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Many parents worry about their infants' skin conditions, which can greatly impact their quality of life (QOL). This is applicable even to skin problems that are not severe enough to require medical intervention. This study aimed to explore the impact of infants' skin problems on their mothers' QOL depending on the type of the problems. Mothers' QOL was measured using the Dermatitis Family Impact questionnaire (DFI), and a DFI score of 2 or higher was defined as impacting mothers' QOL. A total of 143 mothers believed their infants had skin problems and completed the DFI. Twenty-eight mothers (19.6%) of infants with eczema had an impacted QOL. Diaper dermatitis and facial skin problems significantly affected mothers' QOL (p = 0.042 and 0.031, respectively). In conclusion, diaper dermatitis and facial skin problems in infants can affect mothers’ QOL. Pediatric and perinatal health professionals should consider such impacts and provide support and reassurance to parents.

Background Evidence regarding independent effects of maternal smoking in different time frames of pregnancy and maternal exposure to secondhand smoke on the development of wheeze/asthma in her offspring is limited. We aimed to investigate the effect of maternal exposure to tobacco smoke on wheeze/asthma development at 1 year of age in her offspring using data from the nationwide birth cohort study in Japan. Methods Pregnant women who lived in the 15 designated regional centers throughout Japan were recruited. We obtained information about maternal smoking or secondhand smoke status and wheeze/asthma development in the offspring from a self-administered questionnaire. Results We analyzed 90,210 singleton births. Current maternal smoking during pregnancy increased the risks of wheeze/asthma in the offspring compared with no maternal smoking (wheeze: 1–10 cigarettes/day: adjusted odds ratio (aOR) 1.436, 95% CI 1.270–1.624; ≧11 cigarettes/day: aOR 1.669, 95% CI 1.341–2.078; asthma: 1–10 cigarettes/day: aOR 1.389, 95% CI 1.087–1.774; ≧11 cigarettes/day: aOR 1.565, 95% CI 1.045–2.344). Daily maternal exposure to secondhand smoke during pregnancy also increased the risks of wheeze/asthma in her offspring compared with no secondhand smoke exposure (wheeze: aOR 1.166, 95% CI 1.083–1.256; asthma: aOR 1.258, 95% CI 1.075–1.473). The combination of current maternal smoking during pregnancy and maternal history of allergy increased the risks of wheeze/asthma in her offspring (wheeze: aOR 2.007, 95% CI 1.739–2.317; asthma: aOR 1.995, 95% CI 1.528–2.605). Conclusions We found that current maternal smoking and maternal secondhand smoke exposure during pregnancy increased the risks of wheeze and asthma in her offspring.

Background Wheezing is a common symptom in infants, which may occasionally develop into asthma. There are many factors related to infant wheezing, including anatomical features, viral infections, and passive smoking. There are only a few reports on the association between renovation and pregnancy worldwide, and reports on this association are inadequate in Japan. This study aimed to examine the association between house renovation and new construction during pregnancy and wheezing in infants during the first year of life using data from the Japan Environment and Children's Study (JECS). Methods Data of pregnant women registered in JECS were collected using self-administered questionnaires during the second/third trimester and 1 month after delivery. Childbirth records were completed by the doctors. Similarly, wheezing in infants was evaluated using self-administered questionnaires 1 year after birth. Logistic regression analysis was used to determine the primary outcome. Results In total, 75,731 infants, excluding those with unknown gender, who were not singleton infants, and who relocated during pregnancy and the first month of life, were examined in this study. Renovation during pregnancy increased the prevalence of wheezing (odds ratio [OR]: 1.33, 95% confidence interval [CI]: 1.20–1.48) and recurrent wheezing (OR: 1.22, 95% CI: 1.00–1.48) in the first year of life. The relationship between new construction during pregnancy and wheezing in infants was insignificant (OR: 0.98, 95% CI: 0.90–1.06). Conclusions Renovation during pregnancy may be a risk factor for wheezing in infants, and should be avoided.

Objective Both maternal prepregnancy body mass index (BMI) and gestational weight gain (GWG) influence maternal and pediatric outcomes. We sought to clarify the impact of prepregnancy BMI-specific GWG and its patterns on the risk of low birth weight (LBW) or macrosomia using data from a large nationwide study in Japan. Methods This cohort study (n = 98,052) used data from the Japan Environment and Children’s Study (JECS). The outcome variables in this study were LBW and macrosomia. We stratified the subjects into groups according to prepregnancy BMI. Results GWG from pre-pregnancy to the first trimester had a small effect on the risk of LBW and macrosomia. From the first to second trimesters, insufficient GWG was associated with the risk of LBW, and from the second trimester to delivery, a GWG of less than 2 kg was associated with the risk of LBW. These associations were commonly observed in all prepregnancy BMI categories. Irrespective of the GWG from pre-pregnancy to the first trimester, GWG from the first to second trimesters affects LBW and/or macrosomia. Irrespective of the GWG from the first to second trimesters, GWG from the second trimester to delivery affects LBW and/or macrosomia. LBW or macrosomia was associated with the prevalence of a sustained low or high BMI percentile until three years of age, respectively. Conclusions The present large national cohort study indicates that the risk of LBW or macrosomia is associated with GWG in women in Japan; the significance of this risk depends on the GWG patterns.

