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Background: The EU LifeCycle Project was launched in 2017 to combine, harmonize, and analyze data from more than 250,000 participants across Europe and Australia, involving cohorts participating in the EU-funded LifeCycle Project. The purpose of this cohort description is to provide a detailed overview of the major measures within mental health domains that are available in 17 European and Australian cohorts participating in the LifeCycle Project. Methods: Data on cognitive, behavioral, and psychological development has been collected on participants from birth until adulthood through questionnaire and medical data. We developed an inventory of the available data by mapping individual instruments, domain types, and age groups, providing the basis for statistical harmonization across mental health measures. Results: The mental health data in LifeCycle contain longitudinal and cross-sectional data from birth throughout the life course, covering domains across a wide range of behavioral and psychopathology indicators and outcomes, including executive function, depression, ADHD, and cognition. These data span a unique combination of qualitative data collected through behavioral/cognitive/mental health questionnaires and examination, as well as data from biological samples and indices in the form of imaging (MRI, fetal ultrasound) and DNA methylation data. Harmonized variables on a subset of mental health domains have been developed, providing statistical equivalence of measures required for longitudinal meta-analyses across instruments and cohorts. Conclusion: Mental health data harmonized through the LifeCycle project can be used to study life-course trajectories and exposure-outcome models that examine early life risk factors for mental illness and develop predictive markers for later-life disease.

Background: Being born small for gestational age (SGA

Altered maternal haemoglobin levels during pregnancy are associated with pre-clinical and clinical conditions affecting the fetus. Evidence from animal models suggests that these associations may be partially explained by differential DNA methylation in the newborn with possible long-term consequences. To test this in humans, we meta-analyzed the epigenome-wide associations of maternal haemoglobin levels during pregnancy with offspring DNA methylation in 3,967 newborn cord blood and 1,534 children and 1,962 adolescent whole-blood samples derived from 10 cohorts. DNA methylation was measured using Illumina Infinium Methylation 450K or MethylationEPIC arrays covering 450,000 and 850,000 methylation sites, respectively. There was no statistical support for the association of maternal haemoglobin levels with offspring DNA methylation either at individual methylation sites or clustered in regions. For most participants, maternal haemoglobin levels were within the normal range in the current study, whereas adverse perinatal outcomes often arise at the extremes. Thus, this study does not rule out the possibility that associations with offspring DNA methylation might be seen in studies with more extreme maternal haemoglobin levels. Study-specific funding information can be found in the Supplementary Methods. JR, AH, EL, and SS were supported by the European Union’s Horizon 2020 research and innovation program [grant numbers 633595 (DynaHEALTH) and 733206 (LifeCycle)], Academy of Finland [grant number 285547 (EGEA)] and the Biocenter Oulu. ACJ was funded by the National Institute of Environmental Health Sciences [grant number R00ES023450]. AK was supported by the National Institute of Environmental Health Sciences [grant number R01ES021357]. DCa was funded by the UK Medical Research Council [grant number MC_UU_00011/7]. EKa received funding from the Horizon2020 grant for RECAP Research on Children and Adults Born Preterm [grant number 733280], Academy of Finland [grant number 315690], Foundation for Pediatric Research, Novo Nordisk Foundation, Signe and Ane Gyllenberg Foundation and Sigrid Jusélius Foundation. EKe received funding from the Finnish Medical Association. MG was supported by Miguel Servet fellowship from the Institute of Health Carlos III [grant numbers MS13/00054, CP18/00018]. MVä received funding from the Research Funds of Oulu University Hospital, Juho Vainio Foundation and Signe and Ane Gyllenberg Foundation. RCH was supported by the National Health and Medical Research Council Fellowship Grants [grant number 1053384]. SJL was supported by the intramural research program of the National Institutes of Health, National Institute of Environmental Health Sciences. SM received funding from the University of Oulu Graduate School. SR was supported by National Health and Medical Research Council EU [grant number 1142858] and the Department of Health, Western Australia FutureHealth fund in connection with the European Union’s Horizon 2020 [grant number 733206].

[EN]Background: The urban environment may influence neurodevelopment from conception onwards, but there is no evaluation of the impact of multiple groups of exposures simultaneously. We investigated the association between early-life urban environment and cognitive and motor function in children. Methods: We used data from 5403 mother-child pairs from four population-based birth-cohorts (UK, France, Spain, and Greece). We estimated thirteen urban home exposures during pregnancy and childhood, including: built environment, natural spaces, and air pollution. Verbal, non-verbal, gross motor, and fine motor functions were assessed using validated tests at five years old. We ran adjusted multi-exposure models using the Deletion-Substitution-Addition algorithm. Results: Higher greenness exposure within 300 m during pregnancy was associated with higher verbal abilities (1.5 points (95% confidence interval 0.4, 2.7) per 0.20 unit increase in greenness). Higher connectivity density within 100 m and land use diversity during pregnancy were related to lower verbal abilities. Childhood exposure to PM2.5 mediated 74% of the association between greenness during childhood and verbal abilities. Higher exposure to PM2.5 during pregnancy was related to lower fine motor function (-1.2 points (-2.1, -0.4) per 3.2 mu g/m3 increase in PM2.5). No associations were found with non-verbal abilities and gross motor function. Discussion: This study suggests that built environment, greenness, and air pollution may impact child cognitive and motor function at five years old. This study adds evidence that well-designed urban planning may benefit children's cognitive and motor development. Acknowledgements We are grateful to all the participating children, parents, practi-tioners and researchers in the four countries who took part in this study. This work was supported by funding from the European Community's Seventh Framework Programme [FP7/2007-206 n 308333; the HELIX project] . This INMA cohort was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds, FIS PI06/0867, FIS-PI09/00090, FIS and FIS-PI18/01142 incl. FEDER funds, FIS-FEDER: PI03/1615, PI04/1509, PI04/1112, PI04/1931, PI05/1079, PI05/1052, PI06/1213, PI07/0314, PI09/02647, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, PI16/00118 and PI17/00663; FIS-FSE: 17/00260; Miguel Servet-FEDER CP11/00178, CP15/00025, CPII16/00051, and CPII18/00018) , from UE (FP7-ENV-2011 cod 282957, HEALTH.2010.2.4.5-1, and H2020 n 824989) , Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundacio La marato de TV3 (090430) , Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, and UGP-15-249) , Alicia Koplowitz Foundation 2017, CIBERESP, Department of Health of the Basque Government (2013111089, 2009111069, 2013111089, 2015111065 and 2018111086) , Provincial Government of Gipuzkoa (DFG06/002, DFG08/001, DFG15/221 and DFG 89/17) and annual agreements with the municipalities of the study area (Zumarraga, Urretxu , Legazpi, Azkoitia y Azpeitia y Beasain) . We acknowledge support from the Spanish Ministry of Science and Inno-vation and the State Research Agency through the "Centro de Excelencia Severo Ochoa 2019-2023" Program (CEX2018-000806-S) , and support from the Generalitat de Catalunya through the CERCA Program. The work was also supported by MICINN [MTM2015-68140-R] and Centro Nacional de Genotipado-CEGEN-PRB2-ISCIII (Spain) . The Rhea project was financially supported by European projects, and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011-2014; "Rhea Plus": Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012-15) . This paper presents independent research funded by the National Institute for Health Research (NIHR) under its Collaboration for Applied Health Research and Care (CLAHRC) for Yorkshire and Humber (UK) . The EDEN study was supported by Foundation for medical research (FRM) , National Agency for Research (ANR) , National Institute for Research inPublic health (IRESP: TGIR cohorte sante 2008 program) , French Min-istry of Health (DGS) , French Ministry of Research, INSERM Bone and Joint Diseases National Research (PRO-A) , and Human Nutrition Na-tional Research Programs, Paris-Sud University, Nestle, French National Institute for Population Health Surveillance (InVS) , French National Institute for Health Education (INPES) , the European Union FP7 pro-grams (ESCAPE, ENRIECO, Medall projects) , Diabetes National Research Program (through a collaboration with the French Association of Diabetic Patients (AFD) ) , French Agency for Environmental Health Safety and French National Agency for Food Security (now ANSES) , Mutuelle Generale de l'Education Nationale a complementary health insurance (MGEN) , French-speaking association for the study of diabetes and metabolism (ALFEDIAM) . Core support for Born in Bradford is also provided by the Wellcome Trust (WT101597MA, UK) . Born in Bradford (BiB) is only possible because of the enthusiasm and commitment of the children and parents in BiB. We are grateful to all the participants, health professionals, schools and researchers who have made BiB happen. BiB receives funding from the ESRC/MRC, the Wellcome Trust (WT101597MA) and the National Institute for Health Research York-shire and Humber ARC (reference: NIHR20016) . M. Mon-Williams was supported by a Fellowship from the Alan Turing Institute. Additional funding from the National Institute of Environmental Health Science supported Dr Chatzi (R01ES030691, R01ES029944, R01ES030364, R21ES029681, and P30ES007048) . The views expressed are those of the authors, and not necessarily those of the NHS or the NIHR. None of the funders were involved in designing the study, collecting the data, analyzing or interpreting the data, deciding to submit the article for publication, or the writing of the report. Data sharing statement The HELIX data warehouse has been established as an accessible resource for collaborative research involving researchers external to the project. Access to HELIX data is based on approval by the HELIX Project Executive Committee and by the individual cohorts. Further details on the content of the data warehouse (data catalogue) and procedures for external access are described on the project website (http:// www.proj-ecthelix.eu/index.php/es/data-inventory) .

Background: Environmental noise exposure is increasing but limited research has been done on the association with emotional, aggressive, and attention-deficit/hyperactivity disorder (ADHD)-related symptoms in children. Objective: To analyze the association between prenatal and childhood environmental noise exposure and emotional, aggressive, and ADHD-related symptoms in children from two European birth cohorts. Methods: We included 534 children from the Spanish INMA-Sabadell Project and 7424 from the Dutch Generation R Study. Average 24 h noise exposure at the participants' home address during pregnancy and childhood periods were estimated using EU maps from road traffic noise and total noise (road, aircraft, railway, and industry). Symptom outcomes were assessed using validated questionnaires: Strengths and Difficulties Questionnaire, Child Behavioral Checklist, ADHD Criteria of Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition List, and Conner's Parent Rating Scale-Revised at 4, 7 and 9 years (INMA-Sabadell cohort) and 18 months, 3, 5, and 9 years (Generation R Study). Adjusted linear mixed models of prenatal and repeated childhood noise exposure with repeated symptom outcomes were run separately by cohort and overall estimates were combined with random-effects meta-analysis. Results: Average prenatal and childhood road traffic noise exposure levels were 61.3 (SD 6.1) and 61.7 (SD 5.8) for INMA-Sabadell and 54.6 (SD 7.9) and 51.6 (SD 7.1) for Generation R, respectively. Prenatal and childhood road traffic noise exposure were not associated with emotional, aggressive, or ADHD-related symptoms. No heterogeneity was observed between cohorts and results were comparable for total noise exposure. Conclusions: No association was observed between prenatal or childhood road traffic or total noise exposure and symptom outcomes in children. Future studies should include a more comprehensive noise exposure assessment considering noise sensitivity and noise exposure at different settings such as work for pregnant women and school for children. Background: Environmental noise exposure is increasing but limited research has been done on the association with emotional, aggressive, and attention-deficit/hyperactivity disorder (ADHD)-related symptoms in children. Objective: To analyze the association between prenatal and childhood environmental noise exposure and emotional, aggressive, and ADHD-related symptoms in children from two European birth cohorts. Methods: We included 534 children from the Spanish INMA-Sabadell Project and 7424 from the Dutch Generation R Study. Average 24 h noise exposure at the participants' home address during pregnancy and childhood periods were estimated using EU maps from road traffic noise and total noise (road, aircraft, railway, and industry). Symptom outcomes were assessed using validated questionnaires: Strengths and Difficulties Questionnaire, Child Behavioral Checklist, ADHD Criteria of Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition List, and Conner's Parent Rating Scale-Revised at 4, 7 and 9 years (INMA-Sabadell cohort) and 18 months, 3, 5, and 9 years (Generation R Study). Adjusted linear mixed models of prenatal and repeated childhood noise exposure with repeated symptom outcomes were run separately by cohort and overall estimates were combined with random-effects meta-analysis. Results: Average prenatal and childhood road traffic noise exposure levels were 61.3 (SD 6.1) and 61.7 (SD 5.8) for INMA-Sabadell and 54.6 (SD 7.9) and 51.6 (SD 7.1) for Generation R, respectively. Prenatal and childhood road traffic noise exposure were not associated with emotional, aggressive, or ADHD-related symptoms. No heterogeneity was observed between cohorts and results were comparable for total noise exposure. Conclusions: No association was observed between prenatal or childhood road traffic or total noise exposure and symptom outcomes in children. Future studies should include a more comprehensive noise exposure assessment considering noise sensitivity and noise exposure at different settings such as work for pregnant women and school for children.

