Changes in prevalence and socioeconomic inequalities in secondhand smoke exposure in Spanish children, 2016-2019.

INTRODUCTION: Children are vulnerable to secondhand smoke (SHS) exposure, especially those with lower socioeconomic status. This study assesses the changes in prevalence and socioeconomic inequalities in SHS exposure in children younger than 12 years old in Spain between 2016 and 2019. METHODS: We conducted two cross-sectional studies among representative samples of households with children aged <12 years in Spain, in 2016 (n=2411) and 2019 (n=2412). Families were interviewed to assess children's SHS exposure in private settings and outdoor public venues and their adoption of home and car smoke-free rules. We used the education level of the home main earner as a proxy for socioeconomic position. Changes over time in the prevalence and socioeconomic inequalities of SHS exposure and smoke-free rules were estimated through adjusted Poisson regression models with robust variance according to sociodemographic covariates (adjusted prevalence ratios, APRs). RESULTS: In 2019, 70.5% of children were exposed to SHS in Spain. No changes between 2016 and 2019 were found for overall SHS exposure, exposure at home, and at school entrances. SHS exposure increased at public transport stations (APR=1.24; 95% CI: 1.03-1.49) and outdoor hospitality venues (APR=1.17; 95% CI: 1.07-1.29) while it decreased in cars (APR=0.74; 95% CI: 0.56-0.98) and parks (APR=0.87; 95% CI: 0.77-0.98). Households with lower education level had higher prevalence of SHS exposure at home in 2019 compared with those with university studies (primary: APR=1.30; 95% CI: 1.11-1.51; secondary: APR=1.12; 95% CI: 1.00-1.25) and were less likely to adopt home indoor smoke-free rules (primary: APR=0.88; 95% CI: 0.79-0.99; secondary: APR=0.95; 95% CI: 0.89-1.02). Socioeconomic inequalities in SHS exposure at home persisted between 2016 and 2019 (p>0.05), while decreased in smoke-free rules in cars (p=0.039). CONCLUSIONS: Reported SHS exposure among children in Spain remained high between 2016 and 2019. Inequalities persisted at home, highlighting the need for measures to reduce such exposure with an equity perspective.

Exploration of thyroglobulin as a biomarker of iodine status in iodine-sufficient and mildly iodine-deficient pregnant women.

PURPOSE: Urinary iodine-to-creatinine ratio (UI/Creat) reflects recent iodine intake but has limitations for assessing habitual intake. Thyroglobulin (Tg) concentration, which increases with thyroid size, appears to be an indicator of longer-term iodine status in children and adults, however, less is known in pregnancy. This study investigated the determinants of serum-Tg in pregnancy and its use as an iodine-status biomarker in settings of iodine-sufficiency and mild-to-moderate deficiency. METHODS: Stored blood samples and existing data from pregnant women from the Netherlands-based Generation R (iodine-sufficient) and the Spain-based INMA (mildly-to-moderately iodine-deficient) cohorts were used. Serum-Tg and iodine status (as spot-urine UI/Creat) were measured at median 13 gestational weeks. Using regression models, maternal socio-demographics, diet and iodine-supplement use were investigated as determinants of serum-Tg, as well as the association between UI/Creat and serum-Tg. RESULTS: Median serum-Tg was 11.1 ng/ml in Generation R (n = 3548) and 11.5 ng/ml in INMA (n = 1168). When using 150 µg/g threshold for iodine deficiency, serum-Tg was higher in women with UI/Creat < 150 vs ≥ 150 µg/g (Generation R, 12.0 vs 10.4 ng/ml, P = 0.010; INMA, 12.8 vs 10.4 ng/ml, P < 0.001); after confounder adjustment, serum-Tg was still higher when UI/Creat < 150 µg/g (regression coefficients: Generation R, B = 0.111, P = 0.050; INMA, B = 0.157, P = 0.010). Iodine-supplement use and milk intake were negatively associated with serum-Tg, whereas smoking was positively associated. CONCLUSION: The association between iodine status and serum-Tg was stronger in the iodine-deficient cohort, than in the iodine-sufficient cohort. Serum-Tg might be a complementary (to UI/Creat) biomarker of iodine status in pregnancy but further evidence is needed.

Maternal iron status during pregnancy and attention deficit/hyperactivity disorder symptoms in 7-year-old children: a prospective cohort study.

