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Accumulating evidence suggests that in utero exposures can influence the development of the immune system. Few studies have investigated whether prenatal exposure to persistent organic pollutants (POPs) is associated with allergy-related phenotypes in childhood, nor explored sex differences. We examined the association between prenatal exposure to POPs and offspring allergic outcomes in early and mid-childhood. We included 682 mother–child pairs from the prospective birth cohort Rhea. We measured dichlorodiphenyldichloroethylene (DDE), hexachlorobenzene (HCB) and 6 polychlorinated biphenyl (PCB) congeners in maternal first trimester serum. Parents completed the questionnaires adapted from the International Study on Asthma and Allergy in Childhood (ISAAC) for allergy-related phenotypes when their children were 4 and 6 years old. We used Poisson regression models to estimate Risk Ratios. Prenatal HCB was associated with increased risk for rhinoconjunctivitis at 6 years (RR (95% CI): 2.5; (1.3, 4.8) for a doubling in the exposure). Among girls, prenatal DDE was associated with increased risk for current wheeze, current asthma and current rhinoconjunctivitis at 4 years (RR (95%CI): 1.4 (0.8, 2.6), 1.6 (1.1, 2.4) and 1.8 (1.0, 3.3) and p-interaction = 0.035, 0.027 and 0.059, respectively), with increased risk for current rhinoconjunctivitis at 6 years (RR (95%CI): 1.7 (0.7, 3.8) and p-interaction = 0.028) and total PCBs were associated with increased risk for current eczema at 4 years (RR (95%CI): 2.1 (1.1, 4.2) and p-interaction = 0.028). In boys, prenatal DDE was associated with decreased risk for current wheeze and current asthma at 4 years. Our findings suggest that even low levels of exposure to POPs prenatally may affect the development of childhood allergy-related outcomes in a sex and age-specific manner.

The present study aims to explore the association of maternal sleep disturbances during late pregnancy on child neuropsychological and behavioral development in preschool years. The study included 638 mother-child pairs from the prospective Rhea mother-child cohort in Crete, Greece. Information on antenatal sleep disturbances was collected through a computer-assisted interview. Children's neuropsychological and behavioral development was assessed using the McCarthy Scales of Children's Abilities (MSCA), the Attention-Deficit Hyperactivity Disorder Test (ADHDT), and the Strengths and Difficulties Questionnaire (SDQ). Multivariate analysis showed that maternal sleep duration less than 8 h was associated with reduced scores in the general cognitive scale (β = -2.28, 95% CI -4.54, -0.02, R

Urinary metabolic profiling is a promising powerful tool to reflect dietary intake and can help understand metabolic alterations in response to diet quality. Here, we used 1H-NMR spectroscopy in a multi-country study in European children (1147 children from 6 different cohorts) and identified a common panel of 4 urinary metabolites (hippurate, N-methylnicotinic acid, urea and sucrose) that was predictive of Mediterranean diet adherence (KIDMED) and ultra-processed food (UPF) consumption and also had higher capacity in discriminating children’s diet quality than that of established sociodemographic determinants. Further, we showed that the identified metabolite panel also reflected the associations of these diet quality indicators with C-peptide, a stable and accurate marker of insulin resistance and future risk of metabolic disease. This methodology enables objective assessment of dietary patterns in European child populations, complementary to traditional questionary methods, and can be used in future studies to evaluate diet quality. Moreover, this knowledge can provide mechanistic evidence of common biological pathways that characterize healthy and unhealthy dietary patterns, and diet-related molecular alterations that could associate to metabolic disease.

Background: Exposure to per- and polyfluoroalkyl substances (PFAS), a prevalent class of persistent pollutants, may increase the risk of type 2 diabetes. Objective: We examined associations between PFAS exposure and glucose metabolism in youth. Methods: Overweight/obese adolescents from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR; n=310) participated in annual visits for an average of 3.3±2.9y. Generalizability of findings were tested in young adults from the Southern California Children’s Health Study (CHS; n=135) who participated in a clinical visit with a similar protocol. At each visit, oral glucose tolerance tests were performed to estimate glucose metabolism and β-cell function via the insulinogenic index. Four PFAS were measured at baseline using liquid chromatography–high-resolution mass spectrometry; high levels were defined as concentrations >66th percentile. Results: In females from the SOLAR, high perfluorohexane sulfonate (PFHxS) levels (≥2.0 ng/mL) were associated with the development of dysregulated glucose metabolism beginning in late puberty. The magnitude of these associations increased postpuberty and persisted through 18 years of age. For example, postpuberty, females with high PFHxS levels had 25-mg/dL higher 60-min glucose (95% CI: 12, 39mg/dL; p

Background Early-life antibiotic use has been hypothesized to promote weight gain and increase the risk of childhood obesity. Objectives To examine the associations of prenatal and infant antibiotics with childhood growth, adiposity and cardiometabolic traits in the Greek Rhea cohort. Methods We used data from 747 mother-child pairs with anthropometric measurements drawn from medical records or measured at 4 and 6 years of age. Antibiotic exposure was assessed by maternal report during pregnancy and at the first year of life. Children were classified as exposed to antibiotics prenatally if the mother received at least one course of oral antibiotics during pregnancy and postnatally if the mother reported that the child received at least one oral antibiotic treatment during the first year of life. Outcomes included repeated weight, body mass index (BMI), waist circumference, body fat (%), total cholesterol and blood pressure. We applied mixed effects, linear and log-binomial regression models after adjusting for important covariates. Results Around 14.6% of the participating children were prenatally exposed to antibiotics and 32.4% received antibiotics during the first year of life. Prenatal exposure to antibiotics was associated with a twofold increase in the risk for obesity (risk ratio [RR]; 95% confidence interval [CI]: 2.09 [1.58, 2.76]) and abdominal obesity (RR [95% CI]: 2.56 [1.89, 3.47]) at 6 years. Postnatal exposure to antibiotics was associated with increased weight (beta [95% CI]: 00.25 [0.06, 0.44]) and BMI (beta [95% CI]: 0.23 [0.003, 0.45]) SD scores from 2 to 7 years of life. Conclusion Early-life antibiotic use was associated with accelerated childhood growth and higher adiposity.