Background: Severe iodine deficiency during pregnancy can cause intellectual disability, presumably through inadequate placental transfer of maternal thyroid hormone to the fetus. The association between mild-to-moderate iodine deficiency and child neurodevelopmental problems is not well understood. Objectives: We investigated the association of maternal iodine status during pregnancy with child attention-deficit hyperactivity disorder (ADHD) and autistic traits. Methods: This was a collaborative study of 3 population-based birth cohorts: Generation R (n = 1634), INfancia y Medio Ambiente (n = 1293), and the Avon Longitudinal Study of Parents and Children (n = 2619). Exclusion criteria were multiple fetuses, fertility treatment, thyroid-interfering medication use, and pre-existing thyroid disease. The mean age of assessment in the cohorts was between 4.4 and 7.7 y for ADHD symptoms and 4.5 and 7.6 y for autistic traits. We studied the association of the urinary iodine-to-creatinine ratio (UI/Creat)

Purpose As a component of thyroid hormones, adequate iodine intake is essential during pregnancy for fetal neurodevelopment. Across Europe, iodine deficiency is common in pregnancy, but data are lacking on the predictors of iodine status at this life stage. We, therefore, aimed to explore determinants of iodine status during pregnancy in three European populations of differing iodine status. Methods Data were from 6566 pregnant women from three prospective population-based birth cohorts from the United Kingdom (ALSPAC, n = 2852), Spain (INMA, n = 1460), and The Netherlands (Generation R, n = 2254). Urinary iodine-to-creatinine ratio (UI/Creat, µg/g) was measured in spot-urine samples in pregnancy (≤ 18-weeks gestation). Maternal dietary intake, categorised by food groups (g/day), was estimated from food-frequency questionnaires (FFQs). Multivariable regression models used dietary variables (energy-adjusted) and maternal characteristics as predictors of iodine status. Results Median UI/Creat in pregnant women of ALSPAC, INMA, and Generation R was 121, 151, and 210 µg/g, respectively. Maternal age was positively associated with UI/Creat in all cohorts (P ˂ 0.001), while UI/Creat varied by ethnicity only in Generation R (P ˂ 0.05). Of the dietary predictors, intake of milk and dairy products (per 100 g/day) was positively associated with UI/Creat in all cohorts [ALSPAC (B = 3.73, P ˂ 0.0001); INMA (B = 6.92, P = 0.002); Generation R (B = 2.34, P = 0.001)]. Cohort-specific dietary determinants positively associated with UI/Creat included fish and shellfish in ALSPAC and INMA, and eggs and cereal/cereal products in Generation R. Conclusions The cohort-specific dietary determinants probably reflect not only dietary habits but iodine-fortification policies; hence, public-health interventions to improve iodine intake in pregnancy need to be country-specific.

Despite extensive study, the role of air pollution in gestational diabetes remains unclear, and there is limited evidence of the beneficial impact of residential greenness on metabolic dysfunction during pregnancy. We used data from mothers in the Spanish INfancia y Medio Ambiente (INMA) Project from 2003–2008. We obtained spatiotemporally resolved estimates of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) exposures in early pregnancy and estimated residential greenness using satellite-based Normal Difference Vegetation Index (NDVI) within 100, 300 and 500 m buffers surrounding the mother’s residence. We applied logistic regression models to evaluate associations between each of the three exposures of interest and (a) glucose intolerance and (b) abnormal lipid levels. We found limited evidence of associations between increases in PM2.5 and NO2 exposures and the metabolic outcomes. Though not statistically significant, high PM2.5 exposure (≥25 µg/m3) was associated with increased odds of glucose intolerance (OR = 1.16, 95% CI: 0.82, 1.63) and high cholesterol (OR = 1.14, 95% CI: 0.90, 1.44). High NO2 exposure (≥39.8 µg/m3) was inversely associated with odds of high triglycerides (OR = 0.70, 95% CI: 0.45, 1.08). Whereas NDVI was not associated with glucose intolerance, odds of high triglycerides were increased, although the results were highly imprecise. Results were unchanged when the air pollutant variables were included in the regression models. Given the equivocal findings in our study, additional investigations are needed to assess effects of air pollution and residential greenness on metabolic dysfunction during pregnancy. This work is supported by a National Institute of Environmental Health Sciences (NIEHS) fellowship from the Training in Precision Environmental Health Sciences (TPEHS) Program (NIH Grant No. T32ES027801). E.S., K.W.W., and C.I.A. were partially supported by a NIEHS P30 Environmental Health Sciences Core Center grant (P30ES030285). The INMA study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041; FIS-FEDER: PI03/1615, PI04/1509, PI04/1112, PI04/1931, PI05/1079, PI05/1052, PI06/0867, PI06/1213, PI07/0314, PI09/02647, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, PI17/00663, FIS-PI18/01142 incl. FEDER funds; Miguel Servet-FEDER CP11/00178, CP15/00025, and CPII16/00051, CPII18/00018), Generalitat de Catalunya-CIRIT 1999SGR 00241, EU Commission (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, and UGP-15-249), and Alicia Koplowitz Foundation 2017, Department of Health of the Basque Government (2005111093), Provincial Government of Gipuzkoa (DFG06/002), and annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain). We also acknowledge support from the Spanish Ministry of Science and Innovation and the State Research Agency through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program.

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., Graphical abstract Prenatal and childhood exposome-wide associations with child fluid intelligence (CPM). The exposures selected by Deletion-substitution-addition algorithm are represented by a triangle. Child fluid intelligence is mainly associated with childhood exposome, fast-food (negative association, left sided) and organic food consumption (positive, right sided), house crowding (negative, left sided), and child environmental tobacco smoke (ETS, negative, left sided). Image 1, Highlights • Previous evidence for environmental risk factor associations with neurodevelopment is based on analyses of single exposures. • We systematically analysed multiple environmental exposures in relation to child neurodevelopment. • The findings describe a list of outcome-related exposures: Diet, house crowding, indoor air pollution and tobacco smoke. • The findings show methodological complexities of analysing multiple exposures and their associations with neurodevelopment.

Purpose To investigate the association between telecommunication and other screen devices use and subjective and objective sleep measures in adolescents at 17–18 years. Methods Cross-sectional study on adolescents aged 17–18 years from a Spanish population-based birth cohort established in Menorca in 1997–1998. Information on devices use was collected using self-reported questionnaires. Mobile Phone Problematic Use Scale was used to assess mobile phone use dependency. Pittsburgh Sleep Quality Index was used to assess subjective sleep (n = 226). ActiGraph wGT3X-BT for 7 nights was used to assess objective sleep (n = 110). Results One or more cordless phone calls/week was associated with a lower sleep quality [Prevalence Ratio (PR) 1.30 (95%Confidence Interval (CI) 1.04; 1.62)]. Habitual and frequent problematic mobile phone use was associated with a lower sleep quality [PR 1.55 (95%CI 1.03; 2.33) and PR 1.67 (95%CI 1.09; 2.56), respectively]. Higher tablet use was associated with decreased sleep efficiency and increased minutes of wake time after sleep onset [β-1.15 (95%CI −1.99; −0.31) and β 7.00 (95%CI 2.40; 11.60) per increase of 10 min/day of use, respectively]. No associations were found between other devices and sleep measures. Conclusions Frequency of cordless phone calls, mobile phone dependency, and tablet use were related to an increase of subjective and objective sleep problems in adolescents. These results seem to indicate that sleep displacement, mental arousal, and exposure to blue light screen emission might play a more important role on sleep than a high RF-EMF exposure to the brain. However, more studies are needed assessing personal RF-EMF levels to draw conclusions.

Results from studies evaluating potential effects of prenatal exposure to radio-frequency electromagnetic fields from cell phones on birth outcomes have been inconsistent. Using data on 55,507 pregnant women and their children from Denmark (1996-2002), the Netherlands (2003-2004), Spain (2003-2008), and South Korea (2006-2011), we explored whether maternal cell-phone use was associated with pregnancy duration and fetal growth. On the basis of self-reported number of cell-phone calls per day, exposure was grouped as none, low (referent), intermediate, or high. We examined pregnancy duration (gestational age at birth, preterm/postterm birth), fetal growth (birth weight ratio, small/large size for gestational age), and birth weight variables (birth weight, low/high birth weight) and meta-analyzed cohort-specific estimates. The intermediate exposure group had a higher risk of giving birth at a lower gestational age (hazard ratio = 1.04, 95% confidence interval: 1.01, 1.07), and exposure-response relationships were found for shorter pregnancy duration (P < 0.001) and preterm birth (P = 0.003). We observed no association with fetal growth or birth weight. Maternal cell-phone use during pregnancy may be associated with shorter pregnancy duration and increased risk of preterm birth, but these results should be interpreted with caution, since they may reflect stress during pregnancy or other residual confounding rather than a direct effect of cell-phone exposure. The Generalized EMF Research Using Novel Methods (GERoNiMO) Project was supported by the European Union (grant 603794). The Amsterdam Born Children and Their Development Study (ABCD) was supported by the Netherlands Organization for Health Research and Development (grant 2100.0076) and the Electromagnetic Fields and Health Research program (grants 85600004 and 85800001). The Danish National Birth Cohort Study (DNBC) was supported by the Danish Epidemiology Science Centre, the Lundbeck Foundation (grant 195/04), the Egmont Foundation, the March of Dimes Birth Defect Foundation, the Augustinus Foundation, and the Medical Research Council (grant SSVF 0646). The Spanish Environment and Childhood Project (INMA) was supported by the European Union (grants FP7-ENV-2011, 282957, and HEALTH.2010.2.4.5-1); Instituto de Salud Carlos III (grants G03/176, CB06/02/0041, FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314, 09/02647, 11/01007, 11/02591, CP11/00178, FIS-PI06/0867, FIS-PS09/00090, FIS-PI041436, FIS-PI081151, FIS-PI042018, FIS-PI09/02311, FISPI13/1944, FIS-PI13/2429, FIS-PI14/0981, FIS-PI13/141687, CP13/00054 (including FEDER funds), and MS13/00054); the Conselleria de Sanitat Generalitat Valenciana; the Generalitat de Catalunya (grants CIRIT1999SGR and 00241); Obra Social Cajastur; the Universidad de Oviedo; the Department of Health of the Basque Government (grants 2005111093 and 2009111069); and the Provincial Government of Gipuzkoa (grants DFG06/004 and DFG08/001). The Korean Mothers and Children’s Environment Health Study (MOCEH) was supported by the National Institute of Environmental Research, the Ministry of the Environment, and the Information and Communication Technology (ICT) research and development program of the Ministry of Science and ICT (grants 2017-0-00961 and 2019-0-00102), South Korea.

