs 20 [13.2%]; RR, 0.20; 95% CI, 0.07-0.57) and anaphylactic (1 [0.7%] vs 13 [8.6%]; RR, 0.08; 95% CI, 0.01-0.58) types. Conclusions and Relevance The evidence suggests that sensitization to cow’s milk and food allergy, including CMA and anaphylaxis, are primarily preventable by avoiding CMF supplementation for at least the first 3 days of life. Trial Registration http://umin.ac.jpIdentifier:UMIN000011577

Background Children with Down syndrome (DS), who are likely to suffer from a large number of muscloskeletal problems, tend to have a unique pattern of walking in clinical settings. Despite such apparent uniqueness, few studies have empirically investigated gait development pattern in DS children, especially at an earlier age. We therefore conducted gait analysis in young DS children who are prescribed insoles, to explore how their gait patterns develop, using the gait parameters identified by Sutherland et al. as determinants of gait maturity of typical children. Methods Participants consisted of 63 DS children (31 boys) aged 1–6 years (mean, 4 years 1 month) with a diagnosis of flat feet who were prescribed orthotic insoles. A 2.4 m sheet-type gait analyzer was used to analyze gait pattern. We measured the following variables: walking velocity (cm/min), cadence (steps/min), step length (cm), and single-limb stance phase ratio (%), and examined their relationship with age on regression analysis. Results Walking velocity and step length were significantly and positively related to age. Cadence was also significantly, but negatively associated with age. In contrast, SLS phase ratio did not have a statistically significant relationship with age. Conclusion Down syndrome children have unique gait development patterns. Although walking velocity, cadence, and step length were found to develop with age, as in typical children, SLS phase ratio did not change with age in DS children. Further studies with a larger sample are necessary to replicate these findings.

As a new screening tool for neuromotor development in children aged two, we developed the Neuromotor 5 min Exam 2-year-old version (N5E2), which can be easily administered by pediatricians or primary care physicians. In this study, as an initial attempt to examine the utility of the N5E2, the inter-rater reliability on scoring for the individual items in this scale was assessed.The participants of the study were 29 children (aged 1-5 years, mean age = 2.79) diagnosed with a variety of neuromotor/developmental disorders/high-risk conditions. Inter-rater reliability was examined on the following 11 items in the N5E2: (1) Retrieving a rolling ball, (2) Gait, (3) Toe-walking, (4) Asymmetries of posture and/or movement, (5) Age at unsupported walking, (6) Speaking in two-word understandable sentences, (7) Hypotonus, (8) Hypertonus, (9) Eye movement, (10) Vision problem, (11) Hearing problem. The items were administered to children by two pediatricians with different expertise and clinical experience, separately.The results showed that among the eleven items in the N5E2 examined, a high level of agreement (κ ≥ 0.60) was found on 4 items, and a moderate level of agreement (0.40 ≤ κ 0.60) was found on 5 items. The level of agreement somewhat improved after the dichotomization of the score; using this format, a high level of rater agreement (κ ≥ 0.60) was found on 6 out of 11 items. The analyses also revealed high inter-rater reliability on the sum score of the 11 items (r = 0.84).The results suggest the possibility that this brief screening tool could be feasible in settings where clinicians' experience varies, based on its inter-rater reliability on individual items between the clinicians with different expertise and amount of clinical experiences.

Background To elucidate whether maternal vitamin D supplementation during lactation improves infantile eczema and other subsequent allergic disorders, a randomized, double-blind, placebo-controlled trial was performed. Methods Mothers (n = 164) of infants with facial eczema at 1 month check-up were randomly assigned to receive vitamin D3 supplements (n = 82; 800 IU/day) or placebo (n = 82) for 6 weeks from May 2009 to January 2011. The primary outcome was infantile eczema quantified on Scoring Atopic Dermatitis (SCORAD) index at 3 month check-up, and the secondary outcomes were atopic dermatitis, food allergy, and wheeze diagnosed by doctors up to 2 years of age. Results There was no significant difference in SCORAD at 3 month check-up between the two groups. Doctor-diagnosed food allergy was significantly more common up to age 2 years in the vitamin D group (10/39, 25.7%) than in the placebo group (3/40, 7.5%; risk ratio (RR), 3.42; 95% confidence interval [CI]: 1.02–11.77; P = 0.030). Moreover, at least one secondary outcome was also significantly more common in the vitamin D group (17/39, 43.6%) than in the placebo group (7/40, 17.5%; RR, 2.49; 95%CI: 1.16–5.34; P = 0.012). Conclusions Vitamin D supplementation may not decrease the severity of infantile eczema at 3 months of age, but may rather increase the risk of later food allergy up to 2 years of age. Because a large number of subjects was lost to follow up, further study is needed to confirm the findings.