Atopic dermatitis (AD) mostly develops in early childhood and tends to resolve with age. However, its time course in severity before and after adolescence varies widely among patients. To investigate the course of disease severity from birth to 19 years old of adult patients with AD, we conducted a nationwide Web-based survey of 3090 Japanese adult subjects diagnosed with AD, using a questionnaire to choose a pattern that most resembled their own out of 10 courses of AD severity. Patients in the 20s and 30s age groups tended to choose the option "gradually improved" or "improved by the age of 12", but patients in the 40s or older age group tended to choose the option "aggravation between the age of 12 and 19". Those who chose "AD development at age 20 or older" increased as the generation was older. This survey revealed that the time course of AD severity from birth to 19 years old varies depending on the generation targeted in this study. It is presumed that the acquired factors affecting the natural history of AD have changed over the past 50 years in Japan.

Background A variety of dietary supplements are commercially available. However, the efficacy and safety of dietary supplement use in children are not well established. Understanding dietary supplement use is important for developing public health policy regarding dietary supplements. This study aimed to investigate the types of dietary supplements used and characteristics of dietary supplement users among Japanese elementary school children. Method We conducted a cross-sectional web-based questionnaire study. Dietary supplement use, socio-demographics, and health-related behaviors were assessed through mother-reported questionnaire. Types of dietary supplements were identified based on ingredient using product barcodes and brand names. Multivariate logistic regression analysis was conducted to investigate the socio-demographics and health-related behaviors associated with supplement use. Results Among 4933 children, 333 (6.8%) were identified as dietary supplement users. The most common supplement was amino acids or protein (1.4%), followed by n–3 fatty acids or fish oil (1.0%), probiotics (1.0%), multivitamins (0.9%), multivitamin-minerals (0.8%), and botanicals (0.8%). Overall, any dietary supplement use was significantly associated with the highest frequency of sports participation (odds ratio [OR], 2.58; 95% confidence interval [CI], 1.65–4.02), highest household income (OR, 1.87; 95% CI, 1.13–3.10), highest maternal educational level (OR, 1.82; 95% CI, 1.31–2.52), and male sex (OR, 1.38; 95% CI, 1.09–1.75). The highest frequency of sports participation was significantly associated with higher odds of use of amino acids or protein (OR, 6.06; 95% CI, 1.78–20.6) and multivitamins (OR, 3.56; 95% CI, 1.11–11.5), compared to the lowest frequency of sports participation. Conclusion This study showed that Japanese children primarily use non-vitamin, non-mineral supplements. Non-vitamin, non-mineral supplements should thus be included in future studies aimed at monitoring dietary supplement use. We also found that dietary supplement use in children was associated with sports participation. Guidelines for dietary supplement use for children, in particular sport participants, are needed.

Prostaglandin D2 (PGD2 ) plays an important role in atopic dermatitis (AD), and 11,15-dioxo-9α-hydroxy-2,3,4,5-tetranorprostan-1,20-dioicacid (PGDM) is a major metabolite of PGD2 . We investigated the relationship between urinary PGDM levels and severity of paediatric AD. In total, 31 patients with AD and 21 healthy controls (HCs) without AD were recruited, and urinary PGDM levels were measured. Of the 31 patients with AD, 14 were reassessed for urinary PGDM after topical steroid therapy. There was no difference in urinary PGDM levels between patients with AD and HCs. Although there was a significant positive correlation between the SCORing Atopic Dermatitis (SCORAD) index and the serum level of thymus and activation-regulated chemokine (TARC), the urinary PGDM levels did not correlate with either SCORAD or serum TARC. Moreover, both SCORAD and serum TARC were significantly improved by topical steroid therapy; however, urinary PGDM levels were not changed. In conclusion, the level of urinary PGD2 metabolites in children with AD is substantially the same as that in HCs even if the disease is severe.