This study was funded by grants from Spanish Institute of Health Carlos III-Ministry of Economy and Competitiveness (INMA Network G03/176, CB06/02/0041, and FIS-FEDER: PI03/1615, PI04/1436, PI08/1151, PI04/2018, PI04/1509, PI04/1112, PI04/1931, PI05/1079, PI05/1052, PI06/1213, PI06/0867, PI07/0314, PI09/02647, PS09/00090, PI09/02311, MS11/0178, PI13/1944, PI13/2032, PI14/00891, PI16/1288, and PI17/00663). Miguel Servet-FEDER: MSII16/ 00051, CP14/00108 & PI16/00261 (Co-funded by European Regional Development Fund “A way to make Europe”), FEDER funds, MS13/00054. Generalitat de Catalunya-CIRIT 1999SGR 00241, JCI2011–09771–MICINN, Generalitat Valenciana (Conselleria de Sanitat048/2010 and 060/2010 and FISABIO-UGP 15-230, 15-244, and 15-249). Generalitat de Catalunya-CIRIT 1999SGR 00241, and Fundació La Marató de TV3 (090430). Alicia Koplowitz Foundation (2017). Universidad de Oviedo. FISS-PI13/2429. Fundación CajasturLiberbank. Department of Health of the Basque Government (2005111093 and 2009111069). The Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001). The Fundación Roger Torné. ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. Mònica Guxens is funded by a Miguel Servet fellowship (MS13/00054) awarded by the Spanish Institute of Health Carlos III (Ministry of Economy and Competitiveness). Antonio J. Signes-Pastor and Margaret R. Karagas are funded by the following projects P01ES022832, RD 83544201, R25CA134286 and P42ES007373., Signes-Pastor, A.J., Vioque, J., Navarrete-Muñoz, E.M., Carey, M., García-Villarino, M., Fernández-Somoano, A., Tardón, A., Santa-Marina, L., Irizar, A., Casas, M., Guxens, M., Llop, S., Soler-Blasco, R., García-de-la-Hera, M., Karagas, M.R., Meharg, A.A.

Background: There have been few studies of children's cognitive development in relation to mothers' cell phone use, and most were limited to outcomes at age 3 years or younger. We examined the relationship between maternal cell phone use during pregnancy and cognitive performance in 5-year old children. Methods: This study included data from 3 birth cohorts: the Danish National Birth Cohort (DNBC) (n = 1209), Spanish Environment and Childhood Project (INMA) (n = 1383), and Korean Mothers and Children's Environment Health Study (MOCEH) (n = 497). All cohorts collected information about maternal cell phone use during pregnancy and cognitive performance in children at age 5. We performed linear regression to compute mean differences (MD) and 95% confidence intervals (CI) in children's general, verbal, and non-verbal cognition scores comparing frequency of maternal prenatal cell phone use with adjustments for numerous potential confounding factors. Models were computed separately for each cohort and using pooled data in meta-analysis. Results: No associations were detected between frequency of prenatal cell phone use and children's cognition scores. Scores tended to be lower in the highest frequency of use category; MD (95% CI) in general cognition scores were 0.78 (−0.76, 2.33) for none, 0.11 (−0.81, 1.03) for medium, and −0.41 (−1.54, 0.73) for high compared to low frequency of use. This pattern was seen across all cognitive dimensions, but the results were imprecise overall. Conclusion: We observed patterns of lower mean cognition scores among children in relation to high frequency maternal prenatal cell phone use. The causal nature and mechanism of this relationship remain unknown. Keywords: Cell phones, Children, Cognition, Pooled analysis, Meta-analysis, Intelligence

We assessed the association between the use of lower- and higher-than-recommended doses of folic acid supplements (FAs) during pregnancy and attentional function in boys and girls at age of 4–5. We analyzed data from 1329 mother-child pairs from the mother-child cohort INfancia y Medio Ambiente Project (INMA) study. Information on FAs use during pregnancy was collected in personal interviews at weeks 12 and 30, and categorized in &lt, 400, 400–999 (recommended dose), and ≥1000 μg/day. Child attentional function was assessed by Conners’ Kiddie Continuous Performance Test. Multivariable regression analyses were used to estimate incidence rate ratios (IRR) and beta coefficients with 95% confidence intervals (CI). Compared to recommended FAs doses, the periconceptional use of &lt, 400 and ≥1000 μg/day was associated with higher risk of omission errors—IRR = 1.14 (95% CI: 1.01, 1.29) and IRR = 1.16 (95% CI: 1.02, 1.33), respectively. The use of FAs &lt, 400 μg/day and ≥1000 μg/day was significantly associated with deficits of attentional function only in boys. FAs use &lt, 400 μg/day was associated with higher omission errors with IRR = 1.22 and increased hit reaction time (HRT) β = 34.36, and FAs use ≥ 1000 μg/day was associated with increased HRT β = 33.18 and HRT standard error β = 3.31. The periconceptional use of FAs below or above the recommended doses is associated with deficits of attentional function in children at age of 4–5, particularly in boys.

Background: Prenatal exposure to mixtures of nonpersistent chemicals is universal. Most studies examining these chemicals in association with fetal growth have been restricted to single exposure models, ignoring their potentially cumulative impact. Objective: We aimed to assess the association between prenatal exposure to a mixture of phthalates, bisphenols, and organophosphate (OP) pesticides and fetal measures of head circumference, femur length, and weight. Methods: Within the Generation R Study, a population-based cohort in Netherlands (n=776), urinary concentrations of 11 phthalate metabolites, 3 bisphenols, and 5 dialkylphosphate (DAP) metabolites were measured at 25 weeks of gestation and averaged. Ultrasound measures of head circumference, femur length, and estimated fetal weight (EFW) were taken at 18-25 and > 25 weeks of gestation, and measurements of head circumference, length, and weight were performed at delivery. We estimated the difference in each fetal measurement per quartile increase in all exposures within the mixture with quantile g-computation. Results: The average EFW at 18-25 wk and > 25 wk was 369 and 1,626g, respectively, and the average birth weight was 3,451g. Higher exposure was associated with smaller fetal and newborn growth parameters in a nonlinear fashion. At 18-25 wk, fetuses in the second, third, and fourth quartiles of exposure (Q2-Q4) had 26g [95% confidence intervals (CI): − 38, −13], 35g (95% CI:−55, −15), and 27g (95% CI: −54, 1) lower EFW compared with those in the first quartile (Q1). A similar dose-response pattern was observed at > 25wk, but all effect sizes were smaller, and no association was observed comparing Q4 to Q1. At birth, we observed no differences in weight between Q1-Q2 or Q1-Q3. However, fetuses in Q4 had 91g (95% CI: −258, 76) lower birth weight in comparison with those in Q1. Results observed at 18-25 and > 25wk were similar for femur length; however, no differences were observed at birth. No associations were observed for head circumference. Discussion: Higher exposure to a mixture of phthalates, bisphenols, and OP pesticides was associated with lower EFW in the midpregnancy period. In late pregnancy, these differences were similar but less pronounced. At birth, the only associations observed appeared when comparing individuals from Q1 and Q4. This finding suggests that even low levels of exposure may be sufficient to influence growth in early pregnancy, whereas higher levels may be necessary to affect birth weight. Joint exposure to nonpersistent chemicals may adversely impact fetal growth, and because these exposures are widespread, this impact could be substantial. https://doi.org/10.1289/EHP9178. This research was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) (ZIAES101575). It was additionally supported by grants from the NIH (RO1ES022972 and RO1ES029779) and NIEHS, NIH (HHSN273201500003C). H.T. was supported by the Netherlands Organization for Scientific Research (NWO) VICI grant (NWO-ZonMW: 016. VICI.170.200). M.G. is funded by a Miguel Servet fellowship (MS13/00054, CP18/00018) awarded by the Spanish Institute of Health Carlos III. We acknowledge support from the Spanish Ministry of Science and Innovation and the State Research Agency through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. The research leading to these results received funding from the European Union Horizon 2020 Research and Innovation Programme under Grant Agreement 733206 (LifeCycle), 874583 (ATHLETE) and 824989 (EUCAN-Connect). V.W.V.J. received grant ERC-2014-CoG-648916 from the European Research Council. R.G. received funding from the Dutch Heart Foundation (grant number 2017T013), the Dutch Diabetes Foundation (grant number 2017.81.002) and Netherlands Organization for Health Research and Development (NWO, ZonMW, grant number 543003109).