Evidence suggests that iron status may be linked to symptoms of childhood attention deficit/hyperactivity disorder (ADHD), but there is little data available on the relationship between iron status in pregnancy and the risk of developing ADHD. And the data that does exist is inconsistent. Our aim here is to assess the effect of maternal serum ferritin (SF) and haemoglobin (Hb) levels during pregnancy on manifestations of ADHD in children at 7 years of age. This prospective study analysed data from 1204 mother-child pairs from three Spanish cohorts participating in the INMA project. Maternal SF and Hb levels during pregnancy and other mother and child characteristics were collected. The children's ADHD behaviours were reported by their parents using Conners' Parent Rating Scale-Revised Short Form (CPRS-R:S). In the unadjusted regression analysis, maternal SF was positively associated with children's T-scores on the subscales Cognitive problems/Inattention (ß: 0.63, 95%CI 0.06-1.19; p = 0.029) and ADHD index (ß: 0.72, 95%CI 0.20-1.24; p = 0.007). These associations were not present after multivariate adjustment or stratification by first and second trimester of pregnancy. The Hb levels were not related to any of the CPRS-R:S subscales in unadjusted or multivariate-adjusted models. We observed no association between maternal SF or Hb levels and the risk of ADHD symptomatology (T-score ≥ 65 for CPRS-R:S subscales). Our results suggest that neither maternal SF nor Hb levels during pregnancy are related to ADHD symptoms in 7-year-old children.

Malignant lymphoma and occupational exposure to extremely low frequency magnetic fields and electrical shocks: a nested case-control study in a cohort of four Nordic countries.

BACKGROUND: Exposure to extremely low frequency magnetic fields (ELF-MFs) and electric shocks is a common occupational risk factor in many workplaces. Recent investigations have highlighted a possible association between such exposures and lymphoma risk. This study was carried out to further explore the association between occupational exposure to ELF-MFs and electric shocks and risk of lymphoma in a large Nordic census-based cohort. METHODS: We included cases of non-Hodgkin's lymphoma (NHL, n=68 978), chronic lymphocytic leukaemia (CLL, n=20 615) and multiple myeloma (MM, n=35 467) diagnosed between 1961 and 2005 in Finland, Iceland, Norway and Sweden. Cases were matched to five controls by year of birth, sex and country. Lifetime occupational ELF-MF and electric shock exposures were assigned to jobs reported in population censuses using job-exposure matrices. The risk of cancer was assessed based on cumulative exposure to ELF-MF and electric shocks. ORs with 95% CIs were estimated using logistic models adjusted for occupational co-exposures relevant to lymphomas. RESULTS: Less than 7% of the cases experienced high levels of ELF-MF. We observed no increased risks among workers exposed to high levels of ELF-MF for NHL (OR: 0.93; CI 0.90 to 0.97), CLL (OR: 0.98; CI 0.92 to 1.05) or MM (OR: 0.96; CI 0.90 to 1.01). CONCLUSION: Our results do not provide support for an association between occupational exposure to ELF-MFs and electric shocks and lymphoma risk.

Maternal occupational exposure to chemicals and child cognitive function.

BACKGROUND: Limited data exist regarding child neurodevelopment in relation to maternal occupational exposure to endocrine-disrupting chemicals (EDCs). METHODS: We included 1058 mother-child pairs from the INfancia y Medio Ambiente (INMA) project (2003-2008). Using a job-exposure matrix, exposure probability scores for ten EDC groups were assigned to each mother based on her longest held job during pregnancy. At the child's 5-year visit, the McCarthy Scales of Children's Abilities was administered, yielding the general cognitive index and scales for specific cognitive domains. We analyzed region-specific associations between EDC exposures and each outcome separately using adjusted linear regression and combined region-specific effect estimates using random-effects meta-analyses. RESULTS: Approximately 24% of women were exposed to at least one EDC group, but exposure to most individual EDC groups was low (<5%). Maternal organic solvent exposure was associated with lower quantitative scores among children (-5.8 points, 95% confidence interval: -11.0, -0.5). Though statistically non-significant, exposures to polycyclic aromatic hydrocarbons, phthalates, alkylphenolic compounds, and miscellaneous chemicals were associated with poorer offspring performance for most or all cognitive domains. CONCLUSIONS: This study found limited evidence for a role of maternal occupational EDC exposures on child cognition. Further research is needed to better characterize exposures among pregnant workers. IMPACT: Using data from a prospective birth cohort, we help fill an important research gap regarding the potential consequences of work-related exposure to endocrine-disrupting chemicals (EDCs) among pregnant women on child neurodevelopment. We expand on existing literature-largely limited to pesticide and organic solvent exposures-by using a job-exposure matrix to estimate exposure to several EDC groups. We found limited evidence of an association between maternal occupational EDC exposure and children's overall cognition. We did observe specific associations between exposure to organic solvents and lower quantitative reasoning scores.

Omega-3 Fatty Acid Intake during Pregnancy and Child Neuropsychological Development: A Multi-Centre Population-Based Birth Cohort Study in Spain.