Aims/Introduction We aimed to evaluate the metabolic status of pregnant women by assessing metabolic biomarkers of participants in the Japan Environment and Children’s Study, a nationwide, multicenter, pregnancy and birth cohort. Materials and Methods Pregnant women aged 14–50 years were studied in 15 centers across Japan. Clinical information was obtained using self‐administered questionnaires. Blood samples were taken during the first two trimesters to measure metabolic biomarkers. Samples were divided into seven groups according to the weeks of pregnancy. Results Among 82,972 pregnant women, 43 had only type 1 diabetes, 78 had only type 2 diabetes, 2,315 had only gestational diabetes and 354 had only dyslipidemia. Glycated hemoglobin, total cholesterol, low‐density lipoprotein cholesterol and triglyceride across all the percentiles increased as prepregnancy body mass index increased, whereas high‐density lipoprotein cholesterol levels across all the percentiles decreased as body mass index increased. Glycated hemoglobin was high in participants with type 1 diabetes or type 2 diabetes only, but not in those with gestational diabetes or hyperlipidemia only. Participants with type 2 diabetes or dyslipidemia only had high triglyceride in the first trimester, which then decreased in the second trimester. Participants with type 2 diabetes only also showed low high‐density lipoprotein cholesterol, whereas participants with dyslipidemia only showed high total cholesterol and low‐density lipoprotein cholesterol throughout. Conclusions Metabolic biomarkers were affected by blood sample timing and underlying metabolic disease. The Japan Environment and Children’s Study will clarify the influences of metabolic status during pregnancy on the health and development of the offspring in future studies., This is the first study to describe the metabolic status of a large cohort of pregnant women aged 14–50 years and living in Japan.

The Japanese Guideline for Childhood Asthma (JGCA) 2020 is a translation of the Japanese Pediatric Guideline for the Treatment and Management of Asthma (JPGL) 2017 into English, which was published by the Japanese Society of Pediatric Allergy and Clinical Immunology. It makes recommendations for best practices in the management of childhood asthma, including management of acute exacerbations and non-pharmacological and pharmacological management. These guidelines will be of interest to non-specialist physicians involved in the care of children with asthma. In JPGL, JPGL2017 is the first evidence-based guidelines updated according to the GRADE system and Minds approach, and it addresses eight clinical questions about the treatment of childhood asthma. In children aged ≤5 years, infant and preschool asthma is diagnosed according to the response to short acting beta2 agonists or the effect of a therapeutic trial during 1 month with controller treatment and worsening after treatment cessation. Long-term management both promotes pharmacological therapy and measures against risk factors that induce exacerbation, better patient education and a partnership with trinity. In addition, long-term management should not be carried out without review but rather be based on a cycle of evaluation, adjustment and treatment. In JPGL2017, the transdermal patch and oral beta2 agonists are positioned as drugs within the concept of "short-term additional treatment" to be used until the symptoms are stabilized when the control state transiently deteriorates.

Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion, which is frequently encountered in clinical practice. Skin barrier dysfunction leads to enhanced skin irritability to non-specific stimuli and epicutaneous sensitization. In the lesion site, a further inflammation-related reduction in skin barrier function, enhanced irritability and scratching-related stimuli deteriorate eczema, leading to vicious cycle of inflammation. The current strategies to treat AD in Japan from the perspective of evidence-based medicine consist of three primary measures: (i) the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice.

Five years have passed since the Japanese Pediatric Guideline for Food Allergy (JPGFA) was first revised in 2011 from its original version. As many scientific papers related to food allergy have been published during the last 5 years, the second major revision of the JPGFA was carried out in 2016. In this guideline, food allergies are generally classified into four clinical types: (1) neonatal and infantile gastrointestinal allergy, (2) infantile atopic dermatitis associated with food allergy, (3) immediate-type of food allergy (urticaria, anaphylaxis, etc.), and (4) special forms of immediate-type of food allergy such as food-dependent exercise-induced anaphylaxis and oral allergy syndrome (OAS). Much of this guideline covers the immediate-type of food allergy that is seen during childhood to adolescence. Infantile atopic dermatitis associated with food allergy type is especially important as the onset of most food allergies occurs during infancy. We have discussed the neonatal and infantile gastrointestinal allergy and special forms of immediate type food allergy types separately. Diagnostic procedures are highlighted, such as probability curves and component-resolved diagnosis, including the recent advancement utilizing antigen-specific IgE. The oral food challenge using a stepwise approach is recommended to avoid complete elimination of causative foods. Although oral immunotherapy (OIT) has not been approved as a routine treatment by nationwide insurance, we included a chapter for OIT, focusing on efficacy and problems. Prevention of food allergy is currently the focus of interest, and many changes were made based on recent evidence. Finally, the contraindication between adrenaline and antipsychotic drugs in Japan was discussed among related medical societies, and we reached an agreement that the use of adrenaline can be allowed based on the physician's discretion. In conclusion, this guideline encourages physicians to follow the principle to let patients consume causative foods in any way and as early as possible.

Background Sampling of salivary cortisol is non-invasive and important for the evaluation of the hypothalamic-pituitary-adrenal axis function and stress levels. However, the reference values for salivary cortisol measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in healthy infants are unclear. The aim of this study was to establish the reference values for salivary cortisol levels in healthy infants. Methods This study was a prospective observational cohort study following the participants until the age of 6 months. We analyzed 71 healthy, full-term infants at age 1 month between December 2017 and March 2018. We repeated saliva sampling every month, measured the salivary cortisol levels in the early morning by LC-MS/MS, and took the subjects' medical history by questionnaire. Results The minimum, 25th, 50th, 75th percentile, and maximum salivary cortisol levels were 0.08, 1.11, 2.21, 5.18, and 30.35 nmol/L, respectively. Conclusions We established the reference values for salivary cortisol in young infants using LC-MS/MS.