Background: The impact of maternal diet during pregnancy on child neurodevelopment is of public health and clinical relevance. We evaluated the associations of dietary quality based on the Dietary Approaches to Stop Hypertension (DASH) score and dietary inflammatory potential based on the energy-adjusted Dietary Inflammatory Index (E-DII) score during pregnancy with emotional and behavioral symptoms of offspring at 7 to 10 years of age. Methods: Individual participant data for 11,870 mother-child pairs from four European cohorts participating in the ALPHABET project were analyzed. Maternal antenatal DASH and E-DII scores were generated from self-completed food frequency questionnaires. Symptoms of depression and anxiety, aggressive behavior, and attention-deficit/hyperactivity disorder in children were assessed using mother-reported tests and classified within the normal or borderline/clinical ranges using validated cutoffs. Adjusted odds ratios were determined by multivariable logistic regression models and aggregated by the two-level individual participant data meta-analysis method. Results: Higher maternal DASH scores (indicating better dietary quality) were associated with lower risk of depressive and anxiety symptoms, aggressive behavior symptoms, and attention-deficit/hyperactivity disorder symptoms within the borderline/clinical ranges: odds ratio [OR] 0.97, 95% confidence interval [CI], 0.95-0.99; OR 0.97, 95% CI, 0.94-0.99; OR 0.97, 95% CI, 0.95-0.98, per one-unit DASH score increase, respectively. For depression and anxiety, aggressive behavior, and attention-deficit/hyperactivity disorder symptoms, a one-unit increase in E-DII scores (a more proinflammatory diet) was associated with a 7% increased risk of all three analyzed emotional and behavioral symptoms: OR 1.07, 95% CI, 1.03-1.11; OR 1.07, 95% CI, 1.02-1.13; OR 1.07, 95% CI, 1.01-1.13, respectively. Conclusions: Our findings suggest that a maternal low-quality and proinflammatory diet may increase the risk of emotional and behavioral symptoms in children. This work was supported by an award from the European Union’s Horizon 2020 research and innovation programme under the ERA-Net Cofund of the Joint Programming Initiative Healthy Diet for Healthy Life (JPI-HDHL) (http://www.healthydietforhealthylife.eu) action number 696295 (Biomarkers for Nutrition and Health). Cofunding was provided by Science Foundation Ireland, Ireland (Grant No. SFI/16/ERA-HDHL/3360 [to CMP]), the UK Biotechnology and Biological Sciences Research Council (ERA-HDHL Biomarkers: BBSRC BB/P028187/1 [to CR]), the Polish National Centre for Research and Development (ERA-HDHL/01/ALPHABET/1/2017 [to KP]), the ZonMw The Netherlands (Grant No. 529051014; 2017) ALPHABET project (Grant No. 696295; 2017 [to LD]) and the French National Agency of Research (reference AnrR16227KK [to BH]). ALSPAC: This work was supported by the UK Medical Research Council and Wellcome (Grant No. 102215/2/13/2) and the University of Bristol. This publication is the work of the authors and Matthew Suderman will serve as guarantors for the contents of this paper. EDEN: This work was supported by the Foundation for Medical Research (FRM), National Agency for Research (ANR), National Institute for Research in Public health (IRESP: TGIR Cohorte Santé 2008 program), French Ministry of Health (DGS), French Ministry of Research, INSERM Bone and Joint Diseases National Research (PRO-A), and Human Nutrition National Research Programs, Paris-Sud University, Nestlé, French National Institute for Population Health Surveillance (InVS), French National Institute for Health Education (INPES), the European Union FP7 programmes (FP7/2007-2013, HELIX, ESCAPE, ENRIECO, Medall projects), Diabetes National Research Program (through a collaboration with the French Association of Diabetic Patients), French Agency for Environmental Health Safety (now ANSES), Mutuelle Générale de l’Education Nationale, a complementary health insurance (MGEN), French National Agency for Food Security, French-speaking Association for the Study of Diabetes and Metabolism (ALFEDIAM). Generation R: This work was supported by the Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam and the Netherlands Organization for Health Research and Development. Dr Liesbeth Duijts received funding from the European Union's Horizon 2020 cofunded programme ERA-Net on Biomarkers for Nutrition and Health (ERA HDHL) (ALPHABET project (Grant No. 696295; 2017), ZonMW The Netherlands (Grant No. 529051014; 2017). Dr. Hanan El Marroun was supported by Stichting Volksbond Rotterdam, the Dutch Brain Foundation (De Hersenstichting, project number GH2016.2.01), and NARSAD Young Investigator Grant No. 27853 from the Brain & Behavior Research Foundation. The project received funding from the European Union’s Horizon 2020 Research and Innovation Programme (LIFECYCLE project, Grant No. 733206; 2016). REPRO_PL: This work was supported by the Ministry of Science and Higher Education, Poland (PBZ-MEiN-/8/2//2006; Contract No. K140/P01/2007/1.3.1.1); by the grant PNRF-218-AI-1/07 from Norway through the Norwegian Financial Mechanism within the Polish-Norwegian Research Fund, National Science Centre under the call of JPI HDHL Nutrition and Cognitive Function (2015/17/Z/NZ7/04273), and the National Science Centre, Poland (DEC-2014/15/B/NZ7/00998). Mònica Guxens (CPII18/00018) and Maribel Casas (CP16/00128) are funded by a Miguel Servet fellowship (from the Spanish Institute of Health Carlos III). We acknowledge support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Programme.

Funder: Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada); doi: https://doi.org/10.13039/501100000024, Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is unknown. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school age. We examined associations of both DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age 4-15 years) in 2477 children from 5 cohorts and of DNA methylation at school age with concurrent ADHD symptoms (age 7-11 years) in 2374 children from 9 cohorts, with 3 cohorts participating at both timepoints. CpGs identified with nominal significance (p < 0.05) in either of the EWAS were correlated between timepoints (ρ = 0.30), suggesting overlap in associations; however, top signals were very different. At birth, we identified nine CpGs that predicted later ADHD symptoms (p < 1 × 10-7), including ERC2 and CREB5. Peripheral blood DNA methylation at one of these CpGs (cg01271805 in the promoter region of ERC2, which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5, which previously was associated with neurite outgrowth and an ADHD diagnosis. In contrast, at school age, no CpGs were associated with ADHD with p < 1 × 10-7. In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.

Current knowledge on environmental causation for psychiatric disorders suggests a complex picture with a multitude of social, physical and chemical exposures occurring at different stages of life. ...

Introduction Most mental disorders have its onset during childhood, but less than one third of affected children seek professional help. The aim of this study is to (1) estimate the lifetime prevalence of mood, anxiety, conduct, and eating disorder diagnoses in 18-year-olds in 2017 and (2) the temporal trends of incidence diagnosis rates in 2009–2017 in children aged 2–18 in Catalonia, Spain. Material and methods We used a registry-based cohort including all children aged 2–18 living in Catalonia in 2009–2017, from the Catalan Health Service. Cases were identified with ICD-9 codes. Lifetime prevalence was calculated for 2017, and annual incidence for 2009–2017. Temporal trends were analyzed with multivariate negative binomial regression models. Results Lifetime prevalence of diagnoses was highest for conduct disorders (5.05%), followed by anxiety (4.37%), mood (3.07%), and eating disorders (2.11%). Median age of diagnosis was 16 years for mood, anxiety and eating disorders, and 15 years for conduct disorders. Comorbidity was present in 20.74% of those diagnosed with a mental disorder. Annual incidence rates for all disorders increased in 2011–2013/2014, and then stabilized. However, incidence rate of anxiety diagnoses in 13–18-year-old children doubled between 2016 and 2017. Conclusions Lifetime prevalence of diagnoses are lower than the expected rates of mental disorders based on interview/survey European studies. Further research is needed into the factors underlying (1) the underdiagnoses of mental disorders in children and (2) the increasing trend of anxiety disorder diagnoses in older children.

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 birth weight but there are still important knowledge gaps regarding the impact of subclinical thyroid function test abnormalities on birth weight, in general or during the late second and third trimester of pregnancy, remains unknown. The aim of this study was to examine associations of maternal thyroid function with birth weight. METHODS: For this individual-participant data meta-analysis we searched Medline (Ovid), Embase.com, Web-of-Science, Cochrane CENTRAL and Google Scholar from inception to March 18(th) 2018, and published open invitations to join the Consortium on Thyroid and Pregnancy, to identify prospective cohort studies with data on maternal thyroid function during pregnancy and birth weight. We excluded participants with multiple pregnancies, in vitro fertilization, pre-existing thyroid disease or thyroid medication usage, miscarriages and stillbirth. Main outcomes were small for gestational age (SGA), large for gestational age (LGA) (defined by the lowest or highest 10(th) population-specific percentile of birth weight standardized to gestational age and sex, respectively) and birth weight. We analysed individual participant data using mixed-effects regression models adjusting for maternal age, body mass index, ethnicity, smoking, parity, gestational age at blood sampling, fetal sex and gestational age at birth (the latter two only in case of birth weight continuously). The study protocol was pre-registered at the International Prospective Register of Systematic Reviews (PROSPERO), number CRD42016043496. RESULTS: From 2,526 published reports, 36 cohorts met the inclusion criteria and were invited to participate of which 15 agreed and after addition of 5 unpublished datasets, a total of 20 cohorts were included. After exclusions, the study population comprised 48,145 mother-child pairs of whom 1,275 (3·1%) had subclinical hypothyroidism (increased TSH with normal FT4) and 929 (2·2%) had isolated hypothyroxinaemia (decreased FT4 with normal TSH). Maternal subclinical hypothyroidism was associated with a higher risk of SGA compared to euthyroidism (11·8% vs. 10·0% respectively, adjusted risk difference 2·4% [95% CI, 0·4 to 4·8]; odds ratio (OR) 1·24 [95% CI 1·04 to 1.48], P=0·015) and lower mean birth weight (adjusted risk difference −38g [95% CI −61 to −15], P=0·001) with a higher effect estimate for measurement in the 3(rd) trimester compared with the 1(st) or 2(nd) trimester. Isolated hypothyroxinaemia was associated with a lower risk of SGA compared to euthyroidism (7·3% vs. 10·0%, adjusted risk difference −2·9 [95% CI, −4·5 to −0·9]; OR, 0·70 [95% CI 0·55 to 0·91], P=0·007) and higher mean birth weight (difference, 45g [95% CI 18 to 73], P=0·001). Each 1-SD higher maternal TSH concentration was associated with lower birth weight (−6g [−10 to −2], per SD, P=0·003), with higher effect estimates in TPOAb-positive than TPO-negative women (P for interaction=0·10). Each 1-SD higher FT4 concentration was associated with lower birth weight (−21g [95% CI −25 to −17] per SD, P

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. This research received financial support from the intramural research program of the National Institute of Environmental Health Sciences, National Institutes of Health (Grant# HHSN273201500003C). Neuroimaging was supported by the ZonMw TOP project no. 91211021. Henning Tiemeier was supported by a grant of the Netherlands Organization for Scientific Research (NWO grant No. 024.001.003, Consortium on Individual Development, and NWO/ ZonMW grant 016.VICI.170.200). Mònica Guxens is funded by a Miguel Servet fellowship (MS13/00054, CPII18/00018) awarded by the Spanish Institute of Health Carlos III. Monica Guxens acknowledges support from the Spanish Ministry of Science and Innovation and State Research Agency through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Programme. Dr. Hanan El Marroun was supported by Stichting Volksbond Rotterdam, the Dutch Brain Foundation (De Hersenstichting, project number GH2016.2.01) and the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 733206 LifeCycle)

