Prenatal risk factors of indoor environment and incidence of childhood eczema in the Japan Environment and Children's Study.

The quality of indoor environment is a risk factor for early childhood eczema and atopic dermatitis; however, its influence during pregnancy on childhood eczema in Japan has not been investigated. In this study, we aimed to determine the indoor environmental factors that are associated with eczema in children up to 3 years of age, using national birth cohort data from the Japan Environment and Children's Study (JECS). Information on indoor environments and eczema symptoms until 3 years of age was collected using self-administered questionnaires to the mothers. A total of 71,883 and 58,639 mother-child pairs at 1.5- and 3-years-old, respectively, were included in the former analyses. To account for prenatal indoor risk factors, 17,568 (1.5-years-old) and 7063 (3-years-old) children without indoor mold and/or ETS exposure were included in the final analysis. A higher mold index, gas heater use, parquet flooring use, and frequent insecticide use showed significantly increased risks for childhood eczema up to 3 years of age. These associations were consistent after stratification analysis among children whose parents did not have a history of allergies. The updated WHO guidelines on indoor air quality should be implemented based on recent findings regarding the effects of prenatal exposure to indoor dampness on health effects of children further in life, including asthma, respiratory effects, eczema, and other immunological effects.

Heavy metals and trace elements in maternal blood and prevalence of congenital limb abnormalities among newborns: the Japan Environment and Children's Study.

BACKGROUND: Heavy metals such as lead (Pb) and cadmium (Cd) have been associated with adverse pregnancy and developmental outcomes, including congenital abnormalities. This study investigated the association between exposure to heavy metals and trace elements during fetal life and congenital limb abnormalities in infants. METHODS: This study is based on a prospective ongoing nationwide birth cohort from the Japan Environment and Children's Study (JECS). The concentrations of Cd, Pb, mercury (Hg), selenium (Se), and manganese (Mn) were measured in maternal blood collected during the mid-late trimesters. Inclusion criteria were available from questionnaires filled in during pregnancy, including information about congenital limb abnormalities at birth or at one month. To examine the associations with limb anomalies and individual chemicals, logistic regression models were applied following log-transformation or division into quartiles of Cd, Pb, Hg, Se, and Mn concentrations. To assess the associations with the heavy metals and trace elements mixture, quantile g-computation was employed. All models were adjusted for age, maternal smoking history, maternal alcohol intake, history of smoking, and infant sex. RESULTS: Data from 90,163 participants were included in the analysis, of whom 369 had congenital limb abnormalities in any of the collected information, and 89,794 had none. Among the 369 cases of congenital limb abnormalities, there were 185 and 142 cases of polydactyly and syndactyly, respectively. The median concentrations of Pb, Cd, Hg, Se, and Mn were 5.85, 0.66, 3.64, 168, and 15.3 ng/g, respectively. There were no associations between maternal blood concentrations of Pb [adjusted odd ratio = 0.83; 95% confidence interval = 0.61, 1.11], Cd [0.87; 0.68, 1.10], Hg [0.88; 0.73, 1.07], Se [1.07; 0.44, 2.59], and Mn [0.91; 0.64, 1.30] with congenital limb abnormalities. No significant association was observed between the mixture of heavy metals and trace elements [0.85; 0.72, 1.02] and any congenital limb abnormalities. Moreover, there was no association with all polydactylies and all syndactylies, or any type of abnormality as a subdivision. CONCLUSION: At the maternal exposure levels of Cd, Pb, Hg, Se, and Mn assessed in the present study, no association was identified with the risk of developing congenital limb abnormalities in children.

Prenatal metal concentrations and physical abnormalities in the Japan Environment and Children's Study.