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.

Background The study aim was to obtain epidemiological data on vitamin D levels for the pediatric population in Japan. We assessed the prevalence of vitamin D deficiency and insufficiency in 2-year-old Japanese children using data from a large ongoing birth cohort study. Methods Data for analysis was obtained from the Japan Environment and Children’s Study (JECS) and a Sub-Cohort Study (SCS) of JECS. We evaluated the children’s serum 25(OH) D levels by 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles, and the rates of vitamin D deficiency or insufficiency. We also presented a weighted prevalence rate for vitamin D deficiency or insufficiency among all children in JECS. Results After excluding children with missing 25(OH)D2 or 25(OH)D3 data, we analyzed 4655 remaining children, of whom 24.7% (95% CI, 23.5–26.0%) had vitamin D deficiency ( Conclusion We analyzed data on serum 25(OH) D levels from a birth cohort study and found that vitamin D deficiency and insufficiency are very common among 2-year-old Japanese children. Sex, season, and latitude affect serum 25(OH) D concentrations.

This prospective cohort study aimed to examine the associations between mold growth, type of stoves, and fragrance materials and early childhood wheezing and asthma, using data from the Japan Environment and Children's Study. Mold growth at home, usage of kerosene/gas stove, wood stove/fireplace, and air freshener/deodorizer were surveyed using a questionnaire at 1.5-year-old, and childhood wheezing and doctor-diagnosed asthma during the previous year were obtained using a 3-year-old questionnaire. Multilevel logistic regression analysis was performed to evaluate the association between exposure to childhood wheezing and asthma. A total of 60 529 children were included in the analysis. In multivariate analyses, mold growth and wood stove/fireplace had significantly higher odds ratios (ORs) for wheezing (mold growth: 1.13; 95% CI, 1.06-1.22; wood stove/fireplace: 1.23; 95% CI, 1.03-1.46). All four exposures had no significant ORs for childhood doctor-diagnosed asthma; however, in the supplemental analysis of northern regions, wood stove/fireplace had a significantly higher OR for asthma. Mold growth and wood stove/fireplace had significant associations with childhood wheezing in the northern regions. Mold elimination in the dwellings and use of clean heating (no air pollution emissions) should be taken into consideration to prevent and improve childhood wheezing and asthma.

We examined the association between maternal air purifier use during pregnancy and neurodevelopmental delay in toddlers by analysing data from 82,457 mother-toddler pairs. Air purifier use was measured using a simple yes/no question. Developmental delays at 1.5, 2.0, 2.5, and 3.0 years were assessed using the Ages and Stages Questionnaire, Third Edition. Generalized additive mixed model analysis with 21 covariates revealed that air purifier use was associated with lower prevalence of developmental delay in all five areas—communication, gross motor, fine motor, problem solving, and personal-social—at all four time points (adjusted risk ratios ranged from 0.827 to 0.927, and only one 95% confidence interval crossed the reference). These findings suggest a negative association between air purifier use during pregnancy and neurodevelopmental delay in toddlers.Trial registration: UMIN000030786 (15/01/2018).

The prevalence of allergic diseases, such as bronchial asthma, atopic dermatitis, nasal allergies (pollinosis), and food allergies, has been increasing in many countries. The hygiene hypothesis was recently considered from the perspective of exposure to antimicrobial agents and preservatives, such as parabens (CAS number, 94-13-3). It currently remains unclear whether parabens, which are included in many daily consumer products such as cosmetics, shampoos, and personal care products as preservative antimicrobial agents, induce or aggravate allergies. Therefore, the aim of the present study was to examine the relationship between exposure to parabens and the prevalence of allergic diseases in Japanese children. The cross-sectional epidemiology of 236 children aged 0–3 years who underwent health examinations in Shika town in Japan assessed individual exposure to parabens using urinary concentrations of parabens. The results obtained showed that the prevalence of atopic dermatitis was significantly higher in children with high urinary concentrations of parabens than in those with low concentrations (p &lt, 0.001). This relationship remained significant after adjustments for confounding factors, such as age, sex, Kaup’s index, and passive smoking (p &lt, 0.001). In conclusion, the present results from a population study suggested a relationship between atopic dermatitis and exposure to parabens. A longitudinal study using a larger sample number and a detailed examination of atopic dermatitis, including EASI scores and exposure to parabens, will be necessary.