Introduction: To date, the evidence for an association between perfluoroalkyl substances (PFAS) exposure and attention deficit and hyperactivity disorder (ADHD) is inconclusive. Objective: We investigated the association between early life exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), and ADHD in a collaborative study including nine European population-based studies, encompassing 4,826 mother-child pairs. Methods: Concentrations of PFOS and PFOA were measured in maternal serum/plasma during pregnancy, or in breast milk, with different timing of sample collection in each cohort. We used a validated pharmacokinetic model of pregnancy and lactation to estimate concentrations of PFOS and PFOA in children at birth and at 3, 6, 12, and 24 months of age. We classified ADHD using recommended cutoff points for each instrument used to derive symptoms scores. We used multiple imputation for missing covariates, logistic regression to model the association between PFAS exposure and ADHD in each study, and combined all adjusted study-specific effect estimates using random-effects meta-analysis. Results: A total of 399 children were classified as having ADHD, with a prevalence ranging from 2.3% to 7.3% in the studies. Early life exposure to PFOS or PFOA was not associated with ADHD during childhood [odds ratios (ORs) ranging from 0.96 (95% CI: 0.87, 1.06) to 1.02 (95% CI: 0.93, 1.11)]. Results from stratified models suggest potential differential effects of PFAS related to child sex and maternal education. Conclusion: We did not identify an increased prevalence of ADHD in association with early life exposure to PFOS and PFOA. However, stratified analyses suggest that there may be an increased prevalence of ADHD in association with PFAS exposure in girls, in children from nulliparous women, and in children from low-educated mothers, all of which warrant further exploration. https://doi.org/10.1289/EHP5444. This research was primarily supported by a grant from the European Community’s Seventh Framework Program (FP7/2007–2013) under grant agreement Developmental Neurotoxicity Assessment of Mixtures in Children (DENAMIC) no. 282957. M.-A.V. is the recipient of a Research Scholars J1 Award from the Fonds de recherche du Québec–Santé. Norwegian Human Milk Study (HUMIS) research was funded by a grant from the Norwegian Research Council, under the NEVRINOR program grant agreement no. 226402; by PROTECTion against Endocrine Disruptors: Detection, mixtures, health effects, risk assessment and communication, and by European Union (EU) Horizon 2020 Marie Skłodowska-Curie Actions Innovative Training Networks–European Training Network no. 722634. We thank Anteneh Desalegn for his work in the HUMIS biobank. The study was approved by the Regional Ethics Committee for Medical Research in Norway (ref. S-02122) and the Norwegian Data Inspectorate (refs. 2002/1398), and participation did not occur until after informed consent was obtained. The Infancia y Medio Ambiente (INMA) study was funded by grants from the EU: NEWGENERIS FP6-2003-Food-3-A-016320, FP7-ENV-2011 cod 282957, HEALTH.2010.2.4.5-1; and by grants from Spain: Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0041, FIS-FEDER:PI 03/1615, PI04/1509, PI04/1112, PI04/1436, PI04/1931, PI/04/2018, PI05/1079, PI05/1052, PI06/0867, PI06/1213, PI07/0314, PI/08/1151, PI09/02647, FIS-PI041436, FIS-PI081151, FISS-PI042018, FISS-PI09/02311, FISPI06/0867 FIS-PS09/00090, FIS-PI07/0252, PS09/00090, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, PI17/00663 and Miguel Servet-FEDER: CP11/00178, MS13/00054, and MSII16/00051), Generalitat de Catalunya-CIRIT 1999SGR 00241, La Fundació La Marató de TV3 (090430), Alicia Koplowitz Foundation 2017, Conselleria de Sanitat Generalitat Valenciana, Department of Health of the Basque Government (2005111093 and 2009111069), Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001), Obra Social Cajastur, Universidad de Oviedo, Consejería de Salud de la Junta de Andalucía (grant no. 183/07), EU Commission (QLK4-1999-01422, QLK4-2002-00603, and CONTAMED FP7-ENV-212502), and Fundación Roger Torné. Global Health Institute Barcelona (ISGlobal) is a member of the CERCA Programme, Generalitat de Catalunya. A full roster of the INMA Project Investigators can be found at http://www.proyectoinma.org/presentacion-inma/listadoinvestigadores/en_listado-investigadores.html. The INUENDO study was funded by the European Commission’s Seventh and Fifth Framework Programmes (FP7-ENV-2008-1-226217 and QLK4-CT-2001-00202). The polychorinated biphenyl (PCB) cohort was funded by the U.S. National Institutes of Health (grants R01 CA096525 and R03 TW007152), the EU Seventh Framework Programme FP7/2007-2023 (grant agreement OBELIX, no. 227391), Slovak Research and Development Agency (grants APVT-21-016804, APVV-0571-12, APVV-0444-11), and by the ITMS project (no. 26240120033) based on the supporting operational research and development program from the European Regional Development Fund. This research was primarily supported by a grant from the European Community’s Seventh Framework Program (FP7/2007–2013) under grant agreement Developmental Neurotoxicity Assessment of Mixtures in Children (DENAMIC) no. 282957. M.-A.V. is the recipient of a Research Scholars J1 Award from the Fonds de recherche du Québec–Santé. Norwegian Human Milk Study (HUMIS) research was funded by a grant from the Norwegian Research Council, under the NEVRINOR program grant agreement no. 226402; by PROTECTion against Endocrine Disruptors: Detection, mixtures, health effects, risk assessment and communication, and by European Union (EU) Horizon 2020 Marie Skłodowska-Curie Actions Innovative Training Networks–European Training Network no. 722634. We thank Anteneh Desalegn for his work in the HUMIS biobank. The study was approved by the Regional Ethics Committee for Medical Research in Norway (ref. S-02122) and the Norwegian Data Inspectorate (refs. 2002/1398), and participation did not occur until after informed consent was obtained. The Infancia y Medio Ambiente (INMA) study was funded by grants from the EU: NEWGENERIS FP6-2003-Food-3-A-016320, FP7-ENV-2011 cod 282957, HEALTH.2010.2.4.5-1; and by grants from Spain: Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0041, FIS-FEDER:PI 03/1615, PI04/1509, PI04/1112, PI04/1436, PI04/1931, PI/04/2018, PI05/1079, PI05/1052, PI06/0867, PI06/1213, PI07/0314, PI/08/1151, PI09/02647, FIS-PI041436, FIS-PI081151, FISS-PI042018, FISS-PI09/02311, FISPI06/0867 FIS-PS09/00090, FIS-PI07/0252, PS09/00090, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, PI17/00663 and Miguel Servet-FEDER: CP11/00178, MS13/00054, and MSII16/00051), Generalitat de Catalunya-CIRIT 1999SGR 00241, La Fundació La Marató de TV3 (090430), Alicia Koplowitz Foundation 2017, Conselleria de Sanitat Generalitat Valenciana, Department of Health of the Basque Government (2005111093 and 2009111069), Provincial Government of Gipuzkoa (DFG06/004 and DFG08/001), Obra Social Cajastur, Universidad de Oviedo, Consejería de Salud de la Junta de Andalucía (grant no. 183/07), EU Commission (QLK4-1999-01422, QLK4-2002-00603, and CONTAMED FP7-ENV-212502), and Fundación Roger Torné. Global Health Institute Barcelona (ISGlobal) is a member of the CERCA Programme, Generalitat de Catalunya. A full roster of the INMA Project Investigators can be found at http://www.proyectoinma.org/presentacion-inma/listadoinvestigadores/en_listado-investigadores.html. The INUENDO study was funded by the European Commission’s Seventh and Fifth Framework Programmes (FP7-ENV-2008-1-226217 and QLK4-CT-2001-00202). The polychorinated biphenyl (PCB) cohort was funded by the U.S. National Institutes of Health (grants R01 CA096525 and R03 TW007152), the EU Seventh Framework Programme FP7/2007-2023 (grant agreement OBELIX, no. 227391), Slovak Research and Development Agency (grants APVT-21-016804, APVV-0571-12, APVV-0444-11), and by the ITMS project (no. 26240120033) based on the supporting operational research and development program from the European Regional Development Fund.

Objectives: We investigated the association between outdoor air pollutants exposure in the first trimester of pregnancy, and growth and cardio-metabolic risk at four years of age, and evaluated the mediating role of birth weight. Methods: We included mother-child pairs (N = 1,724) from the Spanish INMA birth cohort established in 2003-2008. First trimester of pregnancy nitrogen dioxide (NO2) and fine particles (PM2.5) exposure levels were estimated. Height, weight, waist circumference, blood pressure, and lipids were measured at four years of age. Body mass index (BMI) trajectories from birth to four years were identified. Results: Increased PM2.5 exposure in the first trimester of pregnancy was associated with decreased z-scores of weight (zWeight) and BMI (zBMI) (zWeight change per interquartile range increase in PM2.5 exposure = -0.12; 95% CI: -0.23, -0.01; zBMI change = -0.12; 95% CI: -0.23, -0.01). Higher NO2 and PM2.5 exposure was associated to a reduced risk of being in a trajectory with accelerated BMI gain, compared to children with the average trajectory. Birth weight partially mediated the association between PM2.5 and zWeight and zBMI. PM2.5 and NO2 were not associated with the other cardio-metabolic risk factors. Conclusions: This comprehensive study of many growth and cardio-metabolic risk related outcomes suggests that air pollution exposure during pregnancy may be associated with delays in physical growth in the early years after birth. These findings imply that pregnancy exposure to air pollutants has a lasting effect on growth after birth and require follow-up at later child ages. This study was funded by grants from the Eulji University (grant numbers ESCAPE project FP7-ENV-2007-1-211250, DENAMIC project FP7-ENV-2011-282957, HELIX project FP7-ENV-2012-308333, and MEDALL project HEALTH.2010.2.4.5-1), from the Spanish Instituto de Salud Carlos III (grant numbers Red INMA G03/176; CB06/02/0041; PI03/1615 incl. FEDER funds, PI04/1112 incl. FEDER funds, PI041436, PI04/1509 incl. FEDER funds, PI04/1931 incl. FEDER funds, PI042018 incl. FEDER funds, PI05/1079 incl. FEDER funds, PI05/1052 incl. FEDER funds, FIS-PI06/0867, PI06/1213 incl. FEDER funds, PI07/0314 incl. FEDER funds, PI081151 incl. FEDER funds, FIS-PI09/00090, PI09/02311 incl. FEDER funds, PI09/02647 incl. FEDER funds, PI11/01007 incl. FEDER funds, PI11/02591 incl. FEDER funds, PI11/02038 incl. FEDER funds, PI13/1944 incl. FEDER funds, PI13/2032 incl. FEDER funds, PI13/02429 incl. FEDER funds, PI14/00891 incl. FEDER funds, PI14/01687 incl. FEDER funds, PI15/00118 incl. FEDER funds, PI16/1288 incl. FEDER funds, and PI17/00663 incl. FEDER funds, PI18/00547 incl. FEDER funds, PI18/00909 incl. FEDER funds; CP11/00178, CP15/00025, and CPII16/00051; MS13/00054 incl. FEDER funds), CIBERESP, Department of Health of the Basque Government (grant numbers 2005111093, 2013111089), Generalitat de Catalunya-CIRIT (grant numbers 1999SGR 00241), Generalitat Valenciana: FISABIO (grant numbers UGP 15-230, UGP-15-244, and UGP-15-249), Provincial Government of Gipuzkoa (grant number DFG06/002), Alicia Koplowitz Foundation 2017, Fundacio La marato de TV3 (grant number 090430), Obra Social Cajastur/Fundacion Liberbank, Universidad de Oviedo, and annual agreements with the municipalities of the study area of the Gipuzkoa sub-cohort (Zumarraga, Urretxu, Legazpi, Azkoitia, Azpeitia and Beasain). ISGlobal is a member of the Agency for the Research Centres of Catalonia (CERCA) Programme, Generalitat de Catalunya.

Exposure to greenspace has been related to improved mental health, but the available evidence is limited and findings are heterogeneous across different areas. We aimed to evaluate the associations between residential exposure to greenspace and specific psychopathological and psychosomatic symptoms related to mental health among mothers from a Spanish birth cohort. Our study was based on data from 1171 women participating in two follow-ups of a population-based cohort in Valencia, Sabadell, and Gipuzkoa (2004&ndash, 2012). For each participant, residential surrounding greenspace was estimated as the average of the satellite-based Normalized Difference Vegetation Index (NDVI) across different buffers around the residential address at the time of delivery and at the 4-year follow-up. The Symptom Checklist 90 Revised (SCL-90-R) was applied to characterize mental health at the 4-year follow-up. We developed mixed-effects logistic regression models controlled for relevant covariates to evaluate the associations. Higher residential surrounding greenspace was associated with a lower risk of somatization and anxiety symptoms. For General Severity Index (GSI), obsessive&ndash, compulsive, interpersonal sensitivity, depression, hostility, phobic anxiety, paranoid ideation, and psychoticism symptoms, we generally observed protective associations, but none attained statistical significance. Findings from this study suggested a potential positive impactof greenspace on mental health.