BACKGROUND: The association between prenatal metal exposure and congenital anomalies is unclear. We aimed to examine the association between exposure to cadmium, lead, mercury, selenium, and manganese and physical abnormalities. METHODS: Data from 89,887 pregnant women with singleton pregnancies who participated in the Japan Environment and Children's Study (JECS) were used. The correlation between maternal blood metal concentrations and physical abnormalities during the second or third trimester was investigated using logistic regression models. Physical anomalies included those observed at birth or at 1 month, primarily from ICD-10 Chapter 17, particularly congenital anomalies associated with environmental factors (e.g., hypospadias, cryptorchidism, cleft lip and palate, digestive tract atresia, congenital heart disease, and chromosomal abnormalities) and minor abnormalities. RESULTS: After adjusting for covariates, the OR (95% CIs) of physical abnormalities for a one-unit rise in Mn concentrations in all individuals were 1.26 (1.08, 1.48). The OR (95% CIs) of physical abnormalities in the 4th quartile (≥18.7 ng/g) were 1.06 (1.01, 1.13) (p-value for the trend = 0.034) compared with those in the 1st quartile (≤12.5 ng/g). CONCLUSION: In Japan, maternal blood Mn concentrations above threshold during pregnancy may slightly increase the incidence of physical abnormalities. IMPACT: Physical abnormalities (including minor anomalies and congenital anomalies) are associated with prenatal manganese concentrations. They are not associated with cadmium, lead, mercury, and selenium concentrations.

Prenatal alcohol exposure and adverse fetal growth restriction: findings from the Japan Environment and Children's Study.

BACKGROUNDS: Japanese studies on the association between maternal alcohol consumption and fetal growth are few. This study assessed the effect of maternal alcohol consumption on fetal growth. METHODS: This prospective birth cohort included 95,761 participants enrolled between January 2011 and March 2014 in the Japan Environment and Children's Study. Adjusted multiple linear and logistic regression models were used to assess the association between prenatal alcohol consumption and infant birth size. RESULTS: Consumption of a weekly dose of alcohol in the second/third trimester showed a significant negative correlation with standard deviation (SD; Z) scores for body weight, body length, and head circumference at birth, respectively. Consumption of a weekly dose of alcohol during the second/third trimester had a significant positive correlation with incidences of Z-score ≤ -1.5 for birth head circumference. Associations between alcohol consumption in the second/third trimester and Z-score ≤ -1.5 for birth weight or birth length were not significant. Maternal alcohol consumption in the second/third trimester above 5, 20, and 100 g/week affected body weight, body length, and head circumference at birth, respectively. CONCLUSION: Low-to-moderate alcohol consumption during pregnancy might affect fetal growth. Public health policies for pregnant women are needed to stop alcohol consumption during pregnancy. IMPACT: This study examined the association between maternal alcohol consumption and fetal growth restriction in 95,761 pregnant Japanese women using the prospective birth cohort. Maternal alcohol consumption in the second/third trimester more than 5, 20, and 100 g/week might affect fetal growth in body weight, body length, and head circumference, respectively. The findings are relevant and important for educating pregnant women on the adverse health effects that prenatal alcohol consumptions have on infants.

Evaluating association of smoking status during pregnancy with adverse birth outcomes using urinary cotinine concentration: The Japan environment and Children's study (JECS).

Urinary cotinine concentration (UCC) reflects smoking status. However, in pregnant women, its association with adverse birth outcomes related to fetal growth is not widely known. Thus, we aimed to explore this relationship by focusing on dose-response relationships. We investigated 86,638 pregnant women enrolled between 2011 and 2014 in a prospective cohort study in Japan and observed three birth outcomes (preterm birth, low birth weight, and small-for-gestational age). We measured UCC in the second or third trimester, and categorized the participants using cut-off values (negative cotinine concentration, passive cotinine concentration, and active cotinine concentration corresponding to non-smokers, passive smokers, and active smokers, respectively). Logistic regression analyses were conducted to evaluate the risks, and dose-response relationships were visualized using restricted cubic spline curves. Analyses based on self-reported smoking status were also performed. We found that in low active and highly active cotinine concentrations, the adjusted odds ratios (aORs) of birth outcomes were significantly increased (preterm birth, 1.24 [95% CI 1.06-1.46], 1.39 [95% CI 1.19-1.62]; low birth weight, 1.40 [95% CI 1.24-1.58], 2.27 [95% CI 2.05-2.53]; small-for-gestational age, 1.35 [95% CI 1.19-1.52], 2.39 [95% CI 2.16-2.65]). Restricted cubic spline curves demonstrated risk elevations in the active cotinine concentration range. Our research revealed dose-response relationships between UCC during pregnancy and the risks of preterm birth, low birth weight, and small-for-gestational age. Measurement of UCC to ascertain smoking status during pregnancy may be a useful approach for predicting the risks of these birth outcomes.