Background: There are few studies that look at the intake of all types of omega-3 polyunsaturated fatty acids (n-3 PUFAs) during the different stages of pregnancy along with a long-term neuropsychological follow-up of the child. This study aims to explore the association between maternal n-3 PUFA intake during two periods of pregnancy and the child's neuropsychological scores at different ages. Methods: Prospective data were obtained for 2644 pregnant women recruited between 2004 and 2008 in population-based birth cohorts in Spain. Maternal n-3 PUFA intake during the first and third trimester of pregnancy was estimated using validated food frequency questionnaires. Child neuropsychological functions were assessed using Bayley Scales of Infant Development version one (BSID) at 1 year old, the McCarthy Scale of Children's Abilities (MSCA) at 4 years old, and the Attention Network Test (ANT) at 7 years old. Data were analysed using multivariate linear regression models and adjusted for potential covariates, such as maternal social class, education, cohort location, alcohol consumption, smoking, breastfeeding duration, and energy intake. Results: Compared to participants in the lowest quartile (<1.262 g/day) of n-3 PUFA consumption during the first trimester, those in the highest quartile (>1.657 g/day) had a 2.26 points (95% confidence interval (CI): 0.41, 4.11) higher MSCA general cognitive score, a 2.48 points (95% CI: 0.53, 4.43) higher MSCA verbal score, and a 2.06 points (95% CI: 0.166, 3.95) higher MSCA executive function score, and a 11.52 milliseconds (95% CI: −22.95, −0.09) lower ANT hit reaction time standard error. In the third pregnancy trimester, the associations were weaker. Conclusions: Positive associations between n-3 PUFA intake during early pregnancy and child neuropsychological functions at 4 and 7 years of age were found, and further clinical research is needed to confirm these findings.

Association between maternal thyroid function and risk of gestational hypertension and pre-eclampsia: a systematic review and individual-participant data meta-analysis.

BACKGROUND: Adequate maternal thyroid function is important for an uncomplicated pregnancy. Although multiple observational studies have evaluated the association between thyroid dysfunction and hypertensive disorders of pregnancy, the methods and definitions of abnormalities in thyroid function tests were heterogeneous, and the results were conflicting. We aimed to examine the association between abnormalities in thyroid function tests and risk of gestational hypertension and pre-eclampsia. METHODS: In this systematic review and meta-analysis of individual-participant data, we searched MEDLINE (Ovid), Embase, Scopus, and the Cochrane Database of Systematic Reviews from date of inception to Dec 27, 2019, for prospective cohort studies with data on maternal concentrations of thyroid-stimulating hormone (TSH), free thyroxine (FT4), thyroid peroxidase (TPO) antibodies, individually or in combination, as well as on gestational hypertension, pre-eclampsia, or both. We issued open invitations to study authors to participate in the Consortium on Thyroid and Pregnancy and to share the individual-participant data. We excluded participants who had pre-existing thyroid disease or multifetal pregnancy, or were taking medications that affect thyroid function. The primary outcomes were documented gestational hypertension and pre-eclampsia. Individual-participant data were analysed using logistic mixed-effects regression models adjusting for maternal age, BMI, smoking, parity, ethnicity, and gestational age at blood sampling. The study protocol was registered with PROSPERO, CRD42019128585. FINDINGS: We identified 1539 published studies, of which 33 cohorts met the inclusion criteria and 19 cohorts were included after the authors agreed to participate. Our study population comprised 46 528 pregnant women, of whom 39 826 (85·6%) women had sufficient data (TSH and FT4 concentrations and TPO antibody status) to be classified according to their thyroid function status. Of these women, 1275 (3·2%) had subclinical hypothyroidism, 933 (2·3%) had isolated hypothyroxinaemia, 619 (1·6%) had subclinical hyperthyroidism, and 337 (0·8%) had overt hyperthyroidism. Compared with euthyroidism, subclinical hypothyroidism was associated with a higher risk of pre-eclampsia (2·1% vs 3·6%; OR 1·53 [95% CI 1·09-2·15]). Subclinical hyperthyroidism, isolated hypothyroxinaemia, or TPO antibody positivity were not associated with gestational hypertension or pre-eclampsia. In continuous analyses, both a higher and a lower TSH concentration were associated with a higher risk of pre-eclampsia (p=0·0001). FT4 concentrations were not associated with the outcomes measured. INTERPRETATION: Compared with euthyroidism, subclinical hypothyroidism during pregnancy was associated with a higher risk of pre-eclampsia. There was a U-shaped association of TSH with pre-eclampsia. These results quantify the risks of gestational hypertension or pre-eclampsia in women with thyroid function test abnormalities, adding to the total body of evidence on the risk of adverse maternal and fetal outcomes of thyroid dysfunction during pregnancy. These findings have potential implications for defining the optimal treatment target in women treated with levothyroxine during pregnancy, which needs to be assessed in future interventional studies. FUNDING: Arkansas Biosciences Institute and Netherlands Organization for Scientific Research.

Estimated all-day and evening whole-brain radiofrequency electromagnetic fields doses, and sleep in preadolescents.