Background: Prenatal exposures to phthalates and bisphenols are associated with impaired brain development in animals. However, epidemiological studies investigating the association between prenatal phthalate or bisphenol exposure and cognition have produced mixed findings and mostly had modest sample sizes and measured the exposure during the third trimester. Objective: We examined the association between pregnancy maternal urinary biomarkers of phthalate or bisphenol exposure and nonverbal intelligence quotient (IQ) in children 6 years of age. Method: The study sample consisted of 1,282 mother–child pairs participating in the Generation R Study, a population-based birth cohort in Rotterdam, Netherlands (enrollment 2002–2006). We measured maternal urinary concentrations of 18 phthalate metabolites and 8 bisphenols at 25 wks of gestation. Child nonverbal IQ was measured at 6 years of age using the Snijders-Oomen Nonverbal Intelligence Test–Revised. Linear regression models were fit for each of the three collection phases separately, the three collection phases jointly, and for the averaged prenatal exposure across pregnancy. Results: Higher urinary concentrations of phthalate metabolites during early pregnancy were associated with lower child nonverbal IQ score [e.g., B per 10-fold increase in summed low-molecular weight phthalates=−1.7 (95% CI: −3.1, −0.3)]. This association remained unchanged when adjusted for mid and late pregnancy exposures. We also observed an inverse association between late pregnancy di-n-octyl phthalate (DNOP) exposure and nonverbal IQ. Maternal urinary concentrations of bisphenols were not associated with child nonverbal IQ. There was no effect estimate modification by sex. Conclusions: We did not observe that maternal biomarkers of bisphenol exposure are associated with nonverbal IQ. We found that phthalate exposure in early pregnancy and DNOP exposure in late pregnancy are associated with lower nonverbal IQ scores in children. Our results might suggest that particularly early pregnancy is a sensitive window of phthalate exposure, but future studies are needed to replicate our findings. https://doi.org/10.1289/EHP6047

Lungs are highly vulnerable to permanent harmful effects of environmental factors during their in-utero and early life development. The detrimental effects of air pollution on lung development are well known although studies mainly focused on the postnatal exposure period. We investigated the windows of susceptibility during pregnancy and first 7 postnatal years on the association between nitrogen dioxide (NO2) and lung function at the age of 7 years in the INMA cohort in Spain. We estimated monthly average exposure to NO2 for the prenatal and postnatal period at home address of 1230 children with temporally-adjusted land use regression models. Spirometry was performed at age 7. We estimated the change in lung function associated with 10 µg/m3 increase in NO2 concentrations with distributed lag models, which consider the association at a specific time point while controlling for exposure at all other periods. Mean NO2 concentration was 30.3 (±15.2) µg/m3 and the average interquartile range was 19.9 µg/m3. Results on complete cases (n=856) identified two sensitive exposure periods associated with a reduction of the FVC: (i) from the half of the second trimester until the end of pregnancy (e.g. prenatal month 7: -3.3 [95% CI: -5.4, -1.2] ml for 10 µg/m3 increase in NO2) and (ii) at 3 years old (e.g. postnatal month 46: -1.9 [95%CI: -3.5, -0.3] ml). Moreover, a sensitive window when the children turn 3 years old was identified with a decrease on FEV1 of -1.7 [95% CI: -3.0, -0.3] ml for each 10 µg/m3 increase of NO2 (in postnatal month 36). Exposure to NO2 at sensitive periods including pregnancy and first years of life is associated with a lower lung function at 7 years.

Attention deficit/hyperactivity disorder (ADHD) is one of the most common behavioral disorders in childhood. According to a recent systematic review, the worldwide estimate of ADHD prevalence is 7.2% in children. This study aims to assess the prevalence of ADHD diagnoses in 2017 and the incidence of ADHD diagnoses in 2009–2017 in children living in Catalonia, Spain, as well as their temporal and geographical variability, and stratifying by sex and age. We used administrative data for all children aged 4 to 17 years who were insured in the public Catalan Health System in 2009–2017. We identified all ADHD cases diagnosed in 2009–2017 (ICD-9 code 314). We estimated the prevalence of ADHD diagnoses in 2017 and the overall annual incidence of ADHD diagnoses in 2009–2017. We used Poisson regression models to assess temporal trends in the incidence. We estimated a prevalence of ADHD diagnoses of 4.06% (95%CI 4.03, 4.10) in 2017, being 5.81% (95%CI 5.75, 5.87) for boys and 2.20% (95%CI 2.16, 2.24) for girls, the highest prevalence being in 13-to-17-year-olds (7.28% (95%CI 7.20, 7.36)). We did not observe a statistically significant increase of the incidence of ADHD diagnoses during the study period. Geographical differences were found across the healthcare areas in both prevalence and annual incidence and constant during the study period. In conclusion, the prevalence of ADHD diagnoses observed in this study was 4.06%, which was lower than the estimates reported in previous systematic reviews, but in line with the prevalence estimates from other recent European studies. The prevalence was higher in boys than girls, with a sex ratio consistent with previous studies. We did not observe an increase in the temporal trend of incidence of ADHD diagnoses in recent years, but we found geographical differences.

Background/objectives A higher adherence to a Mediterranean diet has been shown to be protective against obesity in adults, but the evidence is still inconclusive in children at early ages. Our objective was to explore the association between adherence to Mediterranean Diet at the age of 4 and the prevalence of overweight, obesity, and abdominal obesity at 4 years of age, and incidence at the age of 8. Subjects/methods We analyzed data from children of the INMA cohort study who attended follow-up visits at age 4 and 8 years (n = 1801 and n = 1527, respectively). Diet was assessed at the age of 4 using a validated food frequency questionnaire. The adherence to MD was evaluated by the relative Mediterranean diet (rMED) score, and categorized as low (0-6), medium (7-10), and high (11-16). Overweight and obesity were defined according to the age-sex specific BMI cutoffs proposed by the International Obesity Task Force, and abdominal obesity as waist circumference >90th percentile. We used Poisson regression models to estimate prevalence ratios at 4 years of age, and Cox regression analysis to estimate hazard ratios (HR) from 4-8 years of age. Results In cross-sectional analyses at the age of 4 no association was observed between adherence to MD and overweight, obesity, or abdominal obesity. In longitudinal analyses, a high adherence to MD at age 4 was associated with lower incidence of overweight (HR = 0.38; 95% CI: 0.21-0.67; p = 0.001), obesity (HR = 0.16; 95% CI: 0.05-0.53; p = 0.002), and abdominal obesity (HR = 0.30; 95% CI: 0.12-0.73; p = 0.008) at the age of 8. Conclusion This study shows that a high adherence to MD at the age of 4 is associated with a lower risk of developing overweight, obesity, and abdominal obesity at age 8. If these results are confirmed by other studies, MD may be recommended to reduce the incidence of obesity at early ages.

Vitamin D deficiency during critical periods of development could lead to persistent brain alterations. We aimed to assess the association between maternal vitamin D-3, the major circulatory form of vitamin D, at pregnancy and neurodevelopmental outcomes during childhood, namely: behavioural problems, Attention Deficit and Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) symptoms, and social competence. This study included 2,107 mother-child pairs of a Spanish population-based birth cohort. Maternal plasma vitamin D-3 was measured in pregnancy. The outcomes were measured through questionnaires at 5, 8, 14, and 18 years old. We ran multivariate regression models adjusted for potential confounding variables. We found that per each 10 ng/mL increment of maternal vitamin D-3, children obtained higher social competence scores (coefficient =0.77; 95% CI=0.19, 1.35) at 5 years old. However, we observed null associations between maternal vitamin D-3 and total behavioural problems and ADHD and ASD symptoms in children from 5 to 18 years old. Further studies carried out in countries where the population is exposed to lower vitamin D levels are needed., The authors are grateful to all the teachers, parents and children who have participated in the INMA project for their generous collaborative efforts. We thank all the investigators who have collected information and samples from the participants. Menorca: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; 97/0588; 00/0021-2; PI061756; PS0901958; PI14/00677 incl. FEDER funds), CIBERESP, Beca de la IV convocatoria de Ayudas a la Investigacion en Enfermedades Neurodegenerativas de La Caixa, and EC Contract No. QLK4-CT-2000-00263. Sabadell: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds; CPII/00018), CIBERESP, Generalitat de Catalunya-CIRIT 1999SGR 00241, Generalitat de Catalunya-AGAUR 2009 SGR 501, Fundacio La marato de TV3 (090430), EU Commission (261357). ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. Valencia: This study was funded by Grants from UE (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), Spain: ISCIII (G03/176; FIS-FEDER: PI11/01007, PI11/02591, PI11/02038, PI12/00610, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, and PI17/00663; Miguel Servet-FEDER CP11/00178, CP15/00025, and MSII16/00051), Generalitat Valenciana: FISABIO (UGP 15-230, UGP15-244, and UGP-15-249), and Alicia Koplowitz Foundation 2017. Asturias: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0041), FIS-PI042018, FIS-PI09/02311, FIS-PI13/02429, FIS-PI18/00909, CIBERESP, Obra Social Cajastur/Fundacion Liberbank and UNIVERSIDAD DE OVIEDO. Gipuzkoa: This study was funded by grants from Instituto de Salud Carlos III (FIS-PI06/0867, FIS-PI09/00090 and FIS-PI13/02187), CIBERESP, Department of Health of the Basque Government (2005111093, 2009111069, 2013111089 and 2015111065), and the Provincial Government of Gipuzkoa (DFG06/002, DFG08/001 and DFG15/221) and annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain).

Objective The objective of this study was to evaluate the associations between maternal metabolic parameters and early childhood BMI trajectories. Methods Two thousand two hundred fifty-one children born in Spain between 2004 and 2008 were analyzed. Five BMI z score trajectories from birth to age 4 years were identified by using latent class growth analysis. Multinomial regression assessed the associations between maternal metabolic parameters and offspring's BMI trajectories. Results Children in the reference BMI trajectory had average size at birth followed by a slower BMI gain. Maternal prepregnancy obesity was associated with trajectories of accelerated BMI gain departing from either higher (relative risk ratio [RRR] = 1.77; 95% CI: 1.07-2.91) or lower size at birth (RRR = 1.91; 95% CI: 1.17-3.12). Gestational weight gain (GWG) above clinical guidelines was associated with a trajectory of higher birth size followed by accelerated BMI gain (RRR = 2.14; 95% CI: 1.53-2.97). Maternal serum triglycerides were negatively associated with BMI trajectories departing from lower birth sizes. Gestational diabetes, maternal serum cholesterol, and C-reactive protein were unrelated to children's BMI trajectories. Conclusions Maternal prepregnancy obesity, GWG, and serum triglycerides are associated with longitudinal BMI trajectories in early childhood that may increase disease risk in later life. Health initiatives should promote healthy weight status before and during pregnancy to improve maternal and child health.