Background: Prenatal exposure to organochlorine compounds (OCs) has been associated with increased childhood body mass index (BMI); however, only a few studies have focused on longitudinal BMI trajectories, and none of them used multiple exposure mixture approaches. Aim: To determine the association between in-utero exposure to eight OCs and childhood BMI measures (BMI and BMI z-score) at 4 years and their yearly change across 4-12 years of age in 279 Rhea child-mother dyads. Methods: We applied three approaches: (1) linear mixed-effect regressions (LMR) to associate individual compounds with BMI measures; (2) Bayesian weighted quantile sum regressions (BWQSR) to provide an overall OC mixture association with BMI measures; and (3)Bayesian varying coefficient kernel machine regressions (BVCKMR) to model nonlinear and nonadditive associations. Results: In the LMR, yearly change of BMI measures was consistently associated with a quartile increase in hexachlorobenzene (HCB) (estimate [95% Confidence or Credible interval] BMI: 0.10 [0.06, 0.14]; BMI z-score: 0.02 [0.01, 0.04]). BWQSR results showed that a quartile increase in mixture concentrations was associated with yearly increase of BMI measures (BMI: 0.10 [0.01, 0.18]; BMI z-score: 0.03 [0.003, 0.06]). In the BVCKMR, a quartile increase in dichlorodiphenyldichloroethylene concentrations was associated with higher BMI measures at 4 years (BMI: 0.33 [0.24, 0.43]; BMI z-score: 0.19 [0.15, 0.24]); whereas a quartile increase in HCB and polychlorinated biphenyls (PCB)-118 levels was positively associated with BMI measures yearly change (BMI: HCB:0.10 [0.07, 0.13], PCB-118:0.08 [0.04, 012]; BMI z-score: HCB:0.03 [0.02, 0.05], PCB-118:0.02 [0.002,04]). BVCKMR suggested that PCBs had nonlinear relationships with BMI measures, and HCB interacted with other compounds. Conclusions: All analyses consistently demonstrated detrimental associations between prenatal OC exposures and childhood BMI measures.

There is growing evidence associating inflammatory markers in complex, higher order neurological functions, such as cognition and memory. We examined whether high levels of various inflammatory markers are associated with cognitive outcomes at 4 years of age in a mother-child cohort in Crete, Greece (Rhea study). We included 642 children in this cross-sectional study. Levels of several inflammatory markers (IFN-γ, IL-1β, IL-6, IL-8, IL-17α, IL-10, MIP-1α, TNF-α and the ratios of IL-6 to IL-10 and TNF-α to IL-10) were determined in child serum via immunoassay. Neurodevelopment at 4 years was assessed by means of the McCarthy Scales of Children’s Abilities. Multivariate linear regression analyses were used to estimate the associations between the exposures and outcomes of interest after adjustment for various confounders. Our results indicate that children with high TNF-α concentrations (≥90th percentile) in serum demonstrated decreased scores in memory (adjusted β = −4.0; 95% CI: −7.7, −0.2), working memory (adjusted β = −4.0; 95% CI: −8.0, −0.1) as well as in memory span scale (adjusted β = −4.0; 95% CI: −7.9, −0.1). We also found that children with high IFN-γ serum levels showed lower scores in memory span scale (adjusted β = −3.4; 95% CI: −7.3, −0.4). Children with elevated TNF-α/IL-10 ratio demonstrated decreased quantitative (adjusted β = −4.3; 95% CI: −8.2, −0.4), motor (adjusted β = −3.5; 95% CI: −7.5, −0.5), executive function (adjusted β = −4.8; 95% CI: −8.5, −1.1), general cognitive (adjusted β = −3.6; 95% CI: −7.3, −0.1), memory (adjusted β = −3.8; 95% CI: −7.6, −0), working memory (adjusted β = −3.5; 95% CI: −7.5, −0.5) and memory span scores (adjusted β = −5.3; 95% CI: −9.1, −1.4) The findings suggest that high levels of TNF-α may contribute to reduced memory performance at preschool age.