Lower Respiratory Tract Infections and Orofacial Clefts: A Prospective Cohort Study From the Japan Environment and Children's Study.

BACKGROUND: Lower respiratory tract infections (LRTIs) are a cause of inpatient and outpatient care among children. Although orofacial clefts seem to be associated with LRTIs, epidemiological studies are scarce on this topic. This study aimed to examine whether infants with orofacial clefts were associated with LRTIs. METHODS: This prospective cohort study used data from the Japan Environment and Children's Study, for which baseline recruitment was conducted during 2011-2014. This study included 81,535 participants. The number of infants with cleft lip and palate (CLP), cleft lip (CL), and cleft palate only (CP) was 67, 49, and 36, respectively. We defined history of LRTIs until 12 months' age reported by their mothers as the dependent variable. Accumulated breastfeeding duration was used as a potential mediator. RESULTS: The incidence proportion of LRTIs among the control group was 6.0%. The incidence proportion among infants with CLP, CL, and CP were 11.9%, 14.3%, and 5.6%, respectively. After adjusting for covariates, compared with the control group, infants with CLP and CL were associated with risk of LRTIs (incidence risk ratio [IRR] of CLP, 2.38; 95% confidence interval [CI], 1.30-4.36 and IRR of CL, 2.73; 95% CI, 1.40-5.33), but not ones with CP (IRR 1.08; 95% CI, 0.28-4.15). Accumulated breastfeeding duration decreased the IRR of CLP only (IRR of CLP, 2.16; 95% CI, 1.19-3.93). CONCLUSION: Infants with orofacial clefts aged 1 year have a potentially high incidence proportion of LRTIs. Accumulated breastfeeding duration might mediate the associations of CLP.

Relations of mold, stove, and fragrance products on childhood wheezing and asthma: A prospective cohort study from the Japan Environment and Children's Study.

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.

Null Association Between Isolated Orofacial Clefts and Sleep Duration: A Cohort Study From the Japan Environment and Children's Study.

Although children with orofacial clefts have an increased risk for sleep-disordered breathing, no studies have examined the association of sleep duration. Thus, this study aimed to examine associations between orofacial clefts and sleep duration at 1 month, 6 months, 1 year, and 3 years of age in Japan.A cohort study from the Japan Environment and Children's Study.This study consisted of 91 497 children, including ones with isolated cleft lip and palate (n = 69), isolated cleft lip only (n = 48), and isolated cleft palate only (n = 37), for which recruitment was undertaken during 2011 to 2014.Seep durations (hours per day) at 1 month, 6 months, 1 year, and 3 years of age, as reported by their mothers.In the control group, mean sleep durations and standard deviations at 1 month, 6 months, 1 year, and 3 years of age were 15.2 (2.5), 13.6 (1.9), 12.9 (1.6), and 11.6 (1.2) h, respectively. Compared to the control group, linear regression models reported effect sizes and 95% confidence intervals shorter than 1 h for sleep duration of each type of isolated orofacial cleft at each time point.This study suggested null associations between isolated orofacial clefts and sleep duration at 1 month, 6 months, 1 year, and 3 years of age. Children with isolated orofacial clefts had sufficient mean sleep duration.

Prevalence of childhood wheeze and modified DNA methylation at 7 years of age according to maternal folate levels during pregnancy in the Hokkaido Study.