We sought to determine whether prenatal co-exposure to As, Cd, Hg, Mn, and Pb was associated with impaired neurodevelopment in preschool children from the Spanish Environment and Childhood (INMA) Project, using the placenta as exposure matrix. We measured metal levels in placenta tissue samples randomly selected from five of the seven population-based birth cohorts participating in the INMA Project, collected between 2000 and 2008. Neuropsychological assessment of cognitive and motor function was carried through the use of the McCarthy Scales of Children's Abilities (MSCA) at the age of 4-5years. Data on placental metal levels, MSCA scores, and relevant covariates was available for 302 children. Mn was detected in all placental samples, Cd in nearly all placentas (99%) and As, Hg, and Pb in 22%, 58%, and 17% of the placentas, respectively. After adjusting for potential confounders, detectable As levels were associated with decrements in global and verbal executive functions and quantitative abilities; detectable Hg was associated with lower scores on the verbal function of posterior cortex in a dose-response manner, and non-linearly related to poorer motor function and gross motor skills; and Mn levels were associated with decrement in perceptual-performance skills in a dose-response manner but with better memory span and quantitative skills. A synergistic interactive effect was found between As and Pb with respect to the general cognitive score, whereas an antagonistic interaction was found between Mn and Hg. Prenatal exposure to As and Hg may be a risk factor for cognitive and motor impairment in children, while the effects of Cd and Mn on neurodevelopment are less clear. Future studies should examine combined and interactive effects of exposure to multiple metals during vulnerable periods of brain development prospectively.

Context: Low maternal free T4 (FT4) has been associated with poor child neurodevelopment in some single-center studies. Evidence remains scarce for the potential adverse effects of high FT4 and whether associations differ in countries with different iodine status. Objective: To assess the association of maternal thyroid function in early pregnancy with child neurodevelopment in countries with a different iodine status. Design, Setting, and Participants: Meta-analysis of individual participant data from 9036 mother–child pairs from three prospective population-based birth cohorts: INMA [Infancia y Medio Ambiente (Environment and Childhood project) (Spain)], Generation R (Netherlands), and ALSPAC (Avon Longitudinal Study of Parents and Children, United Kingdom). The exclusion criteria were multiple pregnancies, fertility treatments, thyroid-interfering medication usage, and known thyroid disease. Main Outcomes: Child nonverbal IQ at 5 to 8 years of age, verbal IQ at 1.5 to 8 years of age, and autistic traits within the clinical range at 5 to 8 years of age. Results: FT4 97.5th percentile was associated with a 1.9-fold (95% CI, 1.0 to 3.4) greater risk of autistic traits. No independent associations were found with TSH. Conclusions: Low maternal FT4 was consistently associated with a lower IQ across the cohorts. Further studies are needed to replicate the findings of autistic traits and investigate the potential modifying role of maternal iodine status. FT4 seems a reliable marker of fetal thyroid state in early pregnancy, regardless of the type of immunoassay. EUthyroid Project: European Union’s Horizon 2020 research and innovation programme (grant 634453). INMA, Spain: This study was funded by grants from the European Union (grants FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1) and Spain: Instituto de Salud Carlos III (grants Red INMA G03/176, CB06/02/0041, FIS-FEDER: PI041436, PI05/1079, PI06/0867, PI081151, FIS- and PS09/00090, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, and PI16/1288, Miguel Servet-FEDER CP11/00178, CP15/00025, and CPII16/00051, MS13/00054), Generalitat Valenciana: FISABIO (grants UGP 15-230, UGP-15-244, and UGP-15-249), Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundació La Marató de TV3 (grants 090430), Department of Health of the Basque Government (grants 2005111093 and 2009111069), and the Provincial Government of Gipuzkoa (grants DFG06/004 and DFG08/001).

Highlights • We assessed cardiometabolic (CM) effects of prenatal POP exposure into adolescence. • Prenatal exposure to POPs (particularly HCB) was positively associated with BMI. • p,p’-DDT and HCB were positively associated with other CM markers in adolescence. • Prenatal POP exposure may increase the risk of metabolic disorders in adolescence and adult life., Background Prenatal exposure to persistent organic pollutants (POPs) has been linked to cardiometabolic (CM) risk factors in childhood, but there are no studies evaluating the persistence of these associations into adolescence, a period of relevant changes in endocrine-dependent organ systems and rapid increases in lean and fat mass. We examined the associations of prenatal POP exposures with body mass index (BMI) from age 4 to 18 years, and with other CM risk markers in adolescence. Methods We analysed 379 children from the Spanish INMA-Menorca birth cohort study with measured cord blood POP concentrations. We calculated BMI z-scores at ages 4, 6, 11, 14 and 18 years using the WHO growth reference. Body fat % was measured at 11 and 18 years and waist-to-height ratio (WHtR) and blood pressure (BP) at 11, 14 and 18 years. We measured CM biomarkers in fasting blood collected at age 14 years and calculated a CM-risk score as the sum of the sex-, and age-specific z-scores for waist circumference, mean arterial BP, homeostatic model assessment of insulin resistance, fasting blood triglycerides, and high-density lipoprotein cholesterol (HDL-C) (n = 217). Generalised estimating equations and multivariate linear regression models assessed the associations with repeated and single time-point measures, respectively. Results Hexachlorobenzene (HCB) exposure in the third tertile, compared to the first tertile, was associated with higher BMI (β = 0.24; 95% CI: 0.01, 0.47) and WHtR z-score (β = 0.27; 95% CI: 0.04, 0.51). A continuous increase in HCB was associated with an elevated body fat % (β per 10-fold increase = 4.21; 95% CI: 0.51, 7.92), systolic BP (β = 0.32; 95% CI: 0.02, 0.64) and diastolic BP z-score (β = 0.32; 95% CI: 0.02, 0.62) across all ages, and with higher CM-risk score (β = 1.59; 95% CI: 0.02, 3.18) and lipid biomarkers (total cholesterol, triglycerides and low-density lipoprotein cholesterol (LDL-C)) at 14 years. Dichlorodiphenyltrichloroethane (p,p’-DDT) exposure was non-monotonically associated with BMI and systolic BP. p,p’-DDE and Σ-polychlorinated biphenyls (PCBs) (sum of congeners 118, 138, 153, 180) were not associated with adiposity or BP. p,p’-DDT exposure was associated with an increased CM-risk score, and ΣPCBs concentrations with LDL-C in all adolescents and with total cholesterol only in girls (p-sex interaction = 0.05). Conclusion This first longitudinal study from 4 to 18 years suggests that the previously reported POP associations with child BMI persist later in adolescence and that prenatal POP exposures are associated with major risk factors for adult CM syndrome.

Background: Prenatal and postnatal exposure to air pollution has been linked to cognitive impairment in children, but very few studies have assessed its association with attentional function. Objectives: To evaluate the association between prenatal and postnatal exposure to nitrogen dioxide (NO2) and attentional function in children at 4–5 years of age. Methods: We used data from four regions of the Spanish INMA—Environment and Childhood—Project, a population-based birth cohort. Using land-use regression models (LUR), we estimated prenatal and postnatal NO2 levels in all of these regions at the participants' residential addresses. We assessed attentional function using the Kiddie-Conners Continuous Performance Test (K-CPT). We combined the region-specific adjusted effect estimates using random-effects meta-analysis. Results: We included 1298 children with complete data. Prenatal exposure to NO2 was associated with an impaired standard error of the hit reaction time (HRT(SE)) (increase of 1.12 ms [95% CI; 0.22 a 2.02] per 10 μg/m3 increase in prenatal NO2) and increased omission errors (6% [95% CI; 1.01 to 1.11] per 10 μg/m3 increase in prenatal NO2). Postnatal exposure to NO2 resulted in a similar but borderline significant increase of omission errors (5% [95% CI; =0.99 to 1.11] per 10 μg/m3 increase in postnatal NO2). These associations did not vary markedly between regions, and were mainly observed in girls. Commission errors and lower detectability were associated with prenatal and postnatal exposure to NO2 only in some regions. Conclusions: This study indicates that higher exposure to ambient NO2, mainly during pregnancy and to a lesser extent postnatally, is associated with impaired attentional function in children at 4–5 years of age., This study was funded by grants from the Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041 and PI031615; PI041931; PI041112; PI041436; PI041509; PI042018; PI051079; PI051052; PI060867; PI061213; PI070314; CP1100178; PI081151 incl. FEDER funds; PS0900090 incl. FEDER funds; PI0902311 incl. FEDER funds; PI0902647 incl. FEDER funds; PI1102591 incl. FEDER funds; PI1102038 incl. FEDER funds; PI131944 incl. FEDER funds; PI132032 incl. FEDER funds; PI1302429 incl. FEDER funds; PI1302187 incl. FEDER funds; PI140891 incl. FEDER funds; PI141687 incl. FEDER funds and MS13/00054), Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundació La marató de TV3 (090430), Department of Health of the Basque Government (2005111093, 2009111069 and 2013111089), the Provincial Government of Gipuzkoa (DFG06/002 and DFG08/001), Convenios anuales con los ayuntamientos de la zona del estudio (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain), from UE (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), from the European Research Council under the ERC Grant Agreement number ERC-AdG 2010 GA#268479 – the BREATHE project, from the Conselleria de Sanitat of Generalitat Valenciana (AP212/11, 002/008, 012/009, 013/2009, 014/009, 015/008, 016/009, 021/007, 021/008, 023/008 and 024/007) and from Obra Social Cajastur/Fundación Liberbank and Universidad de Oviedo. ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya.

BackgroundMaternal pre-pregnancy obesity may impair infant neuropsychological development, but it is unclear whether intrauterine or confounding factors drive this association.MethodsWe assessed whether maternal pre-pregnancy obesity was associated with neuropsychological development in 1,827 Spanish children. At 5 years, cognitive and psychomotor development was assessed using McCarthy Scales of Children's Abilities, attention deficit hyperactivity disorder (ADHD) symptoms using the Criteria of Diagnostic and Statistical Manual of Mental Disorders, and autism spectrum disorder symptoms using the Childhood Asperger Syndrome Test. Models were adjusted for sociodemographic factors and maternal intelligence quotient. We used paternal obesity as negative control exposure as it involves the same source of confounding than maternal obesity.ResultsThe percentage of obese mothers and fathers was 8% and 12%, respectively. In unadjusted models, children of obese mothers had lower scores than children of normal weight mothers in all McCarthy subscales. After adjustment, only the verbal subscale remained statistically significantly reduced (β: -2.8; 95% confidence interval: -5.3, -0.2). No associations were observed among obese fathers. Maternal and paternal obesity were associated with an increase in ADHD-related symptoms. Parental obesity was not associated with autism symptoms.ConclusionMaternal pre-pregnancy obesity was associated with a reduction in offspring verbal scores at pre-school age. This study was funded by grants from European Union (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1)

Purpose Median urinary iodine concentration (UIC) is used to describe the iodine status of a population. However, the link between UIC and iodine intake may vary during pregnancy. The aim of this study was to compare UIC during and after pregnancy, adjusting for factors that affect iodine intake. Methods Two repeated measures of UIC and data on maternal iodine intake estimated through questionnaires were collected during pregnancy and 1–4 years after pregnancy in a subsample of women (n = 598) from a mother and child cohort study in Spain. Random-effects interval regression was used to assess the changes in UIC according to pregnancy status. Results Median UIC was similar during (133 μg/L) and after pregnancy (139 μg/L). After adjusting for iodised salt, iodine supplement consumption, and socio-demographic related variables, UIC was 24.0% (95% CI 11.3, 38.2) higher after than during pregnancy. This difference was maintained in a subsample of women with exhaustive information on diet (n = 291): 26.2%, 95% CI 10.3, 44.4. Conclusions In an iodine sufficient area for the general population, iodine excretion was lower during than after pregnancy when factors affecting iodine intake were controlled for. Current recommendations of median UIC during pregnancy are based on the equivalence between iodine intake and UIC estimated from studies in non-pregnant populations, which might lead to overestimation of iodine deficiency during gestation. Further studies should evaluate the equivalence between iodine intake and its urinary excretion during pregnancy.