Background/objectives Polyunsaturated fatty acid (PUFA) status during pregnancy has been suggested to influence offspring obesity and cardiometabolic health. We assessed whether prenatal PUFA exposure is associated with rapid infant growth, childhood BMI, and cardiometabolic profile.Subjects/methods In the Dutch MEFAB (n = 266) and Greek RHEA (n = 263) cohorts, we measured n-3 and n-6 PUFA concentrations in cord blood phospholipids, which reflect fetal exposure in late pregnancy. We defined rapid infant growth from birth to 6 months of age as an increase in weight z-score >0.67. We analyzed body mass index (BMI) as continuous and in categories of overweight/obesity at 4 and 6 years. We computed a cardiometabolic risk score at 6-7 years as the sum of waist circumference, non-high-density lipoprotein cholesterol and blood pressure z-scores. Associations of PUFAs with child health outcomes were assessed using generalized linear models for binary outcomes and linear regression models for continuous ones after adjusting for important covariates, and for the pooled estimates, a cohort indicator.Results In pooled analyses, we found no association of PUFA levels with rapid infant growth, childhood BMI (beta per SD increase in the total n-3:n-6 PUFA ratio = -0.04 SD; 99% CI: -0.15, 0.06; P = 0.65 at 4 years, and -0.05 SD; 99% CI: -0.18, 0.08; P = 0.78 at 6 years), and overweight/obesity. We also found no associations for clustered cardiometabolic risk and its individual components. The results were similar across cohorts.Conclusions Our findings suggest that PUFA concentrations at birth are not associated with later obesity development and cardiometabolic risk in childhood.

Prenatal cadmium exposure has been associated with impaired fetal growth; much less is known about the impact during later childhood on growth and cardiometabolic traits. To elucidate the associations of prenatal cadmium exposure with child growth, adiposity, and cardiometabolic traits in 515 mother-child pairs in the Rhea Mother-Child Study cohort (Heraklion, Greece, 2007-2012), we measured urinary cadmium concentrations during early pregnancy and assessed their associations with repeated weight and height measurements (taken from birth through childhood), waist circumference, skinfold thickness, blood pressure, and serum lipid, leptin, and C-reactive protein levels at age 4 years. Adjusted linear, Poisson, and mixed-effects regression models were used, with interaction terms for child sex and maternal smoking added. Elevated prenatal cadmium levels (third tertile of urinary cadmium concentration (0.571-2.658 μg/L) vs. first (0.058-0.314 μg/L) and second (0.315-0.570 μg/L) tertiles combined) were significantly associated with a slower weight trajectory (per standard deviation score) in all children (β = -0.17, 95% confidence interval (CI): -0.32, -0.02) and a slower height trajectory in girls (β = -0.30, 95% CI: -0.52,-0.09; P for interaction = 0.025) and in children born to mothers who smoked during pregnancy (β = -0.48, 95% CI: -0.83, -1.13; P for interaction = 0.027). We concluded that prenatal cadmium exposure was associated with delayed growth in early childhood. Further research is needed to understand cadmium-related sex differences and the role of coexposure to maternal smoking during early pregnancy. The Rhea Mother-Child Cohort Study was financially supported by European Union projects (FP6-2003-Food-3-A NewGeneris, Food-CT-2006-036224 Hiwate, FP7/2007- 2011-GA-211250 ESCAPE Project, FP7-2008-226756 Envirogenomarkers, FP7-HEALTH-2009 single-stage 241604 CHICOS, and FP7-ENV.2008.1.2.1.6 proposal 226285 ENRIECO) and the Greek Ministry of Health (Program of Prevention of Obesity and Neurodevelopmental Disorders in Preschool Children, Heraklion District, Crete, Greece, 2011–2014; and “Rhea Plus”: Primary Prevention Program of Environmental Risk Factors for Reproductive Health and Child Health, 2012–2015). The present study was also funded by the Karolinska Institutet, the Swedish Research Council Formas (project 210-2013-751), and the Swedish Research Council (project 2015-03655).

Urinary metabolic profiling is a promising powerful tool to reflect dietary intake and can help understand metabolic alterations in response to diet quality. Here, we used 1H NMR spectroscopy in a multicountry study in European children (1147 children from 6 different cohorts) and identified a common panel of 4 urinary metabolites (hippurate, N-methylnicotinic acid, urea, and sucrose) that was predictive of Mediterranean diet adherence (KIDMED) and ultra-processed food consumption and also had higher capacity in discriminating children's diet quality than that of established sociodemographic determinants. Further, we showed that the identified metabolite panel also reflected the associations of these diet quality indicators with C-peptide, a stable and accurate marker of insulin resistance and future risk of metabolic disease. This methodology enables objective assessment of dietary patterns in European child populations, complementary to traditional questionary methods, and can be used in future studies to evaluate diet quality. Moreover, this knowledge can provide mechanistic evidence of common biological pathways that characterize healthy and unhealthy dietary patterns, and diet-related molecular alterations that could associate to metabolic disease. The HELIX project has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 308,333. The STOP project (http://www.stopchildobesity.eu/) received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 774,548. The STOP Consortium is coordinated by Imperial College London and includes 24 organizations across Europe, the United States, and New Zealand. The content of this publication reflects only the views of the authors, and the European Commission is not liable for any use that may be made of the information it contains. INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6-04-2014_31 V-66). For a full list of funding that supported the EDEN cohort, refer to: Heude B et al. Cohort Profile: The EDEN mother–child cohort on the prenatal and early postnatal determinants of child health and development. Int J Epidemiol. 2016 Apr;45(2):353–63. The Norwegian Mother, Father and Child Cohort Study (MoBa) is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. 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: 2012–2015). Born in Bradford received funding from the Wellcome Trust (101597). Professor Wright and McEachan receive funding from the National Institute for Health Research Applied Research Collaboration for Yorkshire and Humber. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Dr. Maribel Casas received funding from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness) (MS16/00128). Dr. Leda Chatzi was supported by NIH/NIEHS R01 ES029944, R01ES030691, R01ES030364, R21 ES029681, R21 ES028903, and P30 ES007048-23. Dr. David Conti was supported by P01CA196569, R01CA140561, R01 ES016813, R01 ES029944, R01ES030691, and R01ES030364. Dr. Nikos Stratakis was supported by NIH/NIEHS R21 ES029681 and P30 ES007048-23, and NIH/NIDDK P30 DK048522-24. Dr. Hector Keun and Dr. Alexandros Siskos were also supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 874,583 ('ATHLETE'). Dr. Eleni Papadopoulou was supported by the Research Council of Norway, under the MILJØFORSK program (project no. 268465). Dr. Fernanda Rauber was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo 2016/14302-7 and 2018/19820-1. The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is a member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PE I + D + i 2013–2016 from the Instituto de Salud Carlos III (ISCIII) and ERDF. ISGlobal acknowledges support from the Spanish Ministry of Science, Innovation and Universities, 'Centro de Excelencia Severo Ochoa 2013–2017', SEV-2012–0208, and 'Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya' (2017SGR595).