BACKGROUND: A high dose of folic acid during pregnancy may increase the risk of asthma, wheezing, and respiratory disease in childhood. Folate acid can modify inflammation and immune susceptibility of offspring with some epigenetic differentiation, including DNA methylation. This study evaluated associations between maternal folate levels during pregnancy and childhood wheezing; furthermore, the study assessed whether maternal folate-modified DNA methylation is related to asthma. Methods Participants in the current study were 6651 mother-child pairs who had complete data on characteristics and who had completed at least one of the International Study of Asthma and Allergies in Childhood questionnaires when the child was 1, 2, 4, and 7 years of age. Moreover, a case-control study to assess DNA methylation at 7 years of age was conducted among 136 children who experienced wheezing and a control group of 139 children with no history of allergies. Results The median of maternal serum was 16.76 nmol/L, assayed by chemiluminescent immunoassay. We found significantly increased adjusted odds ratios of childhood wheezing at 2 years age according to maternal folate levels, compared with the lowest folate quartile (odds ratio [95% confidence interval] = highest; 1.27 [1.03, 1.56], and second, 1.27 [1.05, 1.55]); however, no changes were observed at 1, 4, and 7 years of age. In a case-control study, no association of maternal folate levels with DNA methylation was observed. Conclusion Our results suggest that maternal folate did not affect persistent wheezing in school-aged children, or DNA methylation of gasdermin B, orosomucoid-like 3, and Ikaros family zinc finger 3 at 7 years of age.

Population Attributable Fractions of Modifiable Risk Factors for Nonsyndromic Orofacial Clefts: A Prospective Cohort Study From the Japan Environment and Children's Study.

BACKGROUND: Population impact of modifiable risk factors on orofacial clefts is still unknown. This study aimed to estimate population attributable fractions (PAFs) of modifiable risk factors for nonsyndromic cleft lip with or without cleft palate (CL±P) and cleft palate only (CP) in Japan. METHODS: We conducted a prospective cohort study using data from the Japan Environment and Children's Study, which recruited pregnant women from 2011 to 2014. We estimated the PAFs of maternal alcohol consumption, psychological distress, maternal active and passive smoking, abnormal body mass index (BMI) (<18.5 and ≥25 kg/m2), and non-use of a folic acid supplement during pregnancy for nonsyndromic CL±P and CP in babies. RESULTS: A total of 94,174 pairs of pregnant women and their single babies were included. Among them, there were 146 nonsyndromic CL±P cases and 41 nonsyndromic CP cases. The combined adjusted PAF for CL±P of the modifiable risk factors excluding maternal alcohol consumption was 34.3%. Only maternal alcohol consumption was not associated with CL±P risk. The adjusted PAFs for CL±P of psychological distress, maternal active and passive smoking, abnormal BMI, and non-use of a folic acid supplement were 1.4% (95% confidence interval [CI], -10.7 to 15.1%), 9.9% (95% CI, -7.0 to 26.9%), 10.8% (95% CI, -9.9 to 30.3%), 2.4% (95% CI, -7.5 to 14.0%), and 15.1% (95% CI, -17.8 to 41.0%), respectively. We could not obtain PAFs for CP due to the small sample size. CONCLUSIONS: We reported the population impact of the modifiable risk factors on CL±P, but not CP. This study might be useful in planning the primary prevention of CL±P.

Maternal psychological distress, education, household income, and congenital heart defects: a prospective cohort study from the Japan environment and children's study.