OBJECTIVE: To investigate the association of estimated all-day and evening whole-brain radiofrequency electromagnetic field (RF-EMF) doses with sleep disturbances and objective sleep measures in preadolescents. METHODS: We included preadolescents aged 9-12 years from two population-based birth cohorts, the Dutch Generation R Study (n = 974) and the Spanish INfancia y Medio Ambiente Project (n = 868). All-day and evening overall whole-brain RF-EMF doses (mJ/kg/day) were estimated for several RF-EMF sources including mobile and Digital Enhanced Cordless Telecommunications (DECT) phone calls (named phone calls), other mobile phone uses, tablet use, laptop use (named screen activities), and far-field sources. We also estimated all-day and evening whole-brain RF-EMF doses in these three groups separately (i.e. phone calls, screen activities, and far-field). The Sleep Disturbance Scale for Children was completed by mothers to assess sleep disturbances. Wrist accelerometers together with sleep diaries were used to measure sleep characteristics objectively for 7 consecutive days. RESULTS: All-day whole-brain RF-EMF doses were not associated with self-reported sleep disturbances and objective sleep measures. Regarding evening doses, preadolescents with high evening whole-brain RF-EMF dose from phone calls had a shorter total sleep time compared to preadolescents with zero evening whole-brain RF-EMF dose from phone calls [-11.9 min (95%CI -21.2; -2.5)]. CONCLUSIONS: Our findings suggest the evening as a potentially relevant window of RF-EMF exposure for sleep. However, we cannot exclude that observed associations are due to the activities or reasons motivating the phone calls rather than the RF-EMF exposure itself or due to chance finding.

Early life multiple exposures and child cognitive function: A multi-centric birth cohort study in six European countries.

Epidemiological studies mostly focus on single environmental exposures. This study aims to systematically assess associations between a wide range of prenatal and childhood environmental exposures and cognition. The study sample included data of 1298 mother-child pairs, children were 6-11 years-old, from six European birth cohorts. We measured 87 exposures during pregnancy and 122 cross-sectionally during childhood, including air pollution, built environment, meteorology, natural spaces, traffic, noise, chemicals and life styles. The measured cognitive domains were fluid intelligence (Raven's Coloured Progressive Matrices test, CPM), attention (Attention Network Test, ANT) and working memory (N-Back task). We used two statistical approaches to assess associations between exposure and child cognition: the exposome-wide association study (ExWAS) considering each exposure independently, and the deletion-substitution-addition algorithm (DSA) considering all exposures simultaneously to build a final multiexposure model. Based on this multiexposure model that included the exposure variables selected by ExWAS and DSA models, child organic food intake was associated with higher fluid intelligence (CPM) scores (beta = 1.18; 95% CI = 0.50, 1.87) and higher working memory (N-Back) scores (0.23; 0.05, 0.41), and child fast food intake (-1.25; -2.10, -0.40), house crowding (-0.39; -0.62, -0.16), and child environmental tobacco smoke (ETS) (-0.89; -1.42, -0.35), were all associated with lower CPM scores. Indoor PM2.5 exposure was associated with lower N-Back scores (-0.09; -0.16, -0.02). Additional associations in the unexpected direction were found: Higher prenatal mercury levels, maternal alcohol consumption and child higher perfluorooctane sulfonic acid (PFOS) levels were associated with better cognitive performance; and higher green exposure during pregnancy with lower cognitive performance. This first comprehensive and systematic study of many prenatal and childhood environmental risk factors suggests that unfavourable child nutrition, family crowdedness and child indoor air pollution and ETS exposures adversely and cross-sectionally associate with cognitive function. Unexpected associations were also observed and maybe due to confounding and reverse causality.

Early-life environmental exposure determinants of child behavior in Europe: A longitudinal, population-based study.

BACKGROUND: Environmental exposures in early life influence the development of behavioral outcomes in children, but research has not considered multiple exposures. We therefore aimed to investigate the impact of a broad spectrum of pre- and postnatal environmental exposures on child behavior. METHODS AND FINDINGS: We used data from the HELIX (Human Early Life Exposome) project, which was based on six longitudinal population-based birth cohorts in Europe. At 6-11 years, children underwent a follow-up to characterize their exposures and assess behavioral problems. We measured 88 prenatal and 123 childhood environmental factors, including outdoor, indoor, chemical, lifestyle and social exposures. Parent-reported behavioral problems included (1) internalizing, (2) externalizing scores, using the child behavior checklist (CBCL), and (3) the Conner's Attention Deficit Hyperactivity Disorder (ADHD) index, all outcomes being discrete raw counts. We applied LASSO penalized negative binomial regression models to identify which exposures were associated with the outcomes, while adjusting for co-exposures. In the 1287 children (mean age 8.0 years), 7.3% had a neuropsychiatric medical diagnosis according to parent's reports. During pregnancy, smoking and car traffic showing the strongest associations (e.g. smoking with ADHD index, aMR:1.31 [1.09; 1.59]) among the 13 exposures selected by LASSO, for at least one of the outcomes. During childhood, longer sleep duration, healthy diet and higher family social capital were associated with reduced scores whereas higher exposure to lead, copper, indoor air pollution, unhealthy diet were associated with increased scores. Unexpected decreases in behavioral scores were found with polychlorinated biphenyls (PCBs) and organophosphate (OP) pesticides. CONCLUSIONS: Our systematic exposome approach identified several environmental contaminants and healthy lifestyle habits that may influence behavioral problems in children. Modifying environmental exposures early in life may limit lifetime mental health risk.