Maintaining thyroid homeostasis during pregnancy is vital for fetal development. The few studies that have investigated associations between metal exposure and gestational thyroid function have yielded mixed findings. To evaluate the association of exposure to a mixture of toxic metals with thyroid parameters in 824 pregnant women from the Rhea birth cohort in Crete, Greece. Concentrations of three toxic metals [cadmium (Cd), antimony (Sb), lead (Pb)] and iodine were measured in urine using inductively coupled plasma mass spectrometry and thyroid hormones [Thyroid Stimulating Hormone (TSH), free thyroxine (fT4), and free triiodothyronine (fT3)] were measured in serum in early pregnancy. Associations of individual metals with thyroid parameters were assessed using adjusted regression models, while associations of the metal mixture with thyroid parameters were assessed using Bayesian Kernel Machine Regression (BKMR).Women with high (3rd tertile) concentrations of urinary Cd, Sb and Pb, respectively, had 13.3 % (95%CI: 2.0 %, 23.2 %), 12.5 % (95%CI: 1.8 %, 22.0 %) and 16.0 % (95%CI: 5.7 %, 25.2 %) lower TSH compared to women with low concentrations (2nd and 1st tertile). In addition, women with high urinary Cd had 2.2 % (95%CI: 0.0 %, 4.4 %) higher fT4 and 4.0 % (95%CI: −0.1 %, 8.1 %) higher fT3 levels, and women with high urinary Pb had 4 % (95%CI: 0.2 %, 8.0 %) higher fT3 levels compared to women with low exposure. The negative association of Cd with TSH persisted only when iodine sufficiency was unfavorable. BKMR attested that simultaneous exposure to toxic metals was associated with decreased TSH and increased fT3 and revealed a potential synergistic interaction of Cd and Pb in association with TSH. The present results suggest that exposure to toxic metals even at low levels can alter gestational thyroid homeostasis.

Background: Child blood pressure (BP) is predictive of future cardiovascular risk. Prenatal exposure to metals has been associated with higher BP in childhood, but most studies have evaluated elements individually and measured BP at a single time point. We investigated impacts of prenatal metal mixture exposures on longitudinal changes in BP during childhood and elevated BP at 11 years of age. Methods: The current study included 176 mother-child pairs from the Rhea Study in Heraklion, Greece and focused on eight elements (antimony, arsenic, cadmium, cobalt, lead, magnesium, molybdenum, selenium) measured in maternal urine samples collected during pregnancy (median gestational age at collection: 12 weeks). BP was measured at approximately 4, 6, and 11 years of age. Covariate-adjusted Bayesian Varying Coefficient Kernel Machine Regression and Bayesian Kernel Machine Regression (BKMR) were used to evaluate metal mixture impacts on baseline and longitudinal changes in BP (from ages 4 to 11) and the development of elevated BP at age 11, respectively. BKMR results were compared using static versus percentile-based cutoffs to define elevated BP. Results: Molybdenum and lead were the mixture components most consistently associated with BP. J-shaped relationships were observed between molybdenum and both systolic and diastolic BP at age 4. Similar associations were identified for both molybdenum and lead in relation to elevated BP at age 11. For molybdenum concentrations above the inflection points (~ 40-80 μg/L), positive associations with BP at age 4 were stronger at high levels of lead. Lead was positively associated with BP measures at age 4, but only at high levels of molybdenum. Potential interactions between molybdenum and lead were also identified for BP at age 11, but were sensitive to the cutoffs used to define elevated BP. Conclusions: Prenatal exposure to high levels of molybdenum and lead, particularly in combination, may contribute to higher BP at age 4. These early effects appear to persist throughout childhood, contributing to elevated BP in adolescence. Future studies are needed to identify the major sources of molybdenum and lead in this population. This work was supported by NIEHS [grant numbers R21ES029681 (Chatzi, Conti, McConnell), R01ES030691 (Chatzi, Conti, McConnell, Eckel), R01ES029944 (Chatzi, Conti, Margetaki), R01 ES030364 (Chatzi, Conti, McConnell, Eckel), R21ES028903 (Chatzi, McConnell, Eckel), P30ES007048 (Chatzi, Conti, McConnell, Eckel), K99 ES030400 (Howe), R00ES024144 (Farzan), and Horizon 2020 – European Framework Programme for Research and Innovation, ATHLETE, (Chatzi, Conti), P01CA196569, R01CA140561, R01ES016813 (Conti)]. The Rhea project was financially supported by the European Union [grant numbers EU FP6–2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211250 Escape, EU FP7–2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226285 ENRIECO, EU- FP7- HEALTH-2012 Proposal No 308333 HELIX) and the Greek Ministry of Health.