Objective Ultra-sensitive hormone assays have detected slight sex differences in blood estradiol (E2) levels in young children before adrenarche. However, the origin of circulating E2 in these individuals remains unknown. This study aimed to clarify how E2 is produced in young girls before adrenarche. Design This is a satellite project of the Japan Environment and Children’s Study organized by the National Institute for Environmental Studies. Methods We collected blood samples from healthy 6-year-old Japanese children (79 boys and 71 girls). Hormone measurements and data analysis were performed in the National Institute for Environmental Studies and the Medical Support Center of the Japan Environment and Children’s Study, respectively. Results E2 and follicle stimulating hormone (FSH) levels were significantly higher in girls than in boys, while dehydroepiandrosterone sulfate (DHEA-S) and testosterone levels were comparable between the two groups. Girls showed significantly higher E2/testosterone ratios than boys. In children of both sexes, a correlation was observed between E2 and testosterone levels and between testosterone and DHEA-S levels. Moreover, E2 levels were correlated with FSH levels only in girls. Conclusions The results indicate that in 6-year-old girls, circulating E2 is produced primarily in the ovary from adrenal steroids through FSH-induced aromatase upregulation. This study provides evidence that female-dominant E2 production starts several months or years before adrenarche. The biological significance of E2 biosynthesis in these young children needs to be clarified in future studies.

Atopic dermatitis (AD) is the most common inflammatory skin disease in children. The serum level of thymus and activation-regulated chemokine (TARC) is a useful AD index to reflect disease severity; however, it requires blood collection from young children. In comparison, urine samples are easier to collect in a pediatric clinical setting. Here, we analyzed the lipids excreted in urine to identify a diagnostic biomarker for AD. We generated a murine dermatitis model by repeated topical application of 2,4-dinitrofluorobenzene (DNFB) or tape-stripping the dorsal skin. Lipid metabolites excreted in the urine were comprehensively analyzed using liquid chromatography-tandem mass spectrometry. To corroborate our findings, we also analyzed urine samples from patients with AD. DNFB application induced AD-like skin lesions, including epidermal thickening, infiltration of eosinophils and T cells, and an increase in Th2 cytokine levels. Assessment of lipids excreted in urine showed a dominance of prostaglandins (PGs), namely, a PGF2α metabolite (13,14-dihydro-15-keto-tetranor-PGF1α ), a PGE2 metabolite (13,14-dihydro-15-keto-tetranor-PGE2 ), and a PGD2 metabolite (13,14-dihydro-15-keto PGJ2 ). mRNA and protein expression of PGF2α , PGE2 , and PGD2 synthase was upregulated in DNFB-treated skin. The tape-stripping model also caused dermatitis but without Th2 inflammation; urine PGF2α and PGD2 metabolite levels remained unaffected. Finally, we confirmed that the urinary levels of the aforementioned PG metabolites, as well as PGI2 metabolite, 6,15-diketo-13,14-dihydro-PGF1α and arachidonic acid metabolite, 17-hydroxyeicosatetraenoic acid (17-HETE) increased in patients with AD. Our data highlights the unique urinary lipid profile in patients with AD, which may provide insight into novel urinary biomarkers for AD diagnosis.

BACKGROUND Children with allergic clinical manifestations tend to have behavioral or emotional problems such as hyperactivity or worse mental health. However, previous studies on this association did not adequately adjust for confounders like parenting stress, demographic characteristics, or allergy presentation. This study aimed to investigate the relationship between childhood allergic clinical manifestations and behavioral problems, adjusting for confounders such as demographic characteristics, parenting stress, and allergy-related variables. METHODS We conducted an online cross-sectional survey among caregivers of children aged 2-6 years (n = 633). The Strengths and Difficulties Questionnaire (SDQ) was used to determine children's behavioral characteristics as the primary outcome. Allergic clinical manifestations, wheeze, rash, and nose symptoms were the exposure variables. Associations were estimated using logistic regression analyses with propensity scores to adjust for confounders. RESULTS We analyzed 633 caregivers of children aged 2-6 years (valid rate, 61.5%). Univariate analyses showed that wheezing was associated with conduct problems (odds ratio [OR] = 1.48, 95% confidence interval [CI]:1.01-2.16), a behavioral component of the SDQ. Rash was also associated with hyperactivity (OR = 1.62, 95% CI: 1.02-2.57). Furthermore, nose symptoms were associated with conduct problems (OR = 1.65, 95% CI:1.16-2.33) and emotional symptoms (OR=1.62, 95% CI:1.06-2.45). After adjusting for potential confounders, wheezing (adjusted OR = 1.69, 95% CI:1.04-2.75) and nose symptoms (adjusted OR = 1.56, 95% CI: 1.05-2.34) remained associated with conduct problems. CONCLUSIONS This study revealed that a history of wheezing and nose symptoms in children is associated with an increased risk of behavioral problems, in particular, conduct problems.