Radiofrequency electromagnetic fields from mobile communication: Description of modeled dose in brain regions and the body in European children and adolescents.

BACKGROUND: Little is known about radiofrequency electromagnetic fields (RF) from mobile technology and resulting dose in young people. We describe modeled integrated RF dose in European children and adolescents combining own mobile device use and surrounding sources. METHODS: Using an integrated RF model, we estimated the daily RF dose in the brain (whole-brain, cerebellum, frontal lobe, midbrain, occipital lobe, parietal lobe, temporal lobes) and the whole-body in 8358 children (ages 8-12) and adolescents (ages 14-18) from the Netherlands, Spain, and Switzerland during 2012-2016. The integrated model estimated RF dose from near-field sources (digital enhanced communication technology (DECT) phone, mobile phone, tablet, and laptop) and far-field sources (mobile phone base stations via 3D-radiowave modeling or RF measurements). RESULTS: Adolescents were more frequent mobile phone users and experienced higher modeled RF doses in the whole-brain (median 330.4 mJ/kg/day) compared to children (median 81.8 mJ/kg/day). Children spent more time using tablets or laptops compared to adolescents, resulting in higher RF doses in the whole-body (median whole-body dose of 81.8 mJ/kg/day) compared to adolescents (41.9 mJ/kg/day). Among brain regions, temporal lobes received the highest RF dose (medians of 274.9 and 1786.5 mJ/kg/day in children and adolescents, respectively) followed by the frontal lobe. In most children and adolescents, calling on 2G networks was the main contributor to RF dose in the whole-brain (medians of 31.1 and 273.7 mJ/kg/day, respectively). CONCLUSION: This first large study of RF dose to the brain and body of children and adolescents shows that mobile phone calls on 2G networks are the main determinants of brain dose, especially in temporal and frontal lobes, whereas whole-body doses were mostly determined by tablet and laptop use. The modeling of RF doses provides valuable input to epidemiological research and to potential risk management regarding RF exposure in young people.

Association between estimated whole-brain radiofrequency electromagnetic fields dose and cognitive function in preadolescents and adolescents.

OBJECTIVE: To investigate the association between estimated whole-brain radiofrequency electromagnetic fields (RF-EMF) dose, using an improved integrated RF-EMF exposure model, and cognitive function in preadolescents and adolescents. METHODS: Cross-sectional analysis in preadolescents aged 9-11 years and adolescents aged 17-18 years from the Dutch Amsterdam Born Children and their Development Study (n = 1664 preadolescents) and the Spanish INfancia y Medio Ambiente Project (n = 1288 preadolescents and n = 261 adolescents), two population-based birth cohort studies. Overall whole-brain RF-EMF doses (mJ/kg/day) were estimated for several RF-EMF sources together including mobile and Digital Enhanced Cordless Telecommunications phone calls (named phone calls), other mobile phone uses than calling, tablet use, laptop use (named screen activities), and far-field sources. We also estimated whole-brain RF-EMF doses in these three groups separately (i.e. phone calls, screen activities, and far-field) that lead to different patterns of RF-EMF exposure. We assessed non-verbal intelligence in the Dutch and Spanish preadolescents, information processing speed, attentional function, and cognitive flexibility in the Spanish preadolescents, and working memory and semantic fluency in the Spanish preadolescents and adolescents using validated neurocognitive tests. RESULTS: Estimated overall whole-brain RF-EMF dose was 90.1 mJ/kg/day (interquartile range (IQR) 42.7; 164.0) in the Dutch and Spanish preadolescents and 105.1 mJ/kg/day (IQR 51.0; 295.7) in the Spanish adolescents. Higher overall estimated whole-brain RF-EMF doses from all RF-EMF sources together and from phone calls were associated with lower non-verbal intelligence score in the Dutch and Spanish preadolescents (-0.10 points, 95% CI -0.19; -0.02 per 100 mJ/kg/day increase in each exposure). However, none of the whole-brain RF-EMF doses was related to any other cognitive function outcome in the Spanish preadolescents or adolescents. CONCLUSIONS: Our results suggest that higher brain exposure to RF-EMF is related to lower non-verbal intelligence but not to other cognitive function outcomes. Given the cross-sectional nature of the study, the small effect sizes, and the unknown biological mechanisms, we cannot discard that our resultsare due to chance finding or reverse causality. Longitudinal studies on RF-EMF brain exposure and cognitive function are needed.