BackgroundMaternal thyroid hormones’ supply is crucial for fetal neurodevelopment; however, the role of maternal mild thyroid dysfunction is not clear. We aimed to assess the association of maternal mild thyroid dysfunction with child neuropsychological development from infancy to early childhood.MethodsWe included 757 mother–child pairs from the prospective ‘Rhea’ cohort on Crete, Greece. Maternal thyroid functioning was assessed by quantitative analysis of serum thyroid-stimulating hormone, free thyroxine, thyroid peroxidase antibodies and thyroglobulin antibodies at early gestation (mean=14 weeks). Neuropsychological assessment was based on Bayley Scales of Infant Development (18 months of age), McCarthy Scales of Children’s Abilities (4 years of age), Raven’s Coloured Progressive Matrices, Trail Making Test and Finger Tapping Test (6 years of age).ResultsIn multivariate adjusted linear regression analyses, maternal hypothyroxinemia was associated with decreased verbal scores at 4 years and reduced motor speed at 6 years of age. Maternal thyroid autoimmunity was associated with decreased child perceptual and motor ability at 4 years of age. Four trajectories of longitudinal non-verbal cognitive development were identified and children exposed to maternal thyroid autoimmunity had increased risk for belonging to an adverse trajectory (‘low’: adjusted relative risk ratio (RRR) = 2.7 95% CI: (1.4, 5.2), ‘high-decreasing’: adjusted RRR = 2.2 95% CI: (1.2, 4.0), ‘low-increasing’: adjusted RRR = 1.8 95% CI: (1.0, 3.2)).ConclusionMaternal hypothyroxinemia is associated with reduced offspring verbal and motor ability. Maternal thyroid autoimmunity is associated with decreased offspring perceptual performance and motor ability and increased risk for adverse non-verbal cognitive development from infancy to childhood.

Supported by the National Institute of Environmental Health Sciences (R21ES029681; R01ES030691, R01ES029944, R01ES030364, R21ES028903, and P30ES007048, to L.C.; R01ES030691, R01ES030364, R21ES028903, and P30ES007048, to R.M.; R01ES030691, R01ES029944, R01ES030364, and P30ES007048, to D.V.C.; R01ES030691, R01ES029944, R01ES030364, and R21ES028903, to D.V.; R01ES030364, to N.S.; and P30ES007048, to E.G), the National Institutes of Health (P01CA196569 and R01CA140561, to D.V.C.; P30DK048522, to N.S.), the Instituto de Salud Carlos III (Ministry of Economy and Competitiveness) (MS16/00128, to M.C.), and the Juan de la Cierva-Incorporacion fellowship (IJC2018-035394-I, to L.M.), awarded by the Spanish Ministerio de Economia, Industria y Competitividad. The Human Early Life Exposome project was supported by the European Community’s Seventh Framework Programme (FP7/2007-2013, under grant 30833). INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. The KANC cohort was supported by the Lithuanian Agency for Science Innovation and Technology (31V-77). For a full list of funding that supported the EDEN cohort, see https://doi.org/10.1093/ije/dyv151. The Norwegian Mother, Father and Child Cohort Study was supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. The Rhea cohort was supported by European projects; the Greek Ministry of Health (Program of Prevention of Obesity and Neurodevelopmental Disorders in Preschool Children, in Heraklion district, Crete, Greece), 2011-2014; and Rhea Plus: Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012-2015. The BiB cohort was supported by a Wellcome Trust infrastructure grant (WT101597MA). R.R.C.M. and J.W. received funding from the National Institute for Health Research Applied Research Collaboration for Yorkshire and Humber. The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and a member of the ProteoRed PRB3 consortium, which is supported by grant PT17/0019 of the PE I + D+i 2013-2016 from the Instituto de Salud Carlos III and European Regional Development Fund. This study was further supported by grants from the Spanish Ministry of Science, Innovation and Universities, Centro de Excelencia Severo Ochoa 2013-2017 (SEV-2012-0208), and Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya (2017SGR595).

DAL’s contribution to this paper is supported by the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013/ERC grant agreement no 669545) and a UK National Institute of Health Senior Investigator (NF-0616-10102). TC’s contribution is supported by European Union’s Horizon 2020 research and innovation programme under grant agreement No 733206 (LifeCycle). MLV has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 707404. The opinions expressed in this document refect only the author’s view. The European Commission is not responsible for any use that may be made of the information it contains. The INfancia y Medio Ambiente (INMA)-Sabadell cohort was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; CP18/00018; PI041436; PI081151; PI1100610 incl. FEDER funds). ISGlobal acknowledge support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S). SA is funded by a Juan de la Cierva—Incorporación Postdoctoral Contract awarded by Ministry of Economy, Industry and Competitiveness (IJCI-2017-34068). JJ holds Miguel Servet-II contract (CPII19/00015) awarded by the Instituto de Salud Carlos III (Co-funded by European Social Fund “Investing in your future”). MC holds a Miquel ServetI cotract (CP16/00128) awarded by the Instituto de Salud Carlos III (co-funded by European Social Fund "Investing in your future"). The INMA-Asturias cohort is funded by grants from Instituto de Salud Carlos III (FISS PI 04/2018, FISS PI09/02311, FISS PI13/02429, FISS PI18/00909 including FEDER funds) and University of Oviedo. This study was funded by Instituto de Salud Carlos III through the projects ‘CP14/00108 & PI16/00261’ (co-funded by European Regional Development Fund ‘A way to make Europe’) (…), Alemany, S., Avella-García, C., Liew, Z., García-Esteban, R., Inoue, K., Cadman, T., López-Vicente, M., González, L., Riaño Galán, I., Andiarena, A., Casas, M., Margetaki, K., Strandberg-Larsen, K., Lawlor, D.A., El Marroun, H., Tiemeier, H., Iñiguez, C., Tardón, A., Santa-Marina, L., Júlvez, J., Porta, D., Chatzi, L., Sunyer, J.