In recent years, there has been an increase in the number of problems associated with neurodevelopmental disorders in children, and there has been a growing interest in the relationship between environmental chemicals and children's health. The objective of this study was to examine whether an association exists between occupational or environmental prenatal maternal exposure to volatile organic compounds and the risk of neurodevelopmental disorders in children using Japanese translations of the Ages & Stages Questionnaires, Third Edition (J-ASQ-3). An increase in the risk of neurodevelopmental delay in 12-month-old children associated with maternal exposure to formalin or formaldehyde was identified in terms of problem-solving (odds ratio (OR): 1.76, 95% confidence interval (CI): 0.99-3.12) and personal-social skills (OR: 3.32, 95% CI: 1.46-7.55). It is not clear whether or not this tendency is reversible, and whether it is observed past 12 months of age. Further research and a preventive approach are needed.

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 ± 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.

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.

Background The aims of the present report were to estimate the prevalence of congenital anomalies (CAs) among infants in Japan using data from the Japan Environment and Children's Study (JECS) and to evaluate the validity of CA classification within JECS. Methods Data on CAs were collected at delivery and at age 1 month from the medical records of 101,825 infants at 15 regional centers. The analyses focused on 61 CAs, selected on the basis of reported associations with environmental exposure. Prevalence per 10,000 pregnancies (including miscarriages, stillbirths, and live births) was stratified according to four reporting patterns (at delivery, at age 1 month, at either, and at both). To evaluate the accuracy of observed CA prevalence, the medical records of 179 cases from a single JECS regional center underwent independent, retrospective re-evaluation. Results The prevalence of major CAs in four reporting patterns (at delivery, at age 1 month, at either, and at both) was 2.4, 2.6, 3.5, and 1.4 for myelomeningocele/spina bifida; 4.3, 4.2, 5.3, and 3.2 for cleft palate; 18.1, 17.4, 19.5, and 15.1 for cleft lip with or without cleft palate; 73.4, 100.3, 120.8, and 52.8 for congenital heart disease; and 10.5, 14.1, 15.0, and 9.6 for Down's syndrome, respectively. In the subsample re-evaluation, CA diagnoses were confirmed for 92.7%, 93.3%, 90.5%, and 97.8% of cases in the four reporting patterns (at delivery, at age 1 month, at either, and at both), respectively. Conclusions The present report generated reliable data concerning the prevalence of major CAs in JECS.

Background: Although the guidelines in most countries do not recommend continuous inhalation of l-isoproterenol to treat pediatric patients with acute severe exacerbation of asthma, lower dose of l-isoproterenol has been widely used in Japan. To determine whether the efficacy of low-dose l-isoproterenol was superior to that of salbutamol, we conducted a double-blind, randomized controlled trial. Methods: Hospitalized patients aged 1–17 years were eligible if they had severe asthma exacerbation defined by the modified pulmonary index score (MPIS). Patients were randomly assigned (1:1) to receive inhalation of l-isoproterenol (10 μg/kg/h) or salbutamol (500 μg/kg/h) for 12 hours via a large-volume nebulizer with oxygen. The primary outcome was the change in MPIS from baseline to 3 hours after starting inhalation. Trial registration number UMIN000001991. Results: From December 2009 to October 2013, 83 patients (42 in the l-isoproterenol group and 41 in the salbutamol group) were enrolled into the study. Of these, one patient in the l-isoproterenol group did not receive the study drug and was excluded from the analysis. Compared with salbutamol, l-isoproterenol reduced MPIS more rapidly. Mean (SD) changes in MPIS at 3 hours were −2.9 (2.5) in the l-isoproterenol group and −0.9 (2.3) in the salbutamol group (difference −2.0, 95% confidence interval −3.1 to −0.9; P

Background Manganese (Mn) is both an essential element and a potential toxicant. Although a few studies have suggested a nonlinear relationship between the maternal whole blood Mn level at delivery and infant birth weight, little is known about the effects of Mn levels during pregnancy on fetal growth, particularly with regard to sex-specific differences. Methods In this nationwide birth cohort study, we examined the association of maternal blood Mn level during pregnancy with infant birth weight, length, and head circumference in 16,473 mother–infant pairs. Pregnant women living in 15 regions across Japan were recruited between January 2011 and March 2014. The analysis of birth size (8,484 males and 7,989 females) was conducted using a nonlinear spline, followed by the use of quadratic regression or linear regression models. The analysis of small-for-gestational-age (SGA) (6,962 males and 6,528 females born vaginally) was conducted using multivariate logistic regression. Additionally, subgroup analysis was conducted according to the timing of blood sampling. Results The median maternal blood Mn level during pregnancy (i.e., 2nd and 3rd trimesters) was 16.2 µg/L (range, 4.3–44.5 µg/L). A positive linear association between the log blood Mn level and head circumference was observed in both male and female infants. However, a nonlinear relationship between the log blood Mn level and birth weight was observed only in male infants, such that the birth weight increased up to a blood Mn level of 18.6 µg/L. In the subgroup analysis stratified by the timing of maternal blood sampling, this nonlinear relationship was obvious only when sampling was performed in the 3rd trimester. Male infants in the lowest blood Mn level quartile (≤ 13.2 µg/L) faced an increased risk of SGA (odds ratio [95% confidence interval] = 1.35 [1.04–1.74]), as did those in the highest blood Mn level quartile (≥ 21.0 µg/L) when sampling was performed during the 3rd trimester (odds ratio [95% confidence interval] = 1.62 [1.10 to 2.39]), compared to those in the third blood Mn level quartile (the category including 18.6 µg/L). No association of blood Mn level with birth weight was observed among female infants, and blood Mn level was not associated with birth length in either male or female infants. Conclusion A low blood Mn level during pregnancy or a high blood Mn level during the 3rd trimester was associated with a lower birth weight and increased risk of SGA in male infants, but not in female infants. A low blood Mn level was found to correlate slightly with a small head circumference among infants of both sexes.