BACKGROUND: The influence of maternal psychological distress on infant congenital heart defects (CHDs) has not been thoroughly investigated. Furthermore, there have been no reports on the combined effect of maternal psychological distress and socioeconomic status on infant CHDs. This study aimed to examine whether maternal psychological distress, socioeconomic status, and their combinations were associated with CHD. METHODS: We conducted a prospective cohort study using data from the Japan Environment and Children's Study, which recruited pregnant women between 2011 and 2014. Maternal psychological distress was evaluated using the Kessler Psychological Distress Scale in the first trimester, while maternal education and household income were evaluated in the second and third trimesters. The outcome of infant CHD was determined using the medical records at 1 month of age and/or at birth. Crude- and confounder-adjusted logistic regression analyses were performed to evaluate the association between maternal psychological distress and education and household income on infant CHD. RESULTS: A total of 93,643 pairs of mothers and infants were analyzed, with 1.1% of infants having CHDs. Maternal psychological distress had a significantly higher odds ratio in the crude analysis but not in the adjusted analysis, while maternal education and household income were statistically insignificant. In the analysis of the combination variable of lowest education and psychological distress, the P for trend was statistically significant in the crude and multivariate model excluding anti-depressant medication, but the significance disappeared in the full model (P = 0.050). CONCLUSIONS: The combination of maternal psychological distress and lower education may be a possible indicator of infant CHD.

Hokkaido birth cohort study on environment and children's health: cohort profile 2021.

BACKGROUND: The Hokkaido Study on Environment and Children's Health is an ongoing study consisting of two birth cohorts of different population sizes: the Sapporo cohort and the Hokkaido cohort. Our primary objectives are to (1) examine the effects that low-level environmental chemical exposures have on birth outcomes, including birth defects and growth retardation; (2) follow the development of allergies, infectious diseases, and neurobehavioral developmental disorders, as well as perform a longitudinal observation of child development; (3) identify high-risk groups based on genetic susceptibility to environmental chemicals; and (4) identify the additive effects of various chemicals, including tobacco. METHODS: The purpose of this report is to provide an update on the progress of the Hokkaido Study, summarize recent results, and suggest future directions. In particular, this report provides the latest details from questionnaire surveys, face-to-face examinations, and a collection of biological specimens from children and measurements of their chemical exposures. RESULTS: The latest findings indicate different risk factors of parental characteristics on birth outcomes and the mediating effect between socioeconomic status and children that are small for the gestational age. Maternal serum folate was not associated with birth defects. Prenatal chemical exposure and smoking were associated with birth size and growth, as well as cord blood biomarkers, such as adiponectin, leptin, thyroid, and reproductive hormones. We also found significant associations between the chemical levels and neuro development, asthma, and allergies. CONCLUSIONS: Chemical exposure to children can occur both before and after birth. Longer follow-up for children is crucial in birth cohort studies to reinforce the Developmental Origins of Health and Disease hypothesis. In contrast, considering shifts in the exposure levels due to regulation is also essential, which may also change the association to health outcomes. This study found that individual susceptibility to adverse health effects depends on the genotype. Epigenome modification of DNA methylation was also discovered, indicating the necessity of examining molecular biology perspectives. International collaborations can add a new dimension to the current knowledge and provide novel discoveries in the future.

Associations between prenatal exposure to organochlorine pesticides and thyroid hormone levels in mothers and infants: The Hokkaido study on environment and children's health.

Organochlorine pesticides (OCPs) are environmental contaminants with potentially adverse effects on neurodevelopment. Previous findings on the association between prenatal exposure to OCPs and the maternal or infant thyroid hormone system are inconsistent. Moreover, the influence of exposure to multiple OCPs and other chemical compounds is not clearly understood. Our study therefore aimed to examine the association between OCP exposure and both maternal and infant thyroid hormone systems. We also explored multiple exposure effects of OCPs and the influence of each compound using weighted quantile sum (WQS) methods. The study population included 514 participants in the Hokkaido study, recruited from 2002 to 2005 at one hospital in Sapporo, Japan. To quantify 29 OCPs, maternal blood samples were analyzed using gas chromatography/mass spectrometry. Blood samples for measuring thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels were obtained from mothers during the early gestational stage (mean 11.4 weeks), and from infants between 7 and 43 days of age. The data of 333 mother child pairs with OCP and thyroid hormone measurements were included in the final analyses. Multivariate regression models showed a negative association between maternal FT4 and levels of o,p'-dichlorodiphenyldichloroethylene (DDE), o,p'-dichlorodiphenyltrichloroethane (DDT), and dieldrin. The WQS analysis showed that o,p'-DDT (48.6%), cis-heptachlorepoxide (22.8%), dieldrin (15.4%) were the primary contributors to the significant multiple exposure effect of OCPs on maternal FT4. For infants, we found a positive association between FT4 and cis-nonachlor and mirex. The most contributory compounds in the multiple exposure effect were trans-nonachlor (27.1%) and cis-nonachlor (13.8%), while several compounds contributed to the WQS via small weights (0.4-9.1%). These results indicate that OCPs, even at very low levels, may influence maternal and child thyroid hormone levels, which could modulate child development.