Background/Aim: Trace elements concentrations have been implicated in cardiometabolic risk in children. Previously, studies have largely focused on individual elements, however, more akin to the re...

Background: Prenatal exposure to organochlorine compounds has been associated with increased risk for pediatric obesity; however, evidence is still inconclusive and most previous studies did not in...

Previous evidence suggests a link between attention deficit hyperactivity disorder (ADHD) symptoms and disordered eating behaviours; however, the direction of the causal association remains unclear. Building on our previous research, we aimed to examine the longitudinal association between eating behaviours at 4 years, ADHD symptoms at 6 years of age, and the role of body mass index (BMI). We included children from the RHEA mother-child cohort in Greece, followed up at 4 and 6 years (n = 926). Parents completed the Children's Eating Behaviour Questionnaire (CEBQ) to assess children's eating behaviour at 4 years and the ADHD Test (ADHDT) and Child Behaviour Checklist for ages 6-18 (CBCL/6-18) to evaluate ADHD symptoms at 4 and 6 years, respectively, as well as measures of BMI. Longitudinal structural equation modeling (SEM) was carried out to evaluate the associations of all variables between 4 and 6 years. Food responsiveness at 4 years was positively associated with hyperactivity at age 6, whereas emotional overeating was negatively associated with hyperactivity. There was no evidence of an association between eating behaviours of preschoolers and BMI at 6 years, or BMI at 4 years and later ADHD symptoms and vice versa. Findings suggest that food responsiveness is an early marker of ADHD symptoms at 6 years of age. In contrast to our hypothesis there was no significant association between ADHD at age 4 and BMI at age 6.

BACKGROUND AND AIMS: Per- and polyfluoroalkyl substances (PFAS) are widespread and persistent pollutants that have been shown to have hepatotoxic effects in animal models. However, human evidence is scarce. We evaluated how prenatal exposure to PFAS associates with established serum biomarkers of liver injury and alterations in serum metabolome in children. APPROACH AND RESULTS: We used data from 1,105 mothers and their children (median age, 8.2 years; interquartile range, 6.6-9.1) from the European Human Early-Life Exposome cohort (consisting of six existing population-based birth cohorts in France, Greece, Lithuania, Norway, Spain, and the United Kingdom). We measured concentrations of perfluorooctane sulfonate, perfluorooctanoate, perfluorononanoate, perfluorohexane sulfonate, and perfluoroundecanoate in maternal blood. We assessed concentrations of alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase in child serum. Using Bayesian kernel machine regression, we found that higher exposure to PFAS during pregnancy was associated with higher liver enzyme levels in children. We also measured child serum metabolomics through a targeted assay and found significant perturbations in amino acid and glycerophospholipid metabolism associated with prenatal PFAS. A latent variable analysis identified a profile of children at high risk of liver injury (odds ratio, 1.56; 95% confidence interval, 1.21-1.92) that was characterized by high prenatal exposure to PFAS and increased serum levels of branched-chain amino acids (valine, leucine, and isoleucine), aromatic amino acids (tryptophan and phenylalanine), and glycerophospholipids (phosphatidylcholine [PC] aa C36:1 and Lyso-PC a C18:1). CONCLUSIONS: Developmental exposure to PFAS can contribute to pediatric liver injury. (Hepatology 2020;72:1758-1770).

Study objectives: The objective of this study was to evaluate the association between gestational sleep deprivation and childhood adiposity and cardiometabolic profile. Methods: Data were used from two population-based birth cohorts (Rhea study and Amsterdam Born Children and their Development study). A total of 3,608 pregnant women and their children were followed up until the age of 11 years. Gestational sleep deprivation was defined as 6 or fewer hours of sleep per day, reported by questionnaire. The primary outcomes included repeated measures of body mass index (BMI), waist circumference, body fat, serum lipids, systolic and diastolic blood pressure (DBP) levels in childhood. We performed a pooled analysis with adjusted linear mixed effect and Cox proportional hazards models. We tested for mediation by birthweight, gestational age, and gestational diabetes. Results: Gestational sleep deprivation was associated with higher BMI (beta; 95% CI: 0.7; 0.4, 1.0 kg/m2) and waist circumference (beta; 95% CI: 0.9; 0.1, 1.6 cm) in childhood, and increased risk for overweight or obesity (HR; 95% CI: 1.4; 1.1, 2.0). Gestational sleep deprivation was also associated with higher offspring DBP (beta; 95% CI: 1.6; 0.5, 2.7 mmHg). The observed associations were modified by sex (all p-values for interaction < 0.05); and were more pronounced in girls. Gestational diabetes and shorter gestational age partly mediated the seen associations. Conclusions: This is the first study showing that gestational sleep deprivation may increase offspring's adiposity and blood pressure, while exploring possible mechanisms. Attention to glucose metabolism and preterm birth might be extra warranted in mothers with gestational sleep deprivation. We are thankful to all the mothers, fathers, and children who participated in the Rhea cohort and Amsterdam Born Children and their Development cohort. The ABCD study has been supported by grants from The Netherlands Organisation for Health Research and Development (ZonMW) and The Netherlands Heart Foundation. Research time of MH was supported by the municipal Amsterdam Healthy Weight Program (Amsterdamse Aanpak Gezond Gewicht). The Rhea project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211250 Escape, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009-single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226285 ENRIECO, EUFP7-HEALTH-2012 Proposal No 308333 HELIX, FP7 European Union project, No. 264357 MeDALL), and the Ministry of health and social solidarity, Greece (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). Dr Lida Chatzi was supported by the National Institute of Environmental Health Sciences (NIEHS/National Institutes of Health (NIH)) grants: R21ES029681, R01ES030691, R01ES029944, R01 ES030364, R21ES028903, and P30ES007048, and by NIH (UH3OD023287). The study was also supported by Seventh Framework Programme and Hartstichting.