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.

BACKGROUND/OBJECTIVES The TOPICOP scale is an easy-to-use scale for assessing topical corticosteroid (TCS) phobia in atopic dermatitis (AD) patients and their caretakers. TCS phobia is a common problem among AD patients and their caretakers. The aim of this study was to examine the relationship between TCS phobia in caretakers of children with AD and the characteristics of patients using the TOPICOP scale. METHODS Caretakers of AD patients who visited the allergy clinic at the National Center for Child Health and Development in Tokyo between February 2014 and May 2014 were recruited. Caretakers of patients in follow-up had already attended an education session on treatment at the institution. All participants completed an anonymous questionnaire on the characteristics of the respondents and patients using the Patient-Oriented Eczema Measure (POEM) and the Japanese version of TOPICOP. RESULTS In total, 243 participants (88.9% female) completed the survey. The average TOPICOP score was 40.3 and the median POEM score was 4. The TOPICOP score was significantly higher for patients younger than 12 months old with moderate to very severe AD (POEM ≥ 8) whose caretaker had not attended an educational session (P

Background Although pregnancies conceived by assisted reproductive technology (ART) have a higher risk of maternal/perinatal complications, the overall risk of adverse outcomes necessitating advanced obstetric care has not been closely examined. The present study aimed to assess and compare the risk of maternal/perinatal complications and adverse outcomes in pregnancy and childbirth conceived by ART with those conceived naturally. Methods This study was conducted as a part of the Japan environment and children’s study (JECS), an ongoing nationwide birth cohort study in Japan. The risk of maternal/perinatal complications and adverse outcomes was assessed by mode of conception (natural conception, ovulation induction [OI] without ART, conventional in vitro fertilization and embryo transfer [IVF-ET], or intracytoplasmic sperm injection [ICSI]) using logistic regression and generalized estimating equations controlling for potential confounders. Results The final dataset included women who conceived naturally (N = 90,506), by OI without ART (N = 3939), by conventional IVF-ET (N = 1476), and by ICSI (N = 1671). Compared with women who conceived naturally, those who conceived by conventional IVF-ET were at higher risk of placenta previa (adjusted OR 2.90 [95% CI 1.94, 4.34]), morbidly adherent placenta (6.85 [3.88, 12.13]), and pregnancy-induced hypertension (1.40 [1.10, 1.78]) whereas those who conceived by ICSI had a higher risk of placental abruption (2.16 [1.20, 3.88]) as well as placenta previa (2.01 [1.29, 3.13]) and morbidly adherent placenta (7.81 [4.56, 13.38]). Women who conceived by ART had a higher risk of blood transfusion (conventional IVF-ET: 3.85 [2.52, 5.88]; ICSI: 3.76 [2.49, 5.66]) and ICU admission (conventional IVF-ET: 2.58 [1.11, 6.01]; ICSI: 3.45 [1.68, 7.06]) even after controlling for potential confounders. Neonates conceived by ART had a higher risk of preterm birth (conventional IVF-ET: 1.42 [1.13, 1.78]; ICSI: 1.31 [1.05, 1.64]). Conclusions Women who conceived by ART had a higher risk of maternal/perinatal complications necessitating advanced obstetric care. Obstetricians should be aware of the increased risk of adverse outcomes among this population.

Background: Atopic dermatitis (AD) and exercise-induced asthma (EIA) are common in asthmatic children, and exercise is the most common trigger other than infection for acute onset asthma attack in children. We examined whether AD is related to exercise-induced wheezing (EIW), some proxy for EIA. Methods: Japanese version of the International Study of Asthma and Allergies in Childhood questionnaires were used. For 12,405 asthmatic school children, AD was defined as itchy rash coming and going for at least 6 months at any time in the last 12 months with affecting places of flexural parts of body, and severity of AD was rated according to frequency of being kept awake at night with the itch as follows: never in the past 12 months, less than one night per week and one or more nights per week. Results: Adjusted for frequency of asthma attack, odds ratios (OR) of children with current AD as compared to those without AD for having EIW were 1.32 (95% confidence interval = 1.15–1.52), 1.35 (1.14–1.68) and 1.10 (0.92–1.31) for primary school, junior high school and high school children, respectively. EIW was more likely observed in accordance with increasing severity of AD in the primary school children with ORs of 1.12, 1.59 and 1.54 (p for trend

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.