Combined exposure to phthalate esters and phosphate flame retardants and plasticizers and their associations with wheeze and allergy symptoms among school children.

BACKGROUND: Phthalate esters and phosphate flame retardants and plasticizers (PFRs) are both used as plasticizers and are commonly detected in indoor environments. Although both phthalates and PFRs are known to be associated with children's wheeze and allergic symptoms, there have been no previous studies examining the effects of mixtures of these exposures. OBJECTIVES: To investigate the association between exposure to mixtures of phthalate esters and PFRs, and wheeze and allergic symptoms among school-aged children. METHODS: A total of 128 elementary school-aged children were enrolled. Metabolites of 3 phthalate esters and 7 PFRs were measured in urine samples. Parent-reported symptoms of wheeze, rhinoconjunctivitis, and eczema were evaluated using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. In the primary model, we created a phthalate ester and PFR mixture exposure index, and estimated odds ratios (ORs) using weighted quantile sum (WQS) regression and quantile g (qg)-computation. The two highest chemicals according to qg-computation weight %s were combined to create a combination high × high exposure estimate, with ORs calculated using the "low × low" exposure group as the reference category. Concentrations of each metabolite were corrected by multiplying this value by the sex- and body size-Standardised creatinine concentration and dividing by the observed creatinine value. All models were adjusted for sex, grade, dampness index and annual house income. RESULTS: The odds ratio of rhinoconjunctivitis for the association between exposure to chemical mixtures according to the WQS index positive models was; OR = 2.60 (95% confidence interval [CI]: 1.38-5.14). However, wheeze and eczema of the WQS index positive model, none of the WQS index negative models or qg-computation result yielded statistically significant results. Combined exposure to the two highest WQS weight %s of "high-high" ΣTCIPP and ΣTPHP was associated with an increased prevalence of rhino-conjunctivitis, OR = 5.78 (1.81-18.43) to the "low × low" group. CONCLUSIONS: Significant associations of mixed exposures to phthalates and PFRs and increased prevalence of rhinoconjunctivitis was found among elementary school-aged children in the WQS positive model. Mixed exposures were not associated with any of allergic symptoms in the WQS negative model or qg-computation approach. However, the combined effects of exposure to two PFRs suggested an additive and/or multiplicative interaction, potentially increasing the prevalence of rhinoconjunctivitis. A further study with a larger sample size is needed to confirm these results.

Risk factors for motor coordination problems in preschool-age children.

BACKGROUND: Motor coordination problems (MCP) in children can sometimes be diagnosed as developmental coordination disorder. Early intervention for developmental coordination disorder is necessary because it often continues into adolescence, causing mental and physical complications. Few studies have investigated the prevalence of childhood MCP in the Japanese population, examining the risk factors for MCP. We therefore investigated the prenatal factors associated with MCP in preschool-age children. METHODS: This study was based on a prospective cohort study, the Hokkaido Study on Environment and Children's Health. Mothers of 4,851 children who reached the age of 5 years within the study-period received questionnaires, including the Japanese version of the Developmental Coordination Disorder Questionnaire (DCDQ-J). We examined the risk factors associated with MCP using logistic regression analysis. RESULTS: Of 3,402 returned DCDQ-J questionnaires, 3,369 were answered completely. From the 3,369 children, we categorized having MCP by using two cut-off scores: that of the DCDQ'07 and the cut-off at the 5th percentile of a total DCDQ-J score. Comparing children with and without MCP, we found significant differences in the education level of the mothers, annual household income during pregnancy, maternal alcohol consumption and smoking during pregnancy, and sex and age of the children at the time of completing the DCDQ-J by both categorizations. Adjusted logistic regression analysis revealed that maternal smoking during the first trimester of pregnancy and male sex were significantly associated with MCP. CONCLUSIONS: Our results suggest that maternal smoking during pregnancy is the main factor associated with MCP in preschool-age children.