Animal studies suggest that prenatal vitamin D status may affect fetal brain growth. However, human studies are scarce with conflicting results. We aimed to investigate the association of maternal 25-hydroxyvitamin D [25(OH) D] levels with multiple neurodevelopmental outcomes at 4 years of age. We included 487 mother–child pairs from the prospective pregnancy cohort, “Rhea” in Crete, Greece. Maternal serum 25(OH) D concentrations were measured at the first prenatal visit (13 ± 2.4 weeks). Cognitive functions at 4 years were assessed by means of the McCarthy Scales of Children’s Abilities. Behavioral difficulties were assessed by means of Strengths and Difficulties Questionnaire and Attention Deficit Hyperactivity Disorder Test. Children of women in the high 25(OH) D tertile (>50.7 nmol/l) had 37% decreased number of hyperactivity–impulsivity symptoms (IRR 0.63, 95% CI 0.39, 0.99, p trend = 0.05) and 40% decreased number of total ADHD-like symptoms (IRR 0.60, 95% CI 0.37, 0.95, p trend = 0.03) at 4 years of age, compared to children of women in the low 25(OH) D tertile (

Background Evidence suggests a complex interplay between infections and allergic diseases. Objective To explore the association of 14 common viruses with eczema, asthma, and rhinoconjunctivitis in childhood. Methods We used cross-sectional (n = 686) and prospective (n = 440) data from children participating in the Rhea birth cohort. Immunoglobulin G to polyomaviruses (BK polyomavirus, JC polyomavirus, KI polyomavirus [KIPyV], WU polyomavirus [WUPyV], human polyomavirus 6, human polyomavirus 7, Trichodysplasia spinulosa polyomavirus, Merkel cell polyomavirus, human polyomavirus 9, and human polyomavirus 10) and herpesviruses (Epstein-Barr virus, Cytomegalovirus, Herpes simplex virus-1, Herpes simplex virus-2) were measured at age 4 years by fluorescent bead-based multiplex serology. Definitions of eczema, asthma, and rhinoconjunctivitis at ages 4 and 6 years were based on questionnaires. Mediation of the associations by immune biomarkers was tested. Results Less likely to have eczema at age 4 years were KIPyV-seropositive (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.27-0.82) and human polyomavirus 6 (OR, 0.44; 95% CI, 0.26-0.73) compared with their seronegative counterparts. Seropositivity to Epstein-Barr virus was negatively associated with eczema at age 4 years (OR, 0.39; 95% CI, 0.22-0.67) and 6 years (OR, 0.50; 95% CI, 0.25-0.99). Children with a higher burden of herpesviruses or of skin polyomaviruses had the lowest odds of eczema at age 4 years. Higher odds for asthma at age 4 years were found for WUPyV-seropositive children (OR, 3.98; 95% CI, 1.38-11.51), and for children seropositive to both respiratory polyomaviruses (KIPyV and WUPyV) (OR, 7.35; 95% CI, 1.66-32.59) compared with children seronegative to both. No associations were observed for rhinoconjunctivitis. There was no evidence of mediation by immune biomarkers. Conclusion A heterogeneous pattern of infections and allergic diseases was observed with common infections associated with a decreased eczema risk and an increased asthma risk in children.

Post-partum depression (PPD) is a severe psychiatric disorder affecting ∼15% of young mothers. Early life stressful conditions in periconceptual, fetal and early infant periods or exposure to maternal psychiatric disorders, have been linked to adverse childhood outcomes interfering with physiological, cognitive and emotional development. The molecular mechanisms of PPD are not yet fully understood. Unraveling the molecular underpinnings of PPD will allow timely detection and establishment of effective therapeutic approaches. To investigate the underlying molecular correlates of PPD in peripheral material, we compared the serum metabolomes of an in detail characterized group of mothers suffering from PPD and a control group of mothers, all from Heraklion, Crete in Greece. Serum samples were analyzed by a mass spectrometry platform for targeted metabolomics, based on selected reaction monitoring (SRM), which measures the levels of up to 300 metabolites. In the PPD group, we observed increased levels of glutathione-disulfide, adenylosuccinate, and ATP, which associate with oxidative stress, nucleotide biosynthesis and energy production pathways. We also followed up the metabolomic findings in a validation cohort of PPD mothers and controls. To the very best of our knowledge, this is the first metabolomic serum analysis in PPD. Our data show that molecular changes related to PPD are detectable in peripheral material, thus paving the way for additional studies in order to shed light on the molecular correlates of PPD.