Objective: The purpose of this study was to evaluate the characteristics of intellectual function of children whose mother had thyroid dysfunction, as well as children with hypothyroidism. Methods: A total of 47 children aged five to seven, who were referred to the center for developmental evaluation at the national child health and development in Tokyo, Japan, were included in this study. The children were divided into two groups: Group A, children with euthyroidism whose mothers had thyroid dysfunction; Group B, children with hypothyroidism. For each group, unpaired t-test was conducted by comparing with the scores of the Japanese version of the Wechsler intelligence scale for children-fourth edition (WISC-IV). Results: There were 26 children in Group A, 21 in Group B. The scores of Full Scale Intelligence Quotient (FSIQ), Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working Memory Index (WMI) and Processing Speed Index (PSI) by WISC-IV were significantly higher in Group A than Group B (FSIQ, VCI; P < 0.01, PRI, WMI, PSI; P < 0.05). Conclusions: There were differences in intellectual function between the children with hypothyroidism and the children who did not have low thyroid hormone level. Low level of thyroid hormone during the neonatal period may be important for intellectual development.

Background: The Japan Environment and Children’s Study (JECS) is a nation-wide birth cohort study involving 100,000 parent-child pairs that was conducted by the Japanese Ministry of the Environment. This study was started in 2011 to evaluate the effect of various environmental factors on children’s health and development. Health outcomes and exposure measurements will continue until the participating children become 13 years old. Method: Exposure to environmental factors was assessed by chemical analyses of bio-specimens (blood, cord blood, urine, breast milk, and hair), household environmental measurements, and computational simulations using monitoring data, as well as questionnaires. The JECS’s priority outcomes include reproduction/pregnancy complications, congenital anomalies, neuropsychiatric disorders, immune system disorders, including Kawasaki disease (KD), and metabolic/endocrine system disorders. Genetic factors, socioeconomic status, history of infection, and lifestyle factors were also examined as covariates and potential confounders. Results: Some of the questionnaires for children under 2 years old have already been collected. The numbers of patients with KD according to age were as follows: 14/71,133 (0.02%) between 0-6 months old, 102/51,351 (0.2%) between 6-12 months old, 71/34,595 (0.21%) between 12-18 months old, and 20/20,995 (0.1%) between 18-24 months old. According to these results, the estimated incidence of KD in children younger than 2 years old could reach more than 0.5%, but this number may increase after further collection of questionnaires. We also conducted a secondary survey regarding KD patients, including family history, clinical symptoms, laboratory data, treatment, and outcome. Conclusion: Recently, similar birth cohorts to JECS were already initiated in many countries, but this is the first large-scale birth cohort focusing KD. The results of this cohort may shed new light on the environmental pathogenesis of KD.

Background The Japan Environment and Children’s Study (JECS) is a nationwide, multicenter, prospective birth cohort investigation launched by the Ministry of Environment in Japan. The purpose of the JECS is to evaluate the influence of prenatal and postnatal exposures to environmental factors on the postnatal health of the children. In this study, we evaluated the allergic characteristics of parents within the JECS cohort. Methods This study covered a wide geographical area and encompassed 15 regional centers. We obtained information regarding doctor diagnosed allergic diseases by using maternal and/or paternal self-administered questionnaires during the first trimester of pregnancy. Blood samples were also obtained from mothers and/or fathers to detect serum IgE concentrations. Results The prevalences of asthma, allergic rhinitis (hay fever), atopic dermatitis, and food allergy were 10.9, 36.0, 15.7 and 4.8%, respectively, among 99,013 mothers; these prevalences among 49,991 fathers were 10.8, 30.3, 11.2 and 3.3%, respectively. Any positive antigen-specific IgE sensitization was found in 73.9% of mothers. The most abundant antigen sensitization in mothers was to Japanese cedar (55.6%), followed by Der p 1 (48%); only 1.0% of mothers were sensitized to egg white. Conclusions This is the first epidemiological report on allergic disorders and allergen sensitization of parents during pregnancy among the Japanese general population. Electronic supplementary material The online version of this article (doi:10.1186/s40413-017-0157-0) contains supplementary material, which is available to authorized users.