Dose-dependent associations between prenatal caffeine consumption and small for gestational age, preterm birth, and reduced birthweight in the Japan Environment and Children's Study.

BACKGROUND: Few previous studies have investigated the association between prenatal caffeine intake and birth size (small for gestational age [SGA], preterm birth, and birthweight Z-score) in Japan. OBJECTIVES: We examined the dose-dependency of this association (prenatal caffeine consumption and birth size) as part of the Japan Environment and Children's Study. METHODS: A prospective birth cohort included 94 876 fetuses in Japan. Participants were enrolled between January 2011 and March 2014. Adjusted multiple linear regression and Cox regression models were used to examine the association between prenatal caffeine levels and infant birth size. RESULTS: The median estimated caffeine consumption during pregnancy was 125.5 mg/day, as determined by self-administered questionnaires. There were 7252 SGA infants (7.6%) and 4281 preterm birth infants (4.5%). Compared with infants of mothers whose caffeine consumption during pregnancy was in the lowest quartile (4.2 to <86.4 mg/day), infants of mothers whose caffeine consumption was in the highest quartile 4 (205.5-5080.0 mg/day) were at an increased risk of SGA (relative risk [RR] 1.18, 95% confidence interval [CI] 1.10, 1.27), and at an increased risk of preterm birth at the second trimester of gestation (RR 1.94, 95% CI 1.12, 3.37), with a 0.32-day reduction in gestational age (95% CI -0.52, -0.12) and with a 0.07 reduction in birthweight Z-score observed (95% CI -0.09, -0.05). CONCLUSIONS: Prenatal caffeine consumption was associated with birth size. However, as the association between prenatal caffeine consumption and birth size was likely confounded by unpredicted potential factors, our confidence in the true causality of the association is moderate.

Prenatal tobacco exposure and ADHD symptoms at pre-school age: the Hokkaido Study on Environment and Children's Health.

BACKGROUND: There have been inconsistent findings reported on maternal passive smoking during pregnancy and child risk of ADHD. In this study, ADHD symptoms at pre-school age children in association with prenatal passive and active tobacco smoke exposure determined by maternal plasma cotinine levels in the third trimester were investigated. METHODS: This was a follow-up study of the birth cohort: the Hokkaido Study on Environment and Children's Health. Children whose parents answered Strengths and Difficulties Questionnaire (SDQ) to identify child ADHD symptoms (hyperactivity/inattention and conduct problems) and total difficulties at age 5 years with available maternal plasma cotinine level at the third trimester were included (n = 3216). Cotinine levels were categorized into 4 groups; ≦ 0.21 ng/ml (non-smoker), 0.22-0.51 ng/ml (low-passive smoker), 0.52-11.48 ng/ml (high-passive smoker), and ≧ 11.49 ng/ml (active smoker). RESULTS: Maternal cotinine levels of active smokers were significantly associated with an increased risk of total difficulties (OR = 1.67) and maternal low- and high-passive smoking also increased the risk (OR = 1.11, 1.25, respectively) without statistical significance. Similarly, maternal cotinine levels of active smokers were associated with an increased risk of hyperactivity/inattention (OR = 1.49). Maternal low- and high-passive smoking and active smoking increased the risk of hyperactivity/inattention (OR = 1.45, 1.43, and OR = 1.59, respectively) only in boys. CONCLUSION: Our findings suggested that maternal active smoking during pregnancy may contribute to the increased risk of child total difficulties and hyperactivity/inattention at pre-school age. Pregnant women should be encouraged to quit smoking and avoid exposure to tobacco smoke.