Prenatal exposure to organophosphate pesticides and brain morphology and white matter microstructure in preadolescents.

BACKGROUND: Prenatal exposure to organophosphate (OP) pesticides associate with impaired neurodevelopment in humans and animal models. However, much uncertainty exists about the brain structural alterations underlying these associations. The objective of this study was to determine whether maternal OP pesticide metabolite concentrations in urine repeatedly measured during gestation are associated with brain morphology and white matter microstructure in 518 preadolescents aged 9-12 years. METHOD: Data came from 518 mother-child pairs participating in the Generation R Study, a population-based birth cohort from Rotterdam, the Netherlands. Maternal urine concentrations were determined for 6 dialkylphosphates (DAPs) including 3 dimethyl (DM) and 3 diethyl (DE) alkyl phosphate metabolites, collected at early, mid, and late pregnancy. At child's age 9-12 years, magnetic resonance imaging was performed to obtain T1-weighted images for brain volumes and surface-based cortical thickness and cortical surface area, and diffusion tensor imaging was used to measure white matter microstructure through fractional anisotropy (FA) and mean diffusivity (MD). Linear regression models were fit for the averaged prenatal exposure across pregnancy. RESULTS: DM and DE metabolite concentrations were not associated with brain volumes, cortical thickness, and cortical surface area. However, a 10-fold increase in averaged DM metabolite concentrations across pregnancy was associated with lower FA (B = -1.00, 95%CI = -1.80, -0.20) and higher MD (B = 0.13, 95%CI = 0.04, 0.21). Similar associations were observed for DE concentrations. CONCLUSIONS: This study provides the first evidence that OP pesticides may alter normal white matter microstructure in children, which could have consequences for normal neurodevelopment. No associations were observed with structural brain morphology, including brain volumes, cortical thickness, and cortical surface area.

Estimated whole-brain and lobe-specific radiofrequency electromagnetic fields doses and brain volumes in preadolescents.

OBJECTIVE: To assess the association between estimated whole-brain and lobe-specific radiofrequency electromagnetic fields (RF-EMF) doses, using an improved integrated RF-EMF exposure model, and brain volumes in preadolescents at 9-12 years old. METHODS: Cross-sectional analysis in preadolescents aged 9-12 years from the Generation R Study, a population-based birth cohort set up in Rotterdam, The Netherlands (n = 2592). An integrated exposure model was used to estimate whole-brain and lobe-specific RF-EMF doses (mJ/kg/day) from different RF-EMF sources including mobile and Digital Enhanced Cordless Telecommunications (DECT) phone calls, other mobile phone uses than calling, tablet use, laptop use, and far-field sources. Whole-brain and lobe-specific RF-EMF doses were estimated for all RF-EMF sources together (i.e. overall) and for three groups of RF-EMF sources that lead to a different pattern of RF-EMF exposure. Information on brain volumes was extracted from magnetic resonance imaging scans. RESULTS: Estimated overall whole-brain RF-EMF dose was 84.3 mJ/kg/day. The highest overall lobe-specific dose was estimated in the temporal lobe (307.1 mJ/kg/day). Whole-brain and lobe-specific RF-EMF doses from all RF-EMF sources together, from mobile and DECT phone calls, and from far-field sources were not associated with global, cortical, or subcortical brain volumes. However, a higher whole-brain RF-EMF dose from mobile phone use for internet browsing, e-mailing, and text messaging, tablet use, and laptop use while wirelessly connected to the internet was associated with a smaller caudate volume. CONCLUSIONS: Our results suggest that estimated whole-brain and lobe-specific RF-EMF doses were not related to brain volumes in preadolescents at 9-12 years old. Screen activities with mobile communication devices while wirelessly connected to the internet lead to low RF-EMF dose to the brain and our observed association may thus rather reflect effects of social or individual factors related to these specific uses of mobile communication devices. However, we cannot discard residual confounding, chance finding, or reverse causality. Further studies on mobile communication devices and their potential negative associations with brain development are warranted, regardless whether associations are due to RF-EMF exposure or to other factors related to their use.

Association of maternal thyroid function with birthweight: a systematic review and individual-participant data meta-analysis.