It currently remains unclear whether parabens, which are preservatives added to cosmetics, shampoos, and personal care products that exhibit biocidal activities, exert allergic effects in adults. The aim of the present study was to examine the relationship between the use of parabens and the prevalence of allergic diseases in Japanese adults. This population-based cross-sectional study comprised 2005 participants aged 40 years or older living in Shika Town in Japan who answered a self-administered questionnaire on allergic diseases and the daily use of household goods. The information obtained was then analyzed to assess the exposure to parabens (response rate: 77.9%). The prevalence of nasal allergies, atopic conjunctivitis, and total allergies was significantly higher in women who used parabens. These differences remained significant after adjustments for confounding factors including age, body mass index, smoking, alcohol, exercise, sleep, income, education, and marital status. No relationship between the prevalence of atopic dermatitis and the use of parabens was observed in men or women. However, the present results demonstrated that the prevalence of nasal allergies and atopic conjunctivitis was associated with use of parabens in women, suggesting that parabens may induce allergic responses.

Background Atopic dermatitis is the first clinical manifestation of the atopic march, with the highest incidence in the first year of life. Those affected often go on to develop other allergic diseases including food allergy, asthma, and allergic rhinitis. Recent evidence suggests that sensitization to foods may occur through a defective skin barrier which is common in atopic dermatitis in early life. We hypothesize that therapeutic aggressive intervention to treat new onset atopic dermatitis may prevent the development of later allergen sensitization, and associated food allergy, asthma, and allergic rhinitis. Methods This study is a multi-center, pragmatic, two-parallel group, assessor-blind, superiority, individually randomized controlled trial. Atopic dermatitis infants (N = 650) 7–13 weeks old who develop an itchy rash within the previous 28 days are randomly assigned to the aggressive treatment or the conventional treatment in a 1:1 ratio. The primary outcome is oral food challenge-proven IgE-mediated hen’s egg allergy at the age of 28 weeks. Discussion This is a novel pragmatic RCT study to examine the efficacy of early aggressive treatment for atopic dermatitis to prevent later food allergy. If our hypothesis is correct, we hope that such a strategy might impact on disease prevention in countries where food allergy is common, and that our results might reduce the frequency and associated costs of all food allergies as well as hens egg food allergy. Long-term follow and other similar studies will help to determine whether such a strategy will reduce the burden of other allergic diseases such as asthma and allergic rhinitis. Trial registration UMIN-CTR: UMIN000028043 Electronic supplementary material The online version of this article (10.1186/s13601-018-0233-8) contains supplementary material, which is available to authorized users.

Few epidemiologic studies have examined the role of maternal iron status in allergic diseases in offspring and findings have been inconsistent. We used a large birth cohort in Japan to explore the association of the markers for maternal iron status (maternal hemoglobin, hematocrit and dietary iron intake during pregnancy) with allergy development in offspring during early childhood. We analyzed information on children age 0–3 years from the Japan Environment and Children’s Study (JECS). We used logistic models and generalized estimating equation models to evaluate the effect of maternal hemoglobin and hematocrit levels and dietary iron intake on allergies in children. Models were also fitted with propensity score-matched datasets. Data were collected for a total of 91,247 mother–child pairs. The prevalence (95% confidence interval) of low hemoglobin and hematocrit was 14.0% (13.7–14.2%) and 12.5% (12.3–12.8%), respectively. After adjusting confounders, low hemoglobin and hematocrit during pregnancy were not associated with childhood allergic outcomes. Findings from models with propensity score-matched datasets also indicated that children born to mothers with low hemoglobin or hematocrit levels during pregnancy did not have a higher risk of developing allergic conditions at 3 years old. We found no meaningful associations between low energy adjusted maternal dietary iron intake and allergies in children. In conclusion, using birth cohort data, we found no evidence supporting an association of low maternal hemoglobin, hematocrit and low dietary iron intake with allergy symptoms during early childhood. Further studies with more suitable proxy markers for blood iron status are needed.

Introduction: Clinical trials of dupilumab demonstrated significant clinical improvements with a favorable safety profile in adults and adolescents with moderate-to-severe atopic dermatitis (AD) inadequately controlled with topical medications. Here, we evaluate dupilumab safety and efficacy data in children aged ≥ 6 to < 12 years with severe AD (Investigator’s Global Assessment [IGA] score = 4) inadequately controlled with topical corticosteroids (TCS). Methods: In the double-blinded, phase 3 LIBERTY AD PEDS trial (NCT03345914), children aged ≥ 6 to < 12 years were randomized 1:1:1 to receive either subcutaneous dupilumab every 4 weeks (q4w, 300 mg …