Association of maternal serum concentration of hydroxylated polychlorinated biphenyls with maternal and neonatal thyroid hormones: The Hokkaido birth cohort study.

BACKGROUND: Evidence on the toxicity of hydroxylated metabolites of polychlorinated biphenyls (OH-PCBs) for thyroid hormones (TH) is limited, and the underlying mechanism remains unknown. OBJECTIVES: We aimed to investigate the effects of environmental prenatal exposure to OH-PCBs and maternal and neonatal TH levels, taking the maternal-fetal TH transfer into account. METHODS: In this prospective birth cohort (the "Hokkaido study") we included 222 mother-neonate pairs. We measured five OH-PCB isomers in maternal serum samples either during pregnancy or within 5 days of delivery. Thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels were obtained from maternal blood samples at an early gestational stage (median; 11.1 weeks) and from heel prick samples of neonates between 4 and 7 days after birth. Multiple linear regression analysis and structural equation modeling (SEM) were performed to investigate the associations between maternal OH-PCB and maternal and neonatal TH levels. RESULTS: Median concentration of ∑OH-PCBs was 25.37 pg/g wet weight. The predominant isomer was 4-OH-CB187, followed by 4-OH-CB146+3-OH-CB153. In the fully adjusted linear regression analysis, maternal ∑OH-PCBs was positively associated with maternal FT4, and 4-OH-CB187 was positively associated with both maternal and neonatal FT4 levels. Maternal OH-PCBs showed no significant association with TSH among mothers and neonates. Path analysis indicated the indirect pathway from 4-OH-CB187 exposure to increased neonatal FT4, via maternal THs and neonatal TSH. CONCLUSIONS: These findings suggest that maternal exposure to OH-PCBs during pregnancy may increase both maternal and neonatal FT4 levels. Neonatal FT4 is presumed to be increased by prenatal 4-OH-CB187 indirectly, and this process may be mediated by maternal THs and neonatal TSH.

Association between prenatal bisphenol A and phthalate exposures and fetal metabolic related biomarkers: The Hokkaido study on Environment and Children's Health.

Bisphenol A and phthalates are widely detected in human urine, blood, breast milk, and amniotic fluid. Both bisphenol A and phthalates have been suggested as playing a role in obesity epidemics. Exposure to these chemicals during fetal development, and its consequences should be concerning because they can cross the placenta. Thus, this study aimed to assess the association between prenatal exposure to bisphenol A and phthalates, and cord blood metabolic-related biomarkers. Maternal serum was used during the first trimester, to determine prenatal exposure to bisphenol A and phthalates. Levels of metabolic-related biomarkers in the cord blood were also determined. Linear regression models were applied to the 365 participants with both, exposure and biomarker assessments, adjusted for maternal age, pre-pregnancy body mass index, parity, education, and sex of the child. The level of bisphenol A was negatively associated with the leptin level (ß = -0.06, 95% confidence interval [CI]: -0.11, -0.01), but was positively associated with the high-molecular-weight adiponectin level, with marginal significance (ß = 0.03, 95%CI: 0.00, 0.06). The mono-isobutyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), mono-(2-ethylhexyl) phthalate (MEHP), and summation of MEHP and MECPP to represent DEHP exposure (∑DEHPm) levels were inversely associated with the leptin levels (ß=-0.14, 95%CI: -0.27, -0.01; ß = -0.12, 95%CI: -0.24, 0.00 with marginal significance; ß=0.08, 95%CI: -0.14, -0.03; and ß = -0.09, 95%CI: -0.16, -0.03, respectively). The present study provided some evidence that prenatal exposure to bisphenol A and certain phthalates may modify fetal adiponectin and leptin levels.