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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.

The Horizon2020 LifeCycle Project is a cross-cohort collaboration which brings together data from multiple birth cohorts from across Europe and Australia to facilitate studies on the influence of early-life exposures on later health outcomes. A major product of this collaboration has been the establishment of a FAIR (findable, accessible, interoperable and reusable) data resource known as the EU Child Cohort Network. Here we focus on the EU Child Cohort Network's core variables. These are a set of basic variables, derivable by the majority of participating cohorts and frequently used as covariates or exposures in lifecourse research. First, we describe the process by which the list of core variables was established. Second, we explain the protocol according to which these variables were harmonised in order to make them interoperable. Third, we describe the catalogue developed to ensure that the network's data are findable and reusable. Finally, we describe the core data, including the proportion of variables harmonised by each cohort and the number of children for whom harmonised core data are available. EU Child Cohort Network data will be analysed using a federated analysis platform, removing the need to physically transfer data and thus making the data more accessible to researchers. The network will add value to participating cohorts by increasing statistical power and exposure heterogeneity, as well as facilitating cross-cohort comparisons, cross-validation and replication. Our aim is to motivate other cohorts to join the network and encourage the use of the EU Child Cohort Network by the wider research community. The LifeCycle project received funding from the European Union’s Horizon 2020 research and innovation programme (Grant Agreement No. 733206 LifeCycle). All study specific acknowledgements and funding are presented in the supplementary material. This manuscript reflects only the author’s view and the Commission is not responsible for any use that may be made of the information it contains.

Purpose It is controversial whether a higher intake of n-3 long-chain polyunsaturated fatty acids (n-3 LC PUFA) through breastfeeding is associated or not to a lower blood pressure (BP) during childhood. We aimed to clarify this point by undertaking a meta-analysis involving the data from seven European birth cohorts. Methods We searched https://www.birthcohort.net for studies that had collected breast milk samples, and had at least one BP measurement in childhood. Principal investigators were contacted, and all agreed to share data. One additional study was identified by contacts with the principal investigators. For each cohort, we analyzed the association of breast milk n-3 LC PUFAs with systolic and diastolic BP with linear mixed effects models or linear regression, and pooled the estimates with a random effects model. We also investigated age-specific and sex-specific associations. Results A total of 2188 participants from 7 cohorts were included. Overall, no associations between breast milk n-3 LC PUFAs and BP were observed. In the pooled analysis, each 0.1 wt% increment in breast milk docosahexaenoic acid (DHA) was associated with a 1.19 (95% CI − 3.31, 0.94) mmHg lower systolic BP. Associations were similar for boys and girls and at different ages. Conclusion In this individual participant meta-analysis, we found no evidence for an association between breast milk n-3 LC PUFAs and BP.

International audience; Background: The preconception period represents an important window for fetal and epigenetic programming. Some micronutrients (B vitamins, choline, betaine, methionine) implicated in one-carbon metabolism (OCM) are essential for major epigenetic processes that take place in early pregnancy. However, few studies have evaluated the implication of the micronutrients in placental DNA methylation.Objective: We investigated whether intake of OCM nutrients in the year before pregnancy was associated with placental DNA methylation in the EDEN mother–child cohort.Design: Maternal dietary intake was assessed with a food-frequency questionnaire. Three dietary patterns, “varied and balanced diet”, “vegetarian tendency”, and “bread and starchy food”, were used to characterize maternal OCM dietary intake. The Illumina Infinium HumanMethylation450 BeadChip was used to measure placental DNA methylation of 573 women included in the analyses. We evaluated the association of dietary patterns with global DNA methylation. Then, we conducted an agnostic epigenome-wide association study (EWAS) and investigated differentially methylated regions (DMRs) associated with each dietary pattern. Results: We found no significant association between the three dietary patterns and global DNA methylation or individual CpG sites. DMR analyses highlighted associations between the “varied and balanced” or “vegetarian tendency” pattern and DMRs located at genes previously implicated in functions essential for embryonic development, such as neurodevelopment. The “bread and starchy food” pattern was associated with regions related to genes whose functions involve various metabolic and cell synthesis-related processes.Conclusions: In mainly well-nourished French women without major deficiencies, OCM intake before pregnancy was not associated with major variation in DNA methylation.

RationaleSevere fetal malnutrition has been related to an increased risk of respiratory diseases later in life, but evidence for the association of a suboptimal diet during pregnancy with respiratory outcomes in childhood is conflicting. We aimed to examine whether a pro-inflammatory or low-quality maternal diet during pregnancy was associated with child's respiratory health.MethodsWe performed an individual participant meta-analysis among 18 326 mother–child pairs from seven European birth cohorts. Maternal pro-inflammatory and low-quality diets were estimated by energy-adjusted Dietary Inflammatory Index (E-DII) and Dietary Approaches to Stop Hypertension (DASH) scores. Preschool wheezing and school-age asthma were measured using questionnaires and lung function by spirometry.ResultsAfter adjustment for lifestyle and sociodemographic factors, we observed that a higher maternal E-DII score (a more pro-inflammatory diet) during pregnancy was associated only with a lower forced vital capacity (FVC) in children (z-score difference −0.05, 95% CI −0.08– −0.02, per interquartile range increase). No linear associations of the maternal E-DII or DASH score with child's wheezing or asthma were observed. In an exploratory examination of the extremes, a very low DASH score (ConclusionThe main results from this individual participant data meta-analysis do not support the hypothesis that maternal pro-inflammatory or low-quality diet in pregnancy are related to respiratory diseases in childhood.

International audience; Nearly 10% of 5-year-old children experience social, emotional or behavioral problems and are at increased risk of developing mental disorders later in life. While animal and human studies have demonstrated that cytokines can regulate brain functions, it is unclear whether individual cytokines are associated with specific behavioral dimensions in population-based pediatric samples. Here, we used data and biological samples from 786 mother-child pairs participating to the French national mother-child cohort EDEN. At the age of 5, children were assessed for behavioral difficulties using the Strengths and Difficulties Questionnaire (SDQ) and had their serum collected. Serum samples were analyzed for levels of well-characterized effector or regulatory cytokines. We then used a penalized logistic regression method (Elastic Net), to investigate associations between serum levels of cytokines and each of the five SDQ-assessed behavioral dimensions after adjustment for relevant covariates and confounders, including psychosocial variables. We found that interleukin (IL)-6, IL-7, and IL-15 were associated with increased odds of problems in prosocial behavior, emotions, and peer relationships, respectively. In contrast , eight cytokines were associated with decreased odds of problems in one dimension: IL-8, IL-10, and IL-17A with emotional problems, Tumor Necrosis Factor (TNF)-α with conduct problems, CC motif chemokine Ligand (CCL)2 with hyperactivity/inattention, C-X-C motif chemokine Ligand (CXCL)10 with peer problems, and CCL3 and IL-16 with abnormal prosocial behavior. Without implying causation, these associations support the notion that cytokines regulate brain functions and behavior and provide a rationale for launching longitudinal studies.

Background Small for gestational age (SGA) birth weight, a risk factor for infant mortality and delayed child development, is associated with maternal educational attainment. Maternal tobacco smoking during pregnancy could contribute to this association. We aimed to quantify the contribution of maternal smoking during pregnancy to social inequalities in child birth weight for gestational age (GA). Methods Data come from the French nation-wide ELFE cohort study, which included 17 155 singletons. Birth weights for GA were calculated using z-scores. Associations between maternal educational attainment, tobacco smoking during pregnancy and child birth weight for GA were ascertained using mediation analysis. Mediation analyses were also stratified by maternal pre-pregnancy body mass index. Results Low maternal educational attainment was associated with an increased odd of tobacco smoking during pregnancy [adjusted OR (ORa) = 2.58 (95% CI 2.34–2.84)] as well as a decrease in child birth weight for GA [RRa = 0.94 (95% CI 0.91–0.98)]. Tobacco smoking during pregnancy was associated with a decrease in offspring birth weight for GA [RRa = 0.73 (95% CI 0.70–0.76)]. Mediation analysis suggests that 39% of the effect of low maternal educational attainment on offspring birth weight for GA was mediated by smoking during pregnancy. A more important direct effect of maternal educational attainment on child birth weight for GA was observed among underweight women [RRa = 0.82 (95% CI 0.72–0.93)]. Conclusions The relationship between maternal educational attainment and child birth weight for GA is strongly mediated by smoking during pregnancy. Reducing maternal smoking could lessen the occurrence of infant SGA and decrease socioeconomic inequalities in birth weight for GA.

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).