Objective Leptin is critical for central nervous system development and maturation. This study aimed to evaluate the potential regulatory role of cord leptin in the neuropsychomotor development of children ages 18 months to 6 years. Methods This study included 424 children from a prospective mother-child cohort (Rhea Study; Crete, Greece) with available cord leptin levels and data on neurodevelopmental outcomes at 18 months (Bayley Scales of Infant and Toddler Development, Third Edition), 4 years (McCarthy Scales of Children's Abilities), and 6 years (Raven's Coloured Progressive Matrices and Trail Making Test). Multivariable linear regression models were used to explore the associations. Results Each 10-ng/mL increase in the cord leptin level was associated with increased scores on the gross motor scale at 18 months (β coefficient: 3.8; 95% CI: 0.0-7.5), with decreased scores in the general cognitive performance (β coefficient: -3.0; 95% CI: -5.5 to -0.4), perceptual performance (β coefficient: -3.4; 95% CI: -6.0 to -9.9), working memory (β coefficient: -3.1; 95% CI: -5.7 to -0.4), executive function (β coefficient -3.1; 95% CI: -5.7 to -0.5), and functions of the posterior cortex (β coefficient: -2.7; 95% CI: -5.2 to -0.1) scales at 4 years, and with a 3.7-unit decrease in the Raven's Coloured Progressive Matrices score at 6 years (β coefficient: -3.7; 95% CI: -6.9 to -0.5). Conclusions Increased cord leptin levels are associated with enhanced gross motor development at 18 months but decreased cognitive performance in early and middle childhood.

Background: High cholesterol levels during childhood have been associated with increased risk of atherosclerosis later in life. Apart from traditional risk factors for dyslipidemia, such as high fa...

Background: Prenatal exposure to air pollution has been associated with increased risk of childhood asthma and allergies, however, less is known regarding the potential modifying effect of maternal...

Lower prenatal exposure to n-3 PUFA relative to n-6 PUFA has been hypothesised to influence allergy development, but evidence remains largely inconsistent. In the Dutch Maastricht Essential Fatty Acid Birth (MEFAB) (n 293) and Greek RHEA Mother–Child (n 213) cohorts, we investigated whether cord blood phospholipid PUFA concentrations are associated with symptoms of wheeze, asthma, rhinitis and eczema at the age of 6–7 years. Information on allergy-related phenotypes was collected using validated questionnaires. We estimated relative risks (RR) and 95 % CI for associations of PUFA with child outcomes using multivariable generalised linear regression models. In pooled analyses, higher concentration of the n-3 long-chain EPA and DHA and a higher total n-3:n-6 PUFA ratio were associated with lower risk of current wheeze (RR 0·61; 95 % CI 0·45, 0·82 per sd increase in EPA+DHA and 0·54; 95 % CI 0·39, 0·75 per unit increase in the n-3:n-6 ratio) and reduced asthma risk (RR 0·50; 95 % CI 0·31, 0·79 for EPA+DHA and 0·43; 95 % CI 0·26, 0·70 for the n-3:n-6 ratio). No associations were observed for other allergy-related phenotypes. The results were similar across cohorts. In conclusion, higher EPA and DHA concentrations and a higher n-3:n-6 fatty acid ratio at birth were associated with lower risk of child wheeze and asthma. Our findings suggest that dietary interventions resulting in a marked increase in the n-3:n-6 PUFA ratio, and mainly in n-3 long-chain PUFA intake in late gestation, may reduce the risk of asthma symptoms in mid-childhood.

BACKGROUND: Prenatal exposure to polyunsaturated fatty acids (PUFAs) may influence childhood growth. However, available evidence mostly derived from short-term studies is inconsistent.OBJECTIVE: To assess whether fetal PUFA exposure is associated with height and body mass index (BMI), a common measure of adiposity, from 6 months to 23 years of age.METHODS: In the MEFAB cohort, we assessed cord blood phospholipid n-3 and n-6 PUFA levels, reflecting fetal exposure in late pregnancy. For 250 (45.2% females) participants, we collected a total of 1770 (n= 802 for females) repeated growth measurements from infancy to young adulthood. We examined sex-specific associations of PUFAs with height and BMI at different developmental ages (infant: 6 months; toddler: 2 years; pre-schooler: 4 years; school-aged child: 7 years; adolescent: 12 years; and young adult: 23 years) using fractional polynomial mixed models adjusted for important covariates.RESULTS: Higher n-3 PUFA levels were associated with higher infant length in males (β= 0.44cm [95% CI: 0.07, 0.82] per SD increase), whereas, for females, higher n-6 PUFA concentrations were associated with lower length in infancy (β= -0.69cm [95% CI: -1.08, -0.30] per SD increase). A higher ratio of n-3 to n-6 PUFAs was associated with higher infant length in both sexes (β= 0.40cm [95% CI: 0.01, 0.78] and 0.42cm [95% CI: 0.05, 0.79] per unit increase for males and females, respectively). These associations were not detectable later in childhood and young adulthood. No associations with BMI were found at any time point examined.CONCLUSIONS: Our findings suggest a small sex-specific influence of PUFA status at birth on length in infancy, but this does not persist in later life up to young adulthood. PUFA status at birth does not seem to affect BMI from infancy till young adulthood.