BACKGROUND: Adequate transplacental passage of maternal thyroid hormone is important for normal fetal growth and development. Maternal overt hypothyroidism and hyperthyroidism are associated with low birthweight, but important knowledge gaps remain regarding the effect of subclinical thyroid function test abnormalities on birthweight-both in general and during the late second and third trimester of pregnancy. The aim of this study was to examine associations of maternal thyroid function with birthweight. METHODS: In this systematic review and individual-participant data meta-analysis, we searched MEDLINE (Ovid), Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar from inception to Oct 15, 2019, for prospective cohort studies with data on maternal thyroid function during pregnancy and birthweight, and we issued open invitations to identify study authors to join the Consortium on Thyroid and Pregnancy. We excluded participants with multiple pregnancies, in-vitro fertilisation, pre-existing thyroid disease or thyroid medication usage, miscarriages, and stillbirths. The main outcomes assessed were small for gestational age (SGA) neonates, large for gestational age neonates, and newborn birthweight. We analysed individual-participant data using mixed-effects regression models adjusting for maternal age, BMI, ethnicity, smoking, parity, gestational age at blood sampling, fetal sex, and gestational age at birth. The study protocol was pre-registered at the International Prospective Register of Systematic Reviews, CRD42016043496. FINDINGS: We identified 2526 published reports, from which 36 cohorts met the inclusion criteria. The study authors for 15 of these cohorts agreed to participate, and five more unpublished datasets were added, giving a study population of 48 145 mother-child pairs after exclusions, of whom 1275 (3·1%) had subclinical hypothyroidism (increased thyroid stimulating hormone [TSH] with normal free thyroxine [FT4]) and 929 (2·2%) had isolated hypothyroxinaemia (decreased FT4 with normal TSH). Maternal subclinical hypothyroidism was associated with a higher risk of SGA than was euthyroidism (11·8% vs 10·0%; adjusted risk difference 2·43%, 95% CI 0·43 to 4·81; odds ratio [OR] 1·24, 1·04 to 1·48; p=0·015) and lower mean birthweight (mean difference -38 g, -61 to -15; p=0·0015), with a higher effect estimate for measurement in the third trimester than in the first or second. Isolated hypothyroxinaemia was associated with a lower risk of SGA than was euthyroidism (7·3% vs 10·0%, adjusted risk difference -2·91, -4·49 to -0·88; OR 0·70, 0·55 to 0·91; p=0·0073) and higher mean birthweight (mean difference 45 g, 18 to 73; p=0·0012). Each 1 SD increase in maternal TSH concentration was associated with a 6 g lower birthweight (-10 to -2; p=0·0030), with higher effect estimates in women who were thyroid peroxidase antibody positive than for women who were negative (pinteraction=0·10). Each 1 SD increase in FT4 concentration was associated with a 21 g lower birthweight (-25 to -17; p<0·0001), with a higher effect estimate for measurement in the third trimester than the first or second. INTERPRETATION: Maternal subclinical hypothyroidism in pregnancy is associated with a higher risk of SGA and lower birthweight, whereas isolated hypothyroxinaemia is associated with lower risk of SGA and higher birthweight. There was an inverse, dose-response association of maternal TSH and FT4 (even within the normal range) with birthweight. These results advance our understanding of the complex relationships between maternal thyroid function and fetal outcomes, and they should prompt careful consideration of potential risks and benefits of levothyroxine therapy during pregnancy. FUNDING: Netherlands Organization for Scientific Research (grant 401.16.020).

Association of Iron Status and Intake During Pregnancy with Neuropsychological Outcomes in Children Aged 7 Years: The Prospective Birth Cohort Infancia y Medio Ambiente (INMA) Study.

Early iron status plays an important role in prenatal neurodevelopment. Iron deficiency and high iron status have been related to alterations in child cognitive development; however, there are no data about iron intake during pregnancy with other environmental factors in relation to long term cognitive functioning of children. The aim of this study is to assess the relationship between maternal iron status and iron intake during pregnancy and child neuropsychological outcomes at 7 years of age. We used data from the INMA Cohort population-based study. Iron status during pregnancy was assessed according to serum ferritin levels, and iron intake was assessed with food frequency questionnaires. Working memory, attention, and executive function were assessed in children at 7 years old with the N-Back task, Attention Network Task, and the Trail Making Test, respectively. The results show that, after controlling for potential confounders, normal maternal serum ferritin levels (from 12 mg/L to 60 mg/L) and iron intake (from 14.5 mg/day to 30.0 mg/day), respectively, were related to better scores in working memory and executive functioning in offspring. Since these functions have been associated with better academic performance and adaptation to the environment, maintaining a good state of maternal iron from the beginning of pregnancy could be a valuable strategy for the community.

Association of Exposure to Ambient Air Pollution With Thyroid Function During Pregnancy.