Background: The association between prenatal air pollution exposure and postnatal growth has hardly been explored. Mitochondrial DNA (mtDNA), as a marker of oxidative stress, and growth at birth can play an intermediate role in this association. Objective: In a subset of the Spanish birth cohort INMA we assessed first whether prenatal nitrogen dioxide (NO2) exposure is associated with infant growth. Secondly, we evaluated whether growth at birth (length and weight) could play a mediating role in this association. Finally, the mediation role of placental mitochondrial DNA content in this association was assessed. Methods: In 336 INMA children, relative placental mtDNA content was measured. Land-use regression models were used to estimate prenatal NO2 exposure. Infant growth (height and weight) was assessed at birth, at 6 months of age, and at 1 year of age. We used multiple linear regression models and performed mediation analyses. The proportion of mediation was calculated as the ratio of indirect effect to total effect. Results: Prenatal NO2 exposure was inversely associated with all infant growth parameters. A 10 mu g/m(3) increment in prenatal NO2 exposure during trimester 1 of pregnancy was significantly inversely associated with height at 6 months of age (-6.6%; 95%CI: -11.4, -1.9) and weight at 1 year of age (-4.2%; 95%CI: -8.3, -0.1). These associations were mediated by birth length (31.7%; 95%CI: 34.5, 14.3) and weight (53.7%; 95%CI: 65.3, -0.3), respectively. Furthermore, 5.5% (95%CI: 10.0, -0.2) of the association between trimester 1 NO2 exposure and length at 6 months of age could be mediated by placental mtDNA content. Conclusions: Our results suggest that impaired fetal growth caused by prenatal air pollution exposure can lead to impaired infant growth during the first year of life. Furthermore, molecular adaptations in placental mtDNA are associated with postnatal consequences of air pollution induced alterations in growth. The research leading to these results was funded by the Spanish Ministry of Health (FIS-PI11/00610).

Background: In 2003 the INMA—INfancia y Medio Ambiente (Environment and Childhood) project, a Spanish national network of birth cohorts including more than 3500 participants, was set up with the aim to assess the health impacts of pre- and postnatal environmental exposures on children. The project has published more than 60 papers on maternal and environmental factors related to neuropsychological development in children, one of the main research interests within the project. With the present review, we evaluate the evidence provided by the INMA project on this topic and discuss how the data can contribute to cover the challenges that children’s environmental health research will face in the coming years. Results: The INMA project has contributed to provide increasing evidence of the association between prenatal exposure to persistent organic pollutants (POPs) and child neuropsychological development, but it has also shown, using innovative methodologies, that postnatal exposure to these compounds does not play a role in this association. The project has also contributed to show the detrimental influence of certain air pollutants on child neuropsychological development, as well as how a balanced maternal fish intake can protect from the potential adverse effects of prenatal exposure to mercury. Also, the project has contributed to the understanding of impacts of nutritional factors including supplement intake and vitamin D levels during pregnancy and the role of breastfeeding on the neuropsychological benefits., This study was supported Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041, 97/0588, 00/0021-2, PI04/1436, PI06/1756, PI08/1151, PS09/01958, PI12/01890, PI14/00677, MS13/00054, CP13/00054 including FIS-FEDER funds 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314, 09/02311, 09/02647, 11/0178, 11/02591, 11/02038, 13/1944, 13/2032, 13/02429, 14/0891, 14/1687, and 16/1288) and Miguel Servet-FEDER MS15/00025, Spanish Ministry of Health - CIBERESP (FIS-97/1102, FIS-PS09/00362, FIS-07/0252, FIS-PI11/00610, FISPI07/0252, FISPI11/0610, FIS-PI04/2018, FIS-PI09/02311, FISPI13/02429, FIS-PI06/0867, FIS-PS09/00090, FIS-PI13/02187, PI13/02406, MS13/00054), Spanish Ministry of Economy and Competitiveness (SAF2012-32991 incl. FEDER funds), EU Comission (QLK4-CT-2000-00263, QLK4-1999-01422, QLK4-2002-00603 and CONTAMED FP7-ENV-212502, FP7-ENV-2011 cod 282957, 261357, 308333 and 603794 and HEALTH.2010.2.4.5-1), Generalitat de Catalunya-CIRIT 1999SGR 00241, Generalitat de Catalunya-AGAUR (2009 SGR501, 2014 SGR 822), Department of Health of the Basque Government (2005111093, 2009111069, 2013111089 and 2015111065), the Provincial Government of Gipuzkoa (DFG06/002, DFG08/001 and DFG15/221), Consejería de Salud de la Junta de Andalucía (grant number 183/07 and SAS-PI-0675-2010), Conselleria de Sanitat, Generalitat Valenciana, Andalusia Regional Government – Consejería de Salud (Grants P09-CTS-5488 Project of Excellence, and SAS PI-0133-2007; PI-0675–2010), Agence Nationale de Securite Sanitaire de l’Alimentation de l’Environnement et du Travail (1262C0010), beca de la IV convocatoria de Ayudas a la Investigación en Enfermedades Neurodegenerativas de La Caixa, Fundació La Caixa (97/009-00 and 00/077-00), Fundació La Marató de TV3 (090430), Obra Social Cajastur/Fundación Liberbank and University of Oviedo, and annual agreements with the municipalities of the area of study (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain)

Background: Maternal vitamin D can have a protective role on child’s respiratory health, but the results from prospective studies are still inconsistent. We examined whether maternal circulating vitamin D levels during pregnancy are associated with wheezing and asthma during childhood in a Spanish birth cohort. Methods: Maternal circulating 25(OH)D3 levels were measured during the first trimester of pregnancy. Information on active wheezing (wheezing episodes plus medication), wheezing patterns (early, late-onset, and persistent wheeze), and physician-diagnosed asthma ever was obtained from parental questionnaires administered from 1 to 7 years in new cohorts(N=1964) and from 1 to 9 years in an old cohort(N=294). We treated maternal 25(OH)D3 levels as continuous (ng/ml) and in tertiles: deficient( Results: Children exposed to insufficient vitamin D levels during pregnancy had lower odds of being active wheezers at 4 years in the new cohorts (odds ratio=0.63; 95% CI=0.42-0.97), compared with those children exposed to deficient levels. Children exposed to higher levels of maternal vitamin D had lower risk of developing late-onset wheezing in the new cohorts (relative risk ratio=0.97; 0.94-1.00). Results were similar in the old cohort. Children exposed to maternal vitamin D levels above 20ng/ml had lower odds of ever having diagnosis asthma in both cohorts although results did not reach significance. Conclusion: Maternal vitamin D levels above deficiency may be associated with reduced risk of wheezing and asthma in the offspring. Vitamin D dietary interventions can be considered for its potential and substantial general health benefits and its inexpensive costs.

There is conflicting evidence about factors associated with failure to complete treatment (FCT) for latent tuberculosis infection (LTBI). We aim to identify the geographic, sociodemographic, and medical factors associated with FCT in Portugal, highlighting the two main metropolitan areas of Porto and Lisbon. We performed a retrospective cohort study including LTBI patients that started treatment in Portugal between 2013 and 2017. We calculated adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) using multivariable logistic regression to identify geographic, sociodemographic, and medical factors associated with FCT. Data on completion of treatment were available for 15,478 of 17,144 patients (90.3%). Of those, 2132 (13.8%) failed to complete treatment. Factors associated with FCT were being older than 15 years (aOR, 1.65 (95% CI = 1.34–2.05) for those aged 16 to 29), being born abroad (aOR, 2.04 (95% CI = 1.19–3.50) for Asia; aOR, 1.57 (95% CI = 1.24–1.98) for Africa), having a chronic disease (aOR, 1.29 (95% CI = 1.04–1.60)), alcohol abuse (aOR, 2.24 (95% CI = 1.73–2.90)), and being intravenous drug user (aOR, 1.68 (95% CI = 1.05–2.68)). Three-month course treatment with isoniazid plus rifampicin was associated with decreased FCT when compared with 6- or 9-month courses of isoniazid-only (aOR, 0.59 (95% CI = 0.45–0.77)). In Lisbon metropolitan area, being born in Africa, and in Porto metropolitan area, alcohol abusing and being intravenous drug user were distinctive factors associated with FCT. Sociodemographic and medical factors associated with FCT may vary by geographical area and should be taken into account when planning interventions to improve LTBI treatment outcomes. This study reinforces that shorter course treatment for LTBI might reduce FCT. Mònica Guxens is funded by a Miguel Servet II fellowship (CPII18/00018) awarded by the Spanish Institute of Health Carlos III. The rest of the authors have declared no funding.

Introduction: Persons with mental illness experience social life restriction and stigma that may have implications for their work ability. The aims of this study are (i) to report experienced and anticipated discrimination and social functioning in persons with mental disabilities in Kenya and (ii) to investigate the association between experienced and anticipated discrimination, social functioning, and employment in this population.Materials and Methods: Cross-sectional study design where we randomly recruited 72 persons with mental illness through two networks of persons with psychosocial disabilities in Kenya. Experienced and anticipated discrimination were measured using the Discrimination and Stigma Scale version 12 (DISC 12) while social functioning was measured using the Social Functioning questionnaire (SFQ).Results: Experienced discrimination was reported by 81.9% in making or keeping friends, 69.7 and 56.3% in finding or keeping job, respectively, and 63.3% in dating or having an intimate relationship. Anticipated discrimination stopped 59.2% from applying for work, 40.8% from applying for education or training courses, and 63.4% from having a close personal relationship. Females reported an overall higher experienced discrimination than males. Unemployed participants had slightly increased rates of experienced and anticipated discrimination (9.5 vs. 9.1 and 2.5 vs. 2.3, respectively) (p > 0.05), while there was a significant association between impaired social functioning and unemployment [14.0 vs. 11.2 (p = 0.037)].Conclusion: The rates of experienced and anticipated discrimination faced by persons with mental disabilities in Kenya is high and with significant gender disparity. Although no strong associations were observed between experienced and anticipated discrimination and employment, impaired social functioning of persons with mental disabilities seems to have implications for employment. Further research is essential to understand the predictors of the discrimination and measures to reduce them in persons with psychosocial disabilities.