Background Early adiposity rebound (AR) has been associated with increased risk of overweight or obesity in adulthood. However, little is known about early predictors of age at AR. We aimed to study the role of perinatal factors and genetic susceptibility to obesity in the kinetics of AR. Methods Body mass index (BMI) curves were modelled by using mixed-effects cubic models, and age at AR was estimated for 1415 children of the EDEN mother–child cohort study. A combined obesity risk-allele score was calculated from genotypes for 27 variants identified by genome-wide association studies of adult BMI. Perinatal factors of interest were maternal age at delivery, parental education, parental BMI, gestational weight gain, maternal smoking during pregnancy, and newborn characteristics (sex, prematurity, and birth weight). We used a hierarchical level approach with multivariable linear regression model to investigate the association between these factors, obesity risk-allele score, and age at AR. Results A higher genetic susceptibility to obesity score was associated with an earlier age at AR. At the most distal level of the hierarchical model, maternal and paternal educational levels were positively associated with age at AR. Children born to parents with higher BMI were more likely to exhibit earlier age at AR. In addition, higher gestational weight gain was related to earlier age at AR. For children born small for gestational age, the average age at AR was 88 [±39] days lower than for children born appropriate for gestational age and 91 [±56] days lower than for children born large for gestational age. Conclusion The timing of AR seems to be an early childhood manifestation of the genetic susceptibility to adult obesity. We further identified low birth weight and gestational weight gain as novel predictors of early AR, highlighting the role of the intrauterine environment in the kinetics of adiposity.

International audience; Background Breastmilk (BM) may participate in driving gut barrier function and immunity in the neonate. We analyzed immune and growth factor concentrations in early BM and their association with maternal/environmental characteristics and with food allergy (FA) in childhood. Methods One BM sample was collected in maternity from some mothers in the EDEN birth cohort (n = 2002 mother-child dyads). A random selection was performed among available samples (subcohort, n = 272), for which all deliveries were full-term, various maternal/environmental characteristics were recorded, and parents answered yearly the question "Has a medical doctor diagnosed a FA in your child?" (26 parent-reported FA cases). Only samples collected between day 2 and day 6 post-partum were considered for descriptive analysis (n = 263). Samples for all other FA cases available were added to the subcohort (46 additional cases; "casecohort" design). Fifty cytokines, antibodies, and growth factor concentrations were determined using multiplexed kits and analyzed using robust statistical procedures. Results BM components exhibited wide concentration ranges and global day-to-day variation. Different clusters of correlated factors appeared, with components from the main cluster related to maternal diet during pregnancy. Primiparity was positively associated with eleven other components, whereas other factors (eg, maternal atopy and smoking) were related to fewer components. Finally, the casecohort design highlighted a positive association between CXCL10, TNF beta, and IL-2 concentrations and reported FA in childhood. Conclusion Beyond the unique description of early BM composition, we show that immune information transmitted to the neonate is related to various maternal factors and identified components associated with FA diagnosis in childhood.

International audience; Objective: 25-hydroxyvitamin D (25OHD) deficiency has been associated with sleep disorders in adults. Only three cross-sectional studies were performed in children and showed an association between 25OHD deficiency and both obstructive sleep apnea syndrome and primary snoring. No longitudinal study has been performed in children from the general population. We analyzed the association between cord-blood vitamin D level at birth and night-sleep duration trajectories for children between 2 and 5-6 years old in a non-clinical cohort.Method: We included 264 children from the French EDEN mother-child birth-cohort with both cord-blood 25OHD level determined by radio-immunoassay at birth, and night-sleep trajectories for children between 2 and 5-6 years old obtained by the group-based trajectory modeling method. Associations between 25OHD and sleep trajectories were assessed by multinomial logistic regression adjusted for maternal and child characteristics.Results: The trajectories short sleep (

The Intergrowth-21st (IG) project proposed prescriptive fetal growth standards for global use based on ultrasound measurements from a multicounty study of low-risk pregnancies selected using strict criteria. We examined whether the IG standards are appropriate for fetal growth monitoring in France and whether potential differences could be due to IG criteria for "healthy" pregnancies.We analysed data on femur length and abdominal circumference at the second and/or the third recommended ultrasound examination from 14 607 singleton pregnancies from the Elfe national birth cohort. We compared concordance of centile thresholds using the IG standards and current French references and used restricted cubic splines to plot z-scores by gestational age. A "healthy pregnancy" sub-sample was created based on maternal and pregnancy selection criteria, as specified by IG.Mean gestational age-specific z-scores for femur length and abdominal circumference using French references fluctuated around 0 (-0.2 to 0.1), while those based on IG standards were higher (0.3-0.8). Using IG standards, 2.5% and 5.2% of fetuses at the third ultrasound were10th centile for femur length and abdominal circumference, respectively, and 31.5% and 16.7% were90th. Only 34% of pregnancies fulfilled IG low-risk criteria, but sub-analyses yielded very similar results.Intergrowth standards differed from fetal biometric measures in France, including among low-risk pregnancies selected to replicate IG's healthy pregnancy sample. These results challenge the project's assumption that careful constitution of a low-risk population makes it possible to describe normative fetal growth across populations.

The goal of the study was to investigate some of the factors suspected to be related to children’s handedness: presentation during the last weeks of gestation and at birth (cephalic or breech), side of presentation (right or left), number of weeks of gestation, season of birth, parents’ handedness and sex. We analyzed the relationships between these factors and the child’s handedness at five years. Children (n = 1897) from the EDEN cohort participated in the study, among which 1129 were tested for handedness at five. The father’s handedness, but not the mother’s, was significantly related to the child’s hand preference. The percentage of left-handed children was significantly larger when the father was non-right-handed compared to right-handed, and tended to be larger among children in non-left-cephalic presentation compared to left-cephalic presentation. Girls, but not boys, were significantly less lateralized when they were born before 37 weeks of pregnancy than after. Finally, children born in winter or spring were slightly but significantly less lateralized than children born in summer or autumn. All six children who were not lateralized at 5 presented one or several of these factors. These results are discussed in light of the mixed model of handedness.

Background Mounting evidence suggests that maternal diet influences pregnancy and birth outcomes, but its contribution to the global epidemic of childhood obesity has not as yet been definitively characterized. We investigated whether maternal whole diet quality and inflammatory potential influence childhood adiposity. Methods We harmonized and pooled individual participant data from 16,295 mother-child pairs in seven European birth cohorts. Maternal pre-, early-, late-, and whole-pregnancy (any time during pregnancy) dietary quality and inflammatory potential assessed with the Dietary Approaches to Stop Hypertension (DASH) score and the energy-adjusted Dietary Inflammatory Index (E-DII™) score, respectively. Primary outcome was childhood overweight and obesity (OWOB) (age-and-sex-specific BMI z-score > 85th percentile). Secondary outcomes were sum of skinfold thickness (SST), fat mass index (FMI) and fat-free mass index (FFMI). We used multivariable regression analyses (adjusting for maternal lifestyle and sociodemographic factors) to assess the associations of maternal DASH and E-DII scores with offspring adiposity outcomes in cohort-specific analyses, with subsequent random-effect meta-analyses. Results The study mothers had a mean (SD) age of 30.2 (4.6) years and a mean BMI of 23.4 (4.2) kg/m2. Higher early-pregnancy E-DII scores (more pro-inflammatory diet) tended to be associated with a higher odds of late-childhood [10.6 (1.2) years] OWOB [OR (95% CI) 1.09 (1.00, 1.19) per 1-SD E-DII score increase], whereas an inverse association was observed for late-pregnancy E-DII score and early-childhood [2.8 (0.3) years] OWOB [0.91 (0.83, 1.00)]. Higher maternal whole pregnancy DASH score (higher dietary quality) was associated with a lower odds of late-childhood OWOB [OR (95% CI) 0.92 (0.87, 0.98) per 1-SD DASH score increase]; associations were of similar magnitude for early and late-pregnancy [0.86 (0.72, 1.04) and 0.91 (0.85, 0.98), respectively]. These associations were robust in several sensitivity analyses and further adjustment for birth weight and childhood diet did not meaningfully alter the associations and conclusions. In two cohorts with available data, a higher whole pregnancy E-DII and lower DASH scores were associated with a lower late-childhood FFMI in males and a higher mid-childhood FMI in females (P interactions Conclusions A pro-inflammatory, low-quality maternal antenatal diet may adversely influence offspring body composition and OWOB risk, especially during late-childhood. Promoting an overall healthy and anti-inflammatory maternal dietary pattern may contribute to the prevention of childhood obesity, a complex health issue requiring multifaceted strategy.

Developing children are particularly vulnerable to the effects of exposure to per- and polyfluoroalkyl substances (PFAS), a group of endocrine disrupting chemicals. We hypothesized that early life exposure to PFASs is associated with poor metabolic health in children. We studied the association between prenatal and postnatal PFASs mixture exposure and cardiometabolic health in children, and the role of inflammatory proteins. In 1,101 mothers-child pairs from the Human Early Life Exposome project, we measured the concentrations of PFAS in blood collected in pregnancy and at 8 years (range = 6-12 years). We applied Bayesian Kernel Machine regression (BKMR) to estimate the associations between exposure to PFAS mixture and the cardiometabolic factors as age and sex- specific z-scores of waist circumference (WC), systolic and diastolic blood pressures (BP), and concentrations of triglycerides (TG), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) cholesterol. We measured thirty six inflammatory biomarkers in child plasma and examined the underlying role of inflammatory status for the exposure-outcome association by integrating the three panels into a network. Exposure to the PFAS mixture was positively associated with HDL-C and systolic BP, and negatively associated with WC, LDL-C and TG. When we examined the independent effects of the individual chemicals in the mixture, prenatal PFHxS was negatively associated with HDL-C and prenatal PFNA was positively associated with WC and these were opposing directions from the overall mixture. Further, the network consisted of five distinct communities connected with positive and negative correlations. The selected inflammatory biomarkers were positively, while the postnatal PFAS were negatively related with the included cardiometabolic factors, and only prenatal PFOA was positively related with the pro-inflammatory cytokine IL-1beta and WC. Our study supports that prenatal, rather than postnatal, PFAS exposure might contribute to an unfavorable lipidemic profile and adiposity in childhood. This work was supported by the Norwegian Research Council under the MILJØFORSK-Miljøforskning for en grønn samfunnsomstilling call (project No. 268465-short name: "CATCHUP project"). The HELIX project is funded by the European Community's Seventh Framework Programme (FP7/2007–2013) under grant agreement no 308,333 – the HELIX project. The HELIX program is built on six existing cohorts that received previous funding. The Born in Bradford (BiB) study presents independent research commissioned by the National Institute for Health Research Collaboration for Applied Health Research and Care (NIHR CLAHRC) and the Programme Grants for Applied Research funding scheme (RP-PG-0407–10044). 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_31V-66). 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/NIHES 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, R01ES030364. Dr. Nikos Stratakis was supported by NIH/NIHES R21 ES029681 and P30 ES007048-23, and NIH/NIDDK P30 DK048522-24. 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 affiliated researchers acknowledge 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)

International audience; BACKGROUND: In several systematic reviews, rapid weight gain in early life has been related to increased risk of later obesity. In line with this finding, the "early protein hypothesis" suggests that reducing early protein intake is a potential lever for obesity prevention. OBJECTIVE: To determine whether the variability of protein content of infant formula used in France over the period 2003-2012 is significantly associated with early growth in children. METHODS: A pooled sample of infants from the EDEN (Etude des Determinants pre et postnatals de la sante et du developpement de l'Enfant) mother-child cohort (born in 2003-2006) and the ELFE (Etude Longitudinale Francaise depuis l'Enfance) birth cohort (born in 2011) (ntotal = 5846) was used. Protein content of the infant formula received at 4 months was classified into five groups. Associations between protein content (or breastfed status) at 4 months and weight-, length- and BMI-for-age z-scores at 6, 12 and 18 months were analysed by multivariable linear regression. RESULTS: This analysis showed a positive association between protein content and weight-, length- and BMI-for-age z-scores at 6 months and only for weight-for-age at 12 months. At 6 months, as compared with the intermediate protein-content group (2.1-2.5 g/100 kcal), infants receiving very-high protein content (>2.8 g/100 kcal) had higher BMI-for-age z-score and those from the very-low protein-content group (

Background: Multiple omics technologies are increasingly applied to detect early, subtle molecular responses to environmental stressors for future disease risk prevention. However, there is an urgent need for further evaluation of stability and variability of omics profiles in healthy individuals, especially during childhood. Methods: We aimed to estimate intra-, inter-individual and cohort variability of multi-omics profiles (blood DNA methylation, gene expression, miRNA, proteins and serum and urine metabolites) measured 6 months apart in 156 healthy children from five European countries. We further performed a multi-omics network analysis to establish clusters of co-varying omics features and assessed the contribution of key variables (including biological traits and sample collection parameters) to omics variability. Results: All omics displayed a large range of intra- and inter-individual variability depending on each omics feature, although all presented a highest median intra-individual variability. DNA methylation was the most stable profile (median 37.6% inter-individual variability) while gene expression was the least stable (6.6%). Among the least stable features, we identified 1% cross-omics co-variation between CpGs and metabolites (e.g. glucose and CpGs related to obesity and type 2 diabetes). Explanatory variables, including age and body mass index (BMI), explained up to 9% of serum metabolite variability. Conclusions: Methylation and targeted serum metabolomics are the most reliable omics to implement in single time-point measurements in large cross-sectional studies. In the case of metabolomics, sample collection and individual traits (e.g. BMI) are important parameters to control for improved comparability, at the study design or analysis stage. This study will be valuable for the design and interpretation of epidemiological studies that aim to link omics signatures to disease, environmental exposures, or both The study has received funding from the European Community’s Seventh Framework Programme (FP7/2007-206) under grant agreement no 308333 (HELIX project) and the H2020-EU.3.1.2. - Preventing Disease Programme under grant agreement no 874583 (ATHLETE project). Additionally, BiB received core infrastructure funding from the Wellcome Trust (WT101597MA) and a joint grant from the UK Medical Research Council (MRC) and Economic and Social Science Research Council (ESRC) (MR/N024397/1). 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_31V-66). 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, EU- FP7- HEALTH-2012 Proposal No 308333 HELIX), 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). 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. We acknowledge 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 Program. MV-U and CR-A were supported by a FI fellowship from the Catalan Government (FI-DGR 2015 and #016FI_B 00272). MC received funding from Instituto Carlos III (Ministry of Economy and Competitiveness) (MS16/00128). LM is funded by a Juan de la Cierva-Incorporación fellowship (IJC2018-035394-I) awarded by the Spanish Ministerio de Economía, Industria y Competitividad SI

Background Adverse birth outcomes are major causes of morbidity and mortality during childhood and associate with a higher risk of noncommunicable diseases in adult life. Maternal periconception and antenatal nutrition, mostly focusing on single nutrients or foods, has been shown to influence infant birth outcomes. However, evidence on whole diet that considers complex nutrient and food interaction is rare and conflicting. We aim to elucidate the influence of whole-diet maternal dietary inflammatory potential and quality during periconceptional and antenatal periods on birth outcomes. Methods and findings We harmonized and pooled individual participant data (IPD) from up to 24,861 mother–child pairs in 7 European mother–offspring cohorts [cohort name, country (recruitment dates): ALSPAC, UK (1 April 1991 to 31 December 1992); EDEN, France (27 January 2003 to 6 March 2006); Generation R, the Netherlands (1 April 2002 to 31 January 2006); Lifeways, Ireland (2 October 2001 to 4 April 2003); REPRO_PL, Poland (18 September 2007 to 16 December 2011); ROLO, Ireland (1 January 2007 to 1 January 2011); SWS, United Kingdom (6 April 1998 to 17 December 2002)]. Maternal diets were assessed preconceptionally (n = 2 cohorts) and antenatally (n = 7 cohorts). Maternal dietary inflammatory potential and quality were ranked using the energy-adjusted Dietary Inflammatory Index (E-DII) and Dietary Approaches to Stop Hypertension (DASH) index, respectively. Primary outcomes were birth weight and gestational age at birth. Adverse birth outcomes, i.e., low birth weight (LBW), macrosomia, small-for-gestational-age (SGA), large-for-gestational-age (LGA), preterm and postterm births were defined according to standard clinical cutoffs. Associations of maternal E-DII and DASH scores with infant birth outcomes were assessed using cohort-specific multivariable regression analyses (adjusted for confounders including maternal education, ethnicity, prepregnancy body mass index (BMI), maternal height, parity, cigarettes smoking, and alcohol consumption), with subsequent random-effects meta-analyses. Overall, the study mothers had a mean ± SD age of 29.5 ± 4.9 y at delivery and a mean BMI of 23.3 ± 4.2 kg/m2. Higher pregnancy DASH score (higher dietary quality) was associated with higher birth weight [β(95% CI) = 18.5(5.7, 31.3) g per 1-SD higher DASH score; P value = 0.005] and head circumference [0.03(0.01, 0.06) cm; P value = 0.004], longer birth length [0.05(0.01, 0.10) cm; P value = 0.010], and lower risk of delivering LBW [odds ratio (OR) (95% CI) = 0.89(0.82, 0.95); P value = 0.001] and SGA [0.87(0.82, 0.94); P value < 0.001] infants. Higher maternal prepregnancy E-DII score (more pro-inflammatory diet) was associated with lower birth weight [β(95% CI) = −18.7(−34.8, −2.6) g per 1-SD higher E-DII score; P value = 0.023] and shorter birth length [−0.07(−0.14, −0.01) cm; P value = 0.031], whereas higher pregnancy E-DII score was associated with a shorter birth length [−0.06(−0.10, −0.01) cm; P value = 0.026] and higher risk of SGA [OR(95% CI) = 1.18(1.11, 1.26); P value < 0.001]. In male, but not female, infants higher maternal prepregnancy E-DII was associated with lower birth weight and head circumference, shorter birth length, and higher risk of SGA (P-for-sex-interaction = 0.029, 0.059, 0.104, and 0.075, respectively). No consistent associations were observed for maternal E-DII and DASH scores with gestational age, preterm and postterm birth, or macrosomia and LGA. Limitations of this study were that self-reported dietary data might have increased nondifferential measurement error and that causality cannot be claimed definitely with observational design. Conclusions In this cohort study, we observed that maternal diet that is of low quality and high inflammatory potential is associated with lower offspring birth size and higher risk of offspring being born SGA in this multicenter meta-analysis using harmonized IPD. Improving overall maternal dietary pattern based on predefined criteria may optimize fetal growth and avert substantial healthcare burden associated with adverse birth outcomes., In this cohort analysis, Ling-Wei Chen and colleagues explore associations of maternal dietary patterns with offspring birth outcomes., Author summary Why was this study done? Adverse birth outcomes are associated with higher morbidity and mortality during childhood and a higher risk of noncommunicable diseases in adult life. The Developmental Origins of Health and Diseases (DOHaD) theory posits that maternal periconceptional and intrauterine nutrition can alter the health trajectory of the offspring. Although individual maternal dietary factors have been studied widely, evidence on the impact of whole-diet maternal dietary inflammatory potential and quality on birth outcomes is scarce and conflicting. What did the researchers do and find? We investigated whether maternal prepregnancy and antenatal dietary quality and inflammatory potential are associated with birth outcomes in a consortium of 7 European cohorts in 5 countries using harmonized individual participant data from up to 24,861 mother–child pairs. After adjusting for confounders, we found that a low-quality and pro-inflammatory maternal diet during pregnancy is significantly associated with lower offspring birth weight and higher risk of offspring being born small-for-gestational-age (SGA). In male, but not female, infants higher maternal prepregnancy energy-adjusted Dietary Inflammatory Index (E-DII) score was associated with lower birth weight and head circumference, shorter birth length, and higher risk of SGA. What do these findings mean? Improving overall maternal dietary quality and reducing dietary inflammatory potential may optimize fetal growth and avert substantial healthcare burden associated with adverse birth outcomes. Policies to ensure availability of affordable healthy foods and programmatic efforts to inform and support women of reproductive age, such as raising awareness of the importance of maternal diet and prenatal and antenatal counseling would help women achieve a healthier diet.

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.

Women with thyroid diseases at the beginning of pregnancy may have suboptimal thyroid hormone levels because of potential difficulties in compensating for the physiological thyroid hormone changes occurring in pregnancy. Our objective was to study the association between preexisting thyroid diseases, pregnancy complications, and neonatal anthropometry. In total, 16,395 women from the ELFE French longitudinal birth cohort were included, and 273 declared pre-pregnancy thyroid diseases. Associations were investigated with multivariable regression models, with adjustment for relevant potential confounders. Body mass index (BMI) was additionally adjusted for in a second stage. As compared with other women, women with pre-pregnancy thyroid diseases were more frequently obese (19.6% vs. 9.8%) and had greater odds of gestational diabetes development (odds ratio [OR] = 1.58 [95% confidence interval [CI] 1.08, 2.30]) or had undergone treatment for infertility (OR = 1.57 [95% CI 1.07, 2.31]). After adjustment for BMI, the association with gestational diabetes was no longer significant (OR = 1.27 [95% CI 0.86, 1.88]). After excluding women with another medical history, those with pre-pregnancy thyroid diseases had increased odds of premature rupture of membranes (OR = 1.51 [95% CI 1.01, 2.25]). Children born from mothers with hypothyroidism before conception due to a disease or as a potential side effect of treatment had a smaller head circumference at birth than other children (β = −0.23 [95% CI −0.44, −0.01] cm). In conclusion, pre-pregnancy thyroid diseases were associated with risk of infertility treatment, gestational diabetes, and premature rupture of membranes. The association between history of hypothyroidism and moderate adverse effects on fetal head circumference growth needs replication.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located nearNEDD4LandSLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R(g)ranging from 0.11 to 0.76, P-values, CP received funding from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. MMcC is a Wellcome Senior Investigator and an NIHR Senior Investigator. MMcC received funding from Wellcome (090532, 106130, 098381, 203141, 212259), NIDDK (U01DK105535), and NIHR (NF-SI-0617-10090). TGMV was supported by ZonMW (TOP 40-00812-9811010). DLC was supported by the American Diabetes Association Grant 1-17-PDF-077. SFAG is supported by the Daniel B. Burke Chair for Diabetes Research and NIH Grant R01 HD058886. NVT is funded by a pre-doctoral grant from the Agencia de Gestio d'Ajuts Universitaris i de Recerca (2017 FI_B 00636), Generalitat de Catalunya -Fons Social Europeu. BK received personal funding from the European Research Council Advanced Grant META-GROWTH (ERC-2012-AdG -no. 322605). BF was supported by an Oak Foundation Fellowship. RMF and RNB are supported by Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150). ATH is supported by a Wellcome Trust Senior Investigator award (grant number 098395/Z/12/Z). DM is supported by a Canada Research Chair. DLC was supported by the American Diabetes Association Grant 1-17-PDF077. JTL was supported by the Finnish Cultural Foundation. DIB received a KNAW Academy Professor Award (PAH/6635). MH received PhD scholarship funding from TARGET (http://target.ku.dk), The Danish Diabetes Academy (http://danishdiabetesacademy.dk) and the Copenhagen Graduate School of Health and Medical Sciences. VWVJ received funding from the Netherlands Organization for Health Research and Development (VIDI 016.136.361) and the European Research Council (ERC-2014-CoG-648916). ISF was supported by the European Research Council, Wellcome Trust (098497/Z/12/Z), Medical Research Council (MRC_MC_UU_12012/5), the NIHR Cambridge Biomedical Research Centre, the Botnar Foundation, the Bernard Wolfe Health Neuroscience Endowment and the European Community's Seventh Framework Programme (FP7/2007-2013) project Beta-JUDO n degrees 279153. IB acknowledges funding from Wellcome (WT206194). ES works in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3). GDS works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00011/1). KC received funds from the French National Agency of Research, F-CRIN/FORCE. All funding for the studies that provided the underlying data for this manuscript can be found in S1 Text. The funders had no role in study design, data collection and analysis, data interpretation, decision to publish, or preparation of the manuscript.

Background Recent research suggests that immune dysregulation in pregnancy could be a risk factor for anxiety and depression symptoms in offspring. Whereas animal studies have demonstrated the importance of the link between perinatal cytokines and abnormal behaviors in offspring, human epidemiological studies in this area remain limited. The objectives of the study were to describe the network of cord serum cytokines at birth and test whether they are associated with subsequent anxiety and depression symptom trajectories in offspring. Methods We used data and biological samples from 871 mother–child pairs followed up from pregnancy to 8 years of age and participating in the French mother–child cohort EDEN (a study on the pre- and early postnatal determinants of child health and development). Cord serum cytokines were measured at birth. Children’s symptoms of anxiety and depression were assessed with the emotional difficulties subscore of the Strength and Difficulties Questionnaire at ages 3, 5, and 8 years, from which trajectories of anxiety-depression symptoms were derived. Results Results showed a significant association between cord serum interleukin-7 at birth and the trajectories of children’s anxiety-depression symptoms between ages 3 to 8 years (adjusted odds ratio, 0.73; 95% confidence interval, 0.57–0.93). The associations considered relevant confounders, including prenatal maternal depressive symptoms. Conclusions Early immune changes may contribute to subsequent anxiety and depression symptoms in childhood. Beyond the understanding of mechanisms underlying the occurrence of emotional difficulties in children, our findings open avenues for future research in human and animals.

Disruption of neurodevelopmental trajectories can alter brain circuitry and increase the risk of psychopathology later in life. While preclinical studies have demonstrated that the immune system and cytokines influence neurodevelopment, whether immune activity and in particular which cytokines at birth are associated with psychopathology remains poorly explored in children. We used data and biological samples from 869 mother-child pairs participating in the French mother-child cohort EDEN. As proxies for immune activity at birth, we measured the levels of 27 cytokines in umbilical cord blood sera (CBS). We then explored the association between CBS cytokine levels and five psychopathological dimensions assessed in 5-year-old children using the Strengths and Difficulties Questionnaire (SDQ). Five cytokines were positively associated with psychopathology: C-X-C motif chemokine Ligand (CXCL)10, interleukin (IL)-10 and IL-12p40 with emotional symptoms, C–C motif chemokine Ligand (CCL)11 with conduct problems, and CCL11, and IL-17A with peer relationships problems. In contrast, seven cytokines were negatively associated with psychopathology: IL-7, IL-15 and Tumor Necrosis Factor (TNF)-β with emotional symptoms, CCL4 and IL-6 with conduct problems, CCL26 and IL-15 with peer relationships problems, and CCL26, IL-7, IL-15, and TNF-α with abnormal prosocial behavior. Without implying causation, these associations support the notion that cytokines influence neurodevelopment in humans and the risk of psychopathology later in life., Highlights • Twelve cytokines at birth are associated with psychopathology in 5-year-old children. • IL-7, IL-10, IL-12p40, IL-15, TNF-β and CXCL10 are associated with emotional symptoms. • IL-6, CCL4 and CCL11 are associated with conduct problems. • IL-15, IL-17A, CCL11 and CCL26 are associated with peer relationship problems. • IL-7, IL-15, TNF-α and CCL26 are associated with prosocial behavior.

Background Fetal smoke exposure is a common and key avoidable risk factor for birth complications and seems to influence later risk of overweight. It is unclear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy, or when only fathers smoke. We aimed to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight. Methods and findings We performed an individual participant data meta-analysis among 229,158 families from 28 pregnancy/birth cohorts from Europe and North America. All 28 cohorts had information on maternal smoking, and 16 also had information on paternal smoking. In total, 22 cohorts were population-based, with birth years ranging from 1991 to 2015. The mothers’ median age was 30.0 years, and most mothers were medium or highly educated. We used multilevel binary logistic regression models adjusted for maternal and paternal sociodemographic and lifestyle-related characteristics. Compared with nonsmoking mothers, maternal first trimester smoking only was not associated with adverse birth outcomes but was associated with a higher risk of childhood overweight (odds ratio [OR] 1.17 [95% CI 1.02–1.35], P value = 0.030). Children from mothers who continued smoking during pregnancy had higher risks of preterm birth (OR 1.08 [95% CI 1.02–1.15], P value = 0.012), small size for gestational age (OR 2.15 [95% CI 2.07–2.23], P value < 0.001), and childhood overweight (OR 1.42 [95% CI 1.35–1.48], P value < 0.001). Mothers who reduced the number of cigarettes between the first and third trimester, without quitting, still had a higher risk of small size for gestational age. However, the corresponding risk estimates were smaller than for women who continued the same amount of cigarettes throughout pregnancy (OR 1.89 [95% CI 1.52–2.34] instead of OR 2.20 [95% CI 2.02–2.42] when reducing from 5–9 to ≤4 cigarettes/day; OR 2.79 [95% CI 2.39–3.25] and OR 1.93 [95% CI 1.46–2.57] instead of OR 2.95 [95% CI 2.75–3.15] when reducing from ≥10 to 5–9 and ≤4 cigarettes/day, respectively [P values < 0.001]). Reducing the number of cigarettes during pregnancy did not affect the risks of preterm birth and childhood overweight. Among nonsmoking mothers, paternal smoking was associated with childhood overweight (OR 1.21 [95% CI 1.16–1.27], P value < 0.001) but not with adverse birth outcomes. Limitations of this study include the self-report of parental smoking information and the possibility of residual confounding. As this study only included participants from Europe and North America, results need to be carefully interpreted regarding other populations. Conclusions We observed that as compared to nonsmoking during pregnancy, quitting smoking in the first trimester is associated with the same risk of preterm birth and small size for gestational age, but with a higher risk of childhood overweight. Reducing the number of cigarettes, without quitting, has limited beneficial effects. Paternal smoking seems to be associated, independently of maternal smoking, with the risk of childhood overweight. Population strategies should focus on parental smoking prevention before or at the start, rather than during, pregnancy., Elise Philips and co-workers investigate parental smoking and associated birth and child outcomes., Author summary Why was this study done? Maternal smoking during pregnancy is an important risk factor for various birth complications and childhood overweight. It is not clear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy. The associations of paternal smoking with birth and childhood outcomes also remain unknown. What did the researchers do and find? We conducted an individual participant data meta-analysis using data from 229,158 families from 28 pregnancy and birth cohorts from Europe and North America to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight. We observed that smoking in the first trimester only did not increase the risk of preterm birth and small size for gestational age but was associated with a higher risk of childhood overweight, as compared to nonsmoking. Reducing the number of cigarettes during pregnancy, without quitting, was still associated with higher risks of these adverse outcomes. Paternal smoking seems to be associated, independently of maternal smoking, with the risks of childhood overweight. What do these findings mean? Population strategies should focus on parental smoking prevention before or at the start of, rather than during, pregnancy. Future studies are needed to assess the specific associations of smoking in the preconception and childhood periods with offspring outcomes.

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).

International audience; Background: Maternal diet quality during pregnancy has been linked to offspring's physical and mental health outcomes across the lifespan. However, few studies have examined its association with subsequent offspring's anxiety and depression issues.Objectives: The objective of the study was to examine the relationship between maternal prenatal dietary patterns and offspring's anxiety and depression symptoms from 3 to 8 years.Methods: We used data from 1242 children enrolled in the French EDEN (Etude des déterminants pré- et postnatals précoces du développement et de la santé de l'enfant) birth cohort. Maternal third trimester dietary patterns-namely, "Healthy" (i.e., high intake in fruit, vegetables, fish, and whole-grain cereals) and "Western" (i.e., high intake in processed and snacking foods) patterns-were evaluated using a validated qualitative FFQ. Children's anxiety and depression symptoms (i.e., fears, worries, misery, nervousness, and somatic symptoms) were assessed by mothers using the Strengths and Difficulties Questionnaire at ages 3, 5, and 8 years, from which trajectories were derived using group-based trajectory modeling. We used logistic regressions to analyze the associations between maternal dietary patterns and children's anxiety and depression symptom trajectories.Results: We identified 2 trajectories of anxiety and depression symptoms from 3 to 8 years of age: low to moderate (n = 1058; reference group) and moderately high (n = 184). Maternal low adherence to the Healthy dietary pattern in the third trimester was significantly associated with moderately high children's anxiety and depression symptom trajectories from 3 to 8 years (OR, 1.87; 95% CI, 1.40-2.51), in crude and adjusted analyses. The maternal Western dietary pattern was not significantly associated with anxiety and depression symptom trajectories.Conclusions: High maternal prenatal adherence to a Healthy dietary pattern was negatively related to anxiety and depression symptoms in children. As maternal diet is a key lifestyle factor, further research should investigate its association with subsequent offspring anxiety and depression symptoms in aiming to later inform prevention strategies focusing on pregnancy.

Background Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods We performed meta-analysis of Illumina’s HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4–18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results We identified 8899 CpGs in cord blood that were associated with gestational age (range 27–42 weeks), at Bonferroni significance, P − 7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.

The assessment of early life socioeconomic position (SEP) is essential to the tackling of social inequalities in health. Although different indicators capture different SEP dimensions, maternal education is often used as the only indicator in birth cohort research, especially in multi-cohort analyses. Household income, as a direct measure of material resources, is one of the most important indicators, but one that is underused because it is difficult to measure through questionnaires. We propose a method to construct a standardized, cross-cohort comparable income indicator, the &ldquo, Equivalized Household Income Indicator (EHII)&rdquo, which measures the equivalized disposable household income, using external data from the pan-European Union Statistics on Income and Living Conditions (EUSILC) surveys, and data from the cohorts. We apply this method to four studies, Piccolipi&ugrave, and NINFEA from Italy and ELFE and EDEN from France, comparing the distribution of EHII with other SEP-related variables available in the cohorts, and estimating the association between EHII and child body mass index (BMI). We found that basic parental and household characteristics may be used, with a fairly good performance, to predict the household income. We observed a strong correlation between EHII and both the self-reported income, whenever available, and other individual socioeconomic-related variables, and an inverse association with child BMI. EHII could contribute to improving research on social inequalities in health, in particular in the context of European birth cohort collaborative studies.

Key Points Question Is fish consumption during pregnancy associated with benefits for the metabolic health of children? Findings In this cohort study of 805 mothers and their singleton offspring, moderate fish consumption during pregnancy was associated with the downregulation of inflammation and improvements in the metabolic profile of children; high mercury exposure during pregnancy had the opposite associations. Meaning The results of this study suggest that fish consumption consistent with current recommendations during pregnancy was associated with improvements in the metabolic health of children., Importance The balance of mercury risk and nutritional benefit from fish intake during pregnancy for the metabolic health of offspring to date is unknown. Objective To assess the associations of fish intake and mercury exposure during pregnancy with metabolic syndrome in children and alterations in biomarkers of inflammation in children. Design, Setting, and Participants This population-based prospective birth cohort study used data from studies performed in 5 European countries (France, Greece, Norway, Spain, and the UK) between April 1, 2003, and February 26, 2016, as part of the Human Early Life Exposome (HELIX) project. Mothers and their singleton offspring were followed up until the children were aged 6 to 12 years. Data were analyzed between March 1 and August 2, 2019. Exposures Maternal fish intake during pregnancy (measured in times per week) was assessed using validated food frequency questionnaires, and maternal mercury concentration (measured in micrograms per liter) was assessed using maternal whole blood and cord blood samples. Main Outcomes and Measures An aggregate metabolic syndrome score for children was calculated using the z scores of waist circumference, systolic and diastolic blood pressures, and levels of triglyceride, high-density lipoprotein cholesterol, and insulin. A higher metabolic syndrome score (score range, −4.9 to 7.5) indicated a poorer metabolic profile. Three protein panels were used to measure several cytokines and adipokines in the plasma of children. Results The study included 805 mothers and their singleton children. Among mothers, the mean (SD) age at cohort inclusion or delivery of their infant was 31.3 (4.6) years. A total of 400 women (49.7%) had a high educational level, and 432 women (53.7%) were multiparous. Among children, the mean (SD) age was 8.4 (1.5) years (age range, 6-12 years). A total of 453 children (56.3%) were boys, and 734 children (91.2%) were of white race/ethnicity. Fish intake consistent with health recommendations (1 to 3 times per week) during pregnancy was associated with a 1-U decrease in metabolic syndrome score in children (β = −0.96; 95% CI, −1.49 to −0.42) compared with low fish consumption (, This cohort study used data from the Human Early Life Exposome (HELIX) project, a collaboration of 5 European birth cohort studies, to examine the associations of maternal fish consumption and mercury exposure during pregnancy with metabolic health and inflammatory biomarkers in children.

International audience; Background: Short sleep duration is associated with concomitant behavioral difficulties, but the longitudinal association between sleep duration and later behavior in early childhood remains unclear. The aim was to study the association between sleep duration trajectories throughout preschool and behavior at age 5-6 years.Participants: 1021 children of the French birth-cohort EDEN were included in this study.Methods: Night-sleep duration trajectories were modeled on the basis of repeated measures collected at age 2, 3 and 5-6 years by parental questionnaires. Behavior was assessed with the Strengths and Difficulties Questionnaire (SDQ), with five subscales measuring conduct problems, emotional symptoms, peer relation problems, antisocial behavior, and hyperactivity-inattention problems. The subscales were dichotomized by the 25th percentile. Multivariable logistic regression, adjusted for baseline behavior, and assessment of multiple confounding factors allowed for studying the independent association between night-sleep duration trajectories from age 2 to 5-6 and behavior at age 5-6.Results: Five distinct sleep-duration trajectories were identified. At age 5-6 years, probability of hyperactivity-inattention problems was increased for boys belonging to the "short sleep" and "medium-low sleep" duration trajectory and girls belonging to the "changing sleep" duration trajectory as compared with children with the medium-high sleep duration trajectory (boys: OR 2.69 [95% CI 1.18-6.16], p = .03 and 1.95 [1.25-3.03], p = .003, and girls: OR 2.79 [1.09- 7.17], p = .03). No associations were observed with the other SDQ subscales.Conclusion: The persistence of short night-sleep durations in preschool years as well as a sudden decrease at age 3 are risk factors of hyperactivity-inattention problems at school start.

This paper aimed to examine the effect of breastfeeding on longitudinal patterns of common infections up to 2 years and respiratory symptoms up to 8 years. To assess the incidence and reoccurrence of infections and allergic symptoms in the first years of life among 1,603 children from the EDEN mother–child cohort, distinct longitudinal patterns of infectious diseases as well as skin rash and respiratory symptoms were identified by group‐based trajectory modelling. To characterize infections, we considered the parent‐reported number of cold/nasopharyngitis and diarrhoea from birth to 12 months and otitis and bronchitis/bronchiolitis from birth to 2 years. To characterize allergy‐related symptoms, we considered the parent‐reported occurrence of wheezing and skin rash from 8 months to 8 years and asthma from 2 to 8 years. Then associations between breastfeeding and these longitudinal patterns were assessed through adjusted multinomial logistic regression. Compared with never‐breastfed infants, ever‐breastfed infants were at a lower risk of diarrhoea events in early infancy as well as infrequent events of bronchitis/bronchiolitis throughout infancy. Only predominant breastfeeding duration was related to frequent events of bronchitis/bronchiolitis and infrequent events of otitis. We found no significant protective effect of breastfeeding on longitudinal patterns of cold/nasopharyngitis, skin rash, or respiratory symptoms. For an infant population with a short breastfeeding duration, on average, our study confirmed a protective effect of breastfeeding on diarrhoea events in early infancy, infrequent bronchitis/bronchiolitis and, to a lesser extent, infrequent otitis events up to 2 years but not on other infections, skin rash, or respiratory symptoms4., In an infant population with a short breastfeeding duration and using longitudinal patterns of infection, skin rash and respiratory symptoms, on average, our study confirmed a protective effect of breastfeeding on diarrhea events in early infancy, infrequent bronchitis/bronchiolitis and, to a lesser extent,infrequent otitis events up to 2 years but not on cold/ nasopharyngitis, skin rash or respiratory symptoms.

Background: Leptin is potentially involved in the correction of early postnatal growth of infants having deviated from their genetic trajectory in utero. Aim: To analyse the potential mediating role of cord blood leptin level in the association between neonatal anthropometry and early postnatal growth in the mother–child EDEN cohort. Subjects and methods: We included term newborns with information on leptin, birth weight and length, and weight and length SD-score changes over the first 2 months. The Baron and Kenny method was used to quantify the mediation contribution of leptin in the association between neonatal anthropometry and postnatal growth, considering several confounders. Analyses were stratified to consider sexual dimorphism. Results: A 1 SD higher birth weight was associated with a lower 2-months weight variation of 0.27 (0.18; 0.36) SD and a 0.16 (0.06; 0.26) SD, in boys and girls, respectively. Leptin explained 20% and 25% of these associations, respectively. Leptin did not mediate the association between birth length and birth-to-2 months length variation. Conclusion: Our results suggest that cord blood leptin may not be involved in the negative association between birth length and postnatal length growth but may play a modest mediating role in early postnatal catch-up or catch-down in weight.

Objective To estimate the prevalence of flatus-only and faecal incontinence, to describe their risk factors and to analyse the association between anal incontinence and psychological distress over the first year postpartum. Design Cohort study from pregnancy to 12 months postpartum. Setting Two university hospital maternity wards in France. Population A total of 2002 pregnant women were recruited between 2003 and 2006. Data on anal incontinence were available for the 1632 women who comprise the sample for analysis. Methods Women were enrolled during pregnancy. A postal questionnaire was sent at 4 and 12 months postpartum. Main outcome measures Anal (flatus-only and faecal) incontinence was assessed at 4 months postpartum. Mental health was assessed at 4 and 12 months postpartum by the Edinburgh Postpartum Depression Scale (EPDS) and use of antidepressant drugs as well as by self-rated mental health. Results At 4 months postpartum, the prevalence for flatus-only incontinence was 14.4% and for faecal incontinence 1.7%; multivariate analysis, restricted to women reporting no anal incontinence before the index pregnancy, showed that continuing breastfeeding at 4 months was related to a higher risk of de novo postpartum anal incontinence (OR = 2.23). Women who reported anal incontinence at 4 months were more frequently depressed (EPDS ≥10 or antidepressant use) at 12 months postpartum: 36.0% of those with faecal incontinence were depressed, 23.3% of those with flatus-only incontinence and only 14.8% of the continent women. Conclusion Postnatal faecal incontinence was rare but associated with poorer maternal mental health. Postnatal screening should be encouraged, and psychological support offered. Tweetable abstract Postnatal faecal incontinence was associated with depression; postnatal screening should be encouraged and psychological support offered.

ObjectiveExposure to cigarette smoking during pregnancy has been robustly associated with cord blood DNA methylation. However, little is known about such effects on the placenta; in particular, whether cigarette smoking before pregnancy could also induce epigenetic alterations in the placenta of former smokers is unknown.Design and resultsPlacental DNA methylation levels were measured in 568 women and compared among non-smokers and women either smoking during their pregnancy or who had ceased smoking before pregnancy. An Epigenome Wide Association Study identified 344 Differentially Methylated Regions (DMRs) significantly associated with maternal smoking status. Among these 344 DMRs, 262 showed “reversible” alterations of DNA methylation, only present in the placenta of current smokers, whereas 44 were also found altered in former smokers, whose placenta had not been exposed directly to cigarette smoking. This observation was further supported by a significant demethylation of LINE-1 sequences in the placentas of both current (−0.43 (−0.83 to −0.02)) and former smokers (−0.55 (−1.02 to −0.08)) compared to nonsmokers. A comparative analysis of the epigenome landscape based on the ENCODE placenta data demonstrated an enrichment of all 344 DMRs in enhancers histone marks. Additionally, smoking-associated DMRs were found near and/or overlapping with 13 imprinting gene clusters encompassing 18 imprinted genes.ConclusionsDNA methylation patterns alterations were found in 344 genomic regions in the placenta of women smoking during their pregnancy, including 44 DMRs and LINE-1 elements, where methylation changes persisted in former smokers, supporting the hypothesis of an “epigenetic memory” of exposure to cigarette smoking before pregnancy. Enhancers regions, including imprinting control regions were also particularly affected by placenta methylation changes associated to smoking, suggesting a biological basis for the sensitivity of these regions to tobacco exposure and mechanisms by which fetal development could be impacted.

Objective Maternal thyroid dysfunction during pregnancy is associated with neurodevelopmental impairment in the offspring. No data are currently available for the offspring of patients treated early for congenital hypothyroidism (CH). The aim of this study was to investigate motor and language milestones at one year of age in a population-based registry of children born to young women with CH. Design and methods We assessed 110 children born to mothers with CH, and 1367 children from the EDEN French population-based birth cohort study prospectively, at the age of one year, with identical questionnaires. Outcomes were assessed in terms of scores for childhood developmental milestones relating to mobility, motor coordination, communication, motricity and language skills. Results After adjustment for confounding factors, children born to mothers with CH were found to have a higher risk of poor motor coordination than those of the EDEN cohort (OR: 4.18, 95% CI: 2.52–6.93). No differences were identified for the other four domains investigated. Children born to mothers with gestational diabetes have a higher risk of low motor coordination score than their peers (OR: 2.10, 95% CI: 1.21–3.66). Children born to mothers with TSH ≥ 10 IU/L during the first six months of pregnancy were more likely to have low motricity or communication skills scores than those born to mothers with lower TSH concentrations (56% vs 21% for each score, P Conclusions Maternal CH may have slight adverse effects on some developmental milestones in the child at one year of age, particularly for children born to mothers with uncontrolled hypothyroidism. However, it remains unclear whether these adverse effects modify subsequent neurodevelopment.

Peroxisome proliferator-activated receptor γ (PPARγ) is essential for placental development, whose SNPs have shown increased susceptibility to pregnancy-related diseases, such as preeclampsia. Our aim was to investigate the association between preeclampsia and three PPARγ SNPs (Pro12Ala, C1431T, and C681G), which together with nine clinical factors were used to build a pragmatic model for preeclampsia prediction. Data were collected from 1648 women from the EDEN cohort, of which 35 women had preeclamptic pregnancies, and the remaining 1613 women had normal pregnancies. Univariate analysis comparing preeclamptic patients to the control resulted in the SNP C1431T being the only factor significantly associated with preeclampsia (p &lt, 0.05), with a confidence interval of 95% and odds ratio ranging from 4.90 to 8.75. On the other hand, three methods of multivariate feature selection highlighted seven features that could be potential predictors of preeclampsia: maternal C1431T and C681G variants, obesity, body mass index, number of pregnancies, primiparity, cigarette use, and education. These seven features were further used as input into eight different machine-learning algorithms to create predictive models, whose performances were evaluated based on metrics of accuracy and the area under the receiver operating characteristic curve (AUC). The boost tree-based model performed the best, with respective accuracy and AUC values of 0.971 ± 0.002 and 0.991 ± 0.001 in the training set and 0.951 and 0.701 in the testing set. A flowchart based on the boost tree model was constructed to depict the procedure for preeclampsia prediction. This final decision tree showed that the C1431T variant of PPARγ is significantly associated with susceptibility to preeclampsia. We believe that this final decision tree could be applied in the clinical prediction of preeclampsia in the very early stages of pregnancy.

The present study aims to determine to which extent social withdrawal at 1 year is associated with the child's IQ at the end of the preschool period. Children (N = 1045) from the EDEN mother-child cohort were assessed for social withdrawal behaviours at 1 year by trained midwives using the Alarm Distress BaBy (ADBB) scale. Midwives also examined infants' language and motor development at 1 year. At the age 5-6 years, IQ scores were based on the WPPSI-III. Linear regression models were used to determine the association between IQ and ADBB, adjusted for a broad range of pre- and postnatal environmental factors and for language and motor skills scores at 1 year. After adjusting for environmental factors, children with social withdrawal at 1 years (ADBB ≥5; N = 195) had significantly lower IQ scores at 5-6 years (-2.81 IQ points; p value 0.007) compared to children without social withdrawal (ADBB

Rationale The present study aims: ( i ) to determine how well developmental milestones at 4, 8, 12 and 24 months may predict IQ at 5–6 years old, ( ii ) to identify cognitive domains during the first two years that best predict later IQ and ( iii ) to determine whether children with IQ in the normal range at 5–6 years old may differ from disabled (IQ 130) with regard to their early cognitive development. Method The main developmental milestones were collected through self-administered questionnaires rated by parents at 4, 8, 12 and 24 months and through parental questionnaires administered by a trained interviewer and questionnaires completed following a medical examination at 12 months. These questionnaires were derived from the Brunet-Lezine Psychomotor Development Scale and they addressed several cognitive domains (gross and fine motor skills, language and socialization). Results ( i ) Developmental milestones predict a substantial part of the later IQ variance from 24 months (R 2 ∼ 20%). ( ii ) Early language skills more strongly predict later IQ than the other cognitive domains. ( iii ) Several cognitive domains, but particularly language skills, predict disabled children at 5–6 years old (from the age of 8 months) and gifted children (from the age of 12 months). Discussion The present study provides valuable information for early developmental assessment and could contribute to a better understanding of intellectual development.

This study aims to determine whether early predictors of cognitive development affect some cognitive functions more than others. Children (N = 1129) from the EDEN mother-child cohort were assessed at the age of 5-to-6 years using verbal and nonverbal cognitive tests. We used structural equation modeling to simultaneously examine the effects of a broad range of predictors on each cognitive dimension and to test to what extent each predictor differentially affected these dimensions. Effects of family stimulation, breastfeeding duration and number of older siblings were more strongly related to verbal than nonverbal cognitive measure. Our findings provide robust evidence that some modifiable aspects of the early environment are associated with children’s cognitive development and may be more strongly associated with their verbal than nonverbal skills.

BACKGROUND According to the Developmental Origins of Health and Diseases concept, exposures in the preconception period may be critical. For the first time, we evaluated the effect of preconception poor anthropometric status on infant's growth in sub-Saharan Africa. METHODS A mother-child cohort was followed prospectively from preconception to 1 year old in Benin. Maternal anthropometric status was assessed by prepregnancy body mass index (BMI), approximated by BMI at the first antenatal visit before 7 weeks' gestation, and gestational weight gain (GWG). BMI was categorized as underweight, normal, overweight, and obesity according to World Health Organization standards. GWG was categorized as low ( 12 kg). In infant, stunting and wasting were defined as length-for-age and weight-for-length z scores less than -2 SD, respectively. We evaluated the association between BMI/GWG and infant's weight and length at birth and during the first year of life, as well as with stunting and wasting at 12 months using mixed linear and logistic regression models. RESULTS In multivariate, preconceptional underweight was associated with a lower infant's weight at birth and during the first year (-164 g; 95% CI, -307 to -22; and -342 g; 95% CI, -624 to -61, respectively) and with a higher risk of stunting at 12 months (adjusted odds ratio [aOR] = 3.98; 95% CI, 1.01-15.85). Furthermore, preconceptional obesity and a high GWG were associated with a higher weight and length at birth and during the first year. CONCLUSION Underweight and obesity before conception as well as GWG were associated with infant's growth. These results argue for preventive interventions starting as early as the preconception period to support child long-term health.

Children with developmental coordination disorder also manifest difficulties in non-motor domains (attentional, emotional, behavioral and socialization skills). Longitudinal studies can help disentangle the complex relationships between the development of motor skills and other cognitive domains. This study aims to examine the contribution of early cognitive factors to changes in motor skills during the preschool period. Children (N = 1144) from the EDEN mother-child cohort were assessed for motor skills with the Copy Design task (NEPSY battery) and the parent-rated Ages and Stages Questionnaire (fine and gross motor skills scores) at ages 3 and 5-6 years. At 3 years, language skills were evaluated using tests from the NEPSY and ELOLA batteries. Emotional problems, conduct problems, inattention and hyperactivity symptoms, peer relationships and pro-social behavior were assessed with the Strengths and Difficulties Questionnaire (SDQ) also at 3 years. Linear and logistic regression models were performed to examine whether positive and negative changes in motor skills between 3 and 5-6 years are associated with specific cognitive skills at 3 years, while adjusting for a broad range of pre- and postnatal environmental factors. In the linear regression model, the SDQ Inattention symptoms score at 3 years was associated with negative changes in motor skills (standardized β = - 0.09, SD = 0.03, p value = 0.007) and language skills at 3 years were associated with positive changes in motor skills (standardized β = 0.05, SD = 0.02, p value = 0.041) during the preschool period. In logistic regression models, the SDQ Inattention symptoms score at 3 years was associated with a higher likelihood of a declining trajectory of motor skills (OR [95% CI] = 1.37 [1.02-1.84]). A higher language skills score at 3 years was associated with an increased likelihood of a resilient trajectory (1.67 [1.17-2.39]). This study provides a better understanding of the natural history of developmental coordination delays by identifying cognitive factors that predict changes in motor skills between the ages of 3 and 5-6 years.

There are over 1,000,000 publications on diet and health and over 480,000 references on inflammation in the National Library of Medicine database. In addition, there have now been over 30,000 peer-reviewed articles published on the relationship between diet, inflammation, and health outcomes. Based on this voluminous literature, it is now recognized that low-grade, chronic systemic inflammation is associated with most non-communicable diseases (NCDs), including diabetes, obesity, cardiovascular disease, cancers, respiratory and musculoskeletal disorders, as well as impaired neurodevelopment and adverse mental health outcomes. Dietary components modulate inflammatory status. In recent years, the Dietary Inflammatory Index (DII®), a literature-derived dietary index, was developed to characterize the inflammatory potential of habitual diet. Subsequently, a large and rapidly growing body of research investigating associations between dietary inflammatory potential, determined by the DII, and risk of a wide range of NCDs has emerged. In this narrative review, we examine the current state of the science regarding relationships between the DII and cancer, cardiometabolic, respiratory and musculoskeletal diseases, neurodevelopment, and adverse mental health outcomes. We synthesize the findings from recent studies, discuss potential underlying mechanisms, and look to the future regarding novel applications of the adult and children’s DII (C-DII) scores and new avenues of investigation in this field of nutritional research.

Importance: Both low and high gestational weight gain have been associated with adverse maternal and infant outcomes, but optimal gestational weight gain remains uncertain and not well defined for all prepregnancy weight ranges. Objectives: To examine the association of ranges of gestational weight gain with risk of adverse maternal and infant outcomes and estimate optimal gestational weight gain ranges across prepregnancy body mass index categories. Design, setting, and participants: Individual participant-level meta-analysis using data from 196 670 participants within 25 cohort studies from Europe and North America (main study sample). Optimal gestational weight gain ranges were estimated for each prepregnancy body mass index (BMI) category by selecting the range of gestational weight gain that was associated with lower risk for any adverse outcome. Individual participant-level data from 3505 participants within 4 separate hospital-based cohorts were used as a validation sample. Data were collected between 1989 and 2015. The final date of follow-up was December 2015. Exposures: Gestational weight gain. Main outcomes and measures: The main outcome termed any adverse outcome was defined as the presence of 1 or more of the following outcomes: preeclampsia, gestational hypertension, gestational diabetes, cesarean delivery, preterm birth, and small or large size for gestational age at birth. Results: Of the 196 670 women (median age, 30.0 years [quartile 1 and 3, 27.0 and 33.0 years] and 40 937 were white) included in the main sample, 7809 (4.0%) were categorized at baseline as underweight (BMI

International audience; The potential beneficial effects of physical activity during pregnancy on postpartum depressive symptoms (PPD) remain inconclusive. Using data from two prospective French birth cohorts, we aimed to examine the relationship between domain-specific physical activity (including leisure-time sedentary behavior) in pregnancy and the occurrence of PPD. Participants of the ELFE cohort (n = 15,538) completed the Pregnancy Physical Activity Questionnaire (PPAQ), which assesses the following physical activity/sedentary behavior domains: household/caregiving, occupational, sports/exercise, transportation and leisure-time sedentary behavior during the third pregnancy trimester. In the EDEN cohort (n = 1745) women completed the Baecke Questionnaire (BQ) measuring occupational, sports/exercise, and leisure-time activity during the first trimester of pregnancy. Depressive symptoms in the first postpartum year were measured using the Edinburgh Postnatal Depression Scale in both cohorts. Associations of physical activity/sedentary behavior with PPD symptoms were determined by logistic regression analysis, with adjustment on potential confounding factors. In the adjusted models, higher levels of household/caregiving activities (OR = 1.10 (95% CI 1.01-1.19)) and leisure-time sedentary behavior (OR = 1.16 (95% CI 1.06-1.23)), in the third pregnancy trimester were associated with an increased odds of PPD. No significant associations were found for physical activity domains during the first pregnancy trimester. Higher levels of household and caregiving activities and leisure-time sedentary behavior in the last trimester of pregnancy appear to increase the likelihood of postpartum depression. Purpose and context should be taken into account when encouraging physical activity as a strategy to help prevent postpartum mental health problems from pregnancy onwards. Reducing sedentary behavior could be a complementary strategy.

Background Maternal obesity and excessive gestational weight gain may have persistent effects on offspring fat development. However, it remains unclear whether these effects differ by severity of obesity, and whether these effects are restricted to the extremes of maternal body mass index (BMI) and gestational weight gain. We aimed to assess the separate and combined associations of maternal BMI and gestational weight gain with the risk of overweight/obesity throughout childhood, and their population impact. Methods and findings We conducted an individual participant data meta-analysis of data from 162,129 mothers and their children from 37 pregnancy and birth cohort studies from Europe, North America, and Australia. We assessed the individual and combined associations of maternal pre-pregnancy BMI and gestational weight gain, both in clinical categories and across their full ranges, with the risks of overweight/obesity in early (2.0–5.0 years), mid (5.0–10.0 years) and late childhood (10.0–18.0 years), using multilevel binary logistic regression models with a random intercept at cohort level adjusted for maternal sociodemographic and lifestyle-related characteristics. We observed that higher maternal pre-pregnancy BMI and gestational weight gain both in clinical categories and across their full ranges were associated with higher risks of childhood overweight/obesity, with the strongest effects in late childhood (odds ratios [ORs] for overweight/obesity in early, mid, and late childhood, respectively: OR 1.66 [95% CI: 1.56, 1.78], OR 1.91 [95% CI: 1.85, 1.98], and OR 2.28 [95% CI: 2.08, 2.50] for maternal overweight; OR 2.43 [95% CI: 2.24, 2.64], OR 3.12 [95% CI: 2.98, 3.27], and OR 4.47 [95% CI: 3.99, 5.23] for maternal obesity; and OR 1.39 [95% CI: 1.30, 1.49], OR 1.55 [95% CI: 1.49, 1.60], and OR 1.72 [95% CI: 1.56, 1.91] for excessive gestational weight gain). The proportions of childhood overweight/obesity prevalence attributable to maternal overweight, maternal obesity, and excessive gestational weight gain ranged from 10.2% to 21.6%. Relative to the effect of maternal BMI, excessive gestational weight gain only slightly increased the risk of childhood overweight/obesity within each clinical BMI category (p-values for interactions of maternal BMI with gestational weight gain: p = 0.038, p < 0.001, and p = 0.637 in early, mid, and late childhood, respectively). Limitations of this study include the self-report of maternal BMI and gestational weight gain for some of the cohorts, and the potential of residual confounding. Also, as this study only included participants from Europe, North America, and Australia, results need to be interpreted with caution with respect to other populations. Conclusions In this study, higher maternal pre-pregnancy BMI and gestational weight gain were associated with an increased risk of childhood overweight/obesity, with the strongest effects at later ages. The additional effect of gestational weight gain in women who are overweight or obese before pregnancy is small. Given the large population impact, future intervention trials aiming to reduce the prevalence of childhood overweight and obesity should focus on maternal weight status before pregnancy, in addition to weight gain during pregnancy., Vincent Jaddoe and colleagues report that a high BMI before pregnancy, rather than excessive gestational weight gain, is more likely to contribute to childhood obesity., Author summary Why was this study done? Maternal pre-pregnancy obesity and excessive gestational weight gain are important risk factors of various pregnancy and birth complications. An accumulating body of evidence suggests that maternal obesity and excessive gestational weight gain also have persistent effects on offspring fat development. It is not clear whether these effects exist across the full ranges of maternal pre-pregnancy body mass index and gestational weight gain, what their combined effects are, and what the population impact of these effects is. What did the researchers do and find? We conducted an individual participant data meta-analysis using data from 162,129 mothers and their children from 37 pregnancy and birth cohorts from Europe, North America, and Australia to assess the separate and combined associations of maternal pre-pregnancy body mass index and gestational weight gain with the risk of overweight/obesity throughout childhood, and their population impact. We observed not only that maternal pre-pregnancy overweight and obesity were associated with an increased risk of childhood overweight/obesity, but that this risk increased gradually over the full range of maternal BMI. Similarly, the risk of childhood overweight/obesity increased across the full range of gestational weight gain. We estimated that 21.7% to 41.7% of childhood overweight/obesity prevalence could be attributed to maternal overweight and obesity together, whereas 11.4% to 19.2% could be attributed to excessive gestational weight gain. The additional effect of excessive gestational weight gain on the risk of childhood overweight/obesity was small among women who are already overweight or obese before pregnancy. What do these findings mean? Maternal pre-pregnancy BMI and, to a smaller extent, gestational weight gain are important modifiable risk factors of childhood overweight/obesity with considerable population impact. Future intervention trials aiming to reduce the prevalence of childhood overweight and obesity should focus on maternal weight status before pregnancy, in addition to weight status during pregnancy.

ObjectiveTo assess the separate and combined associations of maternal pre‐pregnancy body mass index (BMI) and gestational weight gain with the risks of pregnancy complications and their population impact.DesignIndividual participant data meta‐analysis of 39 cohorts.SettingEurope, North America, and Oceania.Population265 270 births.MethodsInformation on maternal pre‐pregnancy BMI, gestational weight gain, and pregnancy complications was