Importance: Air pollutants interact with estrogen nuclear receptors, but their effect on thyroid signaling is less clear. Thyroid function is of particular importance for pregnant women because of the thyroid's role in fetal brain development. Objective: To determine the short-term association of exposure to air pollution in the first trimester with thyroid function throughout pregnancy. Design, Setting, and Participants: In this cohort study, 9931 pregnant women from 4 European cohorts (the Amsterdam Born Children and Their Development Study, the Generation R Study, Infancia y Medio Ambiente, and Rhea) and 1 US cohort (Project Viva) with data on air pollution exposure and thyroid function during pregnancy were included. The recruitment period for the Amsterdam Born Children and Their Development Study was January 2003 to March 2004; for Generation R, April 2002 to January 2006; for Infancia y Medio Ambiente, November 2003 to January 2008; for Rhea, February 2007 to February 2008; and for Project Viva, April 1999 to November 2002. Statistical analyses were conducted from January 2018 to April 2019. Main Outcomes and Measures: Residential air pollution concentrations (ie, nitrogen oxide and particulate matter [PM]) during the first trimester of pregnancy were estimated using land-use regression and satellite-derived aerosol optical depth models. Free thyroxine, thyrotropin, and thyroid peroxidase antibody levels were measured across gestation. Hypothyroxinemia was defined as free thyroxine below the fifth percentile of the cohort distribution with normal thyrotropin levels, following the American Thyroid Association guidelines. Results: Among 9931 participants, the mean (SD) age was 31.2 (4.8) years, 4853 (48.9%) had more than secondary educational levels, 5616 (56.6%) were nulliparous, 404 (4.2%) had hypothyroxinemia, and 506 (6.7%) tested positive for thyroid peroxidase antibodies. Concentrations of nitrogen dioxide and PM with an aerodynamic diameter of 2.5 µm or less (PM2.5) were lower and had less variation in women in the US cohort than those in European cohorts. No associations of nitrogen oxide with thyroid function were found. Higher exposures to PM2.5 were associated with higher odds of hypothyroxinemia in pregnant women (odds ratio per 5-µg/m3 change, 1.21; 95% CI, 1.00-1.47). Although exposure to PM with an aerodynamic diameter of 10 µm or less was not significantly associated with hypothyroxinemia, the coefficient was similar to that for the association of PM2.5 with hypothyroxinemia (odds ratio per 10-µg/m3 change, 1.18; 95% CI, 0.93-1.48). Absorbances of PM2.5 and PM with aerodynamic diameter from 2.5 to 10 µg and were not associated with hypothyroxinemia. There was substantial heterogeneity among cohorts with respect to thyroid peroxidase antibodies (P for heterogeneity, <.001), showing associations of nitrogen oxide and PM with thyroid autoimmunity only in the women in the Generation R Study. Conclusions and Relevance: The findings of this study suggest that first-trimester exposures to PM2.5 were associated with mild thyroid dysfunction throughout pregnancy. The association of PM2.5 exposure with thyroid function during pregnancy is of global health importance because air pollution exposure is widespread and hypothyroxinemia may adversely influence the brain development of offspring.

Organophosphate pesticide metabolite concentrations in urine during pregnancy and offspring attention-deficit hyperactivity disorder and autistic traits.

BACKGROUND: Prenatal exposure to organophosphate (OP) pesticides has been associated with altered neuronal cell development and behavioral changes in animal offspring. However, the few studies investigating the association between prenatal OP pesticide exposure and neurodevelopmental outcomes such as Attention-Deficit Hyperactivity Disorder (ADHD) and autistic traits in children produced mixed findings. OBJECTIVE: The objective of the present study was to examine whether maternal urinary concentrations of OP pesticide metabolites are associated with ADHD and autistic traits in children participating in the Generation R Study, a population-based birth cohort from Rotterdam, the Netherlands. METHOD: Maternal concentrations of 6 dialkylphosphates (DAPs) were measured using gas chromatography coupled with tandem mass spectrometry in urine samples collected at <18 weeks, 18-25 weeks, and > 25 weeks of gestation in 784 mother-child pairs. DAP metabolite concentrations were expressed as molar concentrations divided by creatinine levels and log10 transformed. ADHD traits were measured at ages 3, 6, and 10 years using the Child Behavior Checklist (CBCL) (n = 781) and autistic traits were measured at age 6 years using the Social Responsiveness Scale (SRS) (n = 622). First, regression models were fit for the averaged prenatal exposure across pregnancy. Second, we investigated associations for each collection phase separately, and applied a mutually adjusted model in which the effect of prenatal DAP concentrations from each time period on ADHD and autistic traits were jointly estimated. All associations were adjusted for relevant confounders. RESULTS: Median DAP metabolite concentration was 309 nmol/g creatinine at <18 weeks, 316 nmol/g creatinine at 18-25 weeks, and 308 nmol/g creatinine at >25 weeks of gestation. Overall, DAP metabolite concentrations were not associated with ADHD traits. For instance, a log10 increase in averaged total DAP concentrations across gestation was not associated with a lower ADHD score (-0.03 per SD 95 CI: -0.28 to 0.23). Similarly, no associations between maternal DAP concentrations and autistic traits were detected. CONCLUSIONS: In this study of maternal urinary DAP metabolite concentrations during pregnancy, we did not observe associations with ADHD and autistic traits in children. These are important null observations because of the relatively high background DAP concentrations across pregnancy, the relatively large sample size, and the 10-year follow-up of the offspring. Given the measurement error inherent in our OP pesticide exposure biomarkers, future studies using more urine samples are needed to accurately measure OP pesticide exposure over pregnancy in relation to ADHD and autistic traits.