Children with Down syndrome (DS), who are likely to suffer from a large number of musculoskeletal problems, tend to have a unique pattern of walking in clinical settings. Despite such apparent uniqueness, few studies have empirically investigated gait development pattern in DS children, especially at an earlier age. We therefore conducted gait analysis in young DS children who are prescribed insoles, to explore how their gait patterns develop, using the gait parameters identified by Sutherland et al. as determinants of gait maturity of typical children.Participants consisted of 63 DS children (31 boys) aged 1-6 years (mean, 4 years 1 month) with a diagnosis of flat feet who were prescribed orthotic insoles. A 2.4 m sheet-type gait analyzer was used to analyze gait pattern. We measured the following variables: walking velocity (cm/min), cadence (steps/min), step length (cm), and single-limb stance phase ratio (%), and examined their relationship with age on regression analysis.Walking velocity and step length were significantly and positively related to age. Cadence was also significantly, but negatively associated with age. In contrast, SLS phase ratio did not have a statistically significant relationship with age.Down syndrome children have unique gait development patterns. Although walking velocity, cadence, and step length were found to develop with age, as in typical children, SLS phase ratio did not change with age in DS children. Further studies with a larger sample are necessary to replicate these findings.

When an effective pain relief cannot be achieved by systemic administration of analgesics, which provide adequate pain relief for up to 70 to 90 percent of patients, alternative remedies should be offered. We reported a patient with colon cancer who was effective for pain control using an epidural catheter with subcutaneous reservoir (epidural subcutaneous catheter implantation). Four other patients with an epidural catheter with subcutaneous reservoir during 2007 to 2008 also showed significant improvement in their pain level calculating by numerical rating scale (NRS). Furthermore we were able to minimize the risk of infection for homecare. However the epidural catheter with subcutaneous reservoir should be needed not only to manage dosages of epidural morphine accurately but also to prevent the incidence of catheter obstruction by general practitioners in home care service. This solution is necessary to establish the common strict guidelines between hospital doctors and general practitioners.

In a prior randomized trial, we found that the incidence of influenza A was less in the vitamin D3 group than among those on placebo, but the total incidence of either influenza A or B did not differ between groups. In this trial, the incidence of influenza A or B was less in the vitamin D3 group than in the placebo group only during the first half of the study. To elucidate whether vitamin D3 has preventive actions against influenza A, we conducted another trial during the 2009 pandemic of the H1N1 subtype of influenza A. Students (n = 247) of a Japanese high school were randomly assigned to receive vitamin D3 supplements (n = 148; 2000 IU per day) or a placebo (n = 99) in a double-blind study for 2 months. The primary outcome was incidence of influenza A diagnosed by a rapid influenza diagnostic test by medical doctors. Influenza A was equally likely in the vitamin D3 group (20/148: 13.5%) compared with the placebo group (12/99: 12.1%). By post hoc analysis, influenza A occurred significantly less in the vitamin D3 group (2/148: 1.4%) compared with the placebo group (8/99: 8.1%) (risk ratio, 0.17; 95% confidence interval, 0.04 to 0.77; P = 0.009) in the first month. However, during the second month, the vitamin D3 group experienced more events and effectively caught up with the placebo group. Vitamin D3 supplementation did not lower the overall incidence of influenza A during the 2009 H1N1 pandemic. A post hoc analysis suggests that the initial benefit during the first month of treatment was lost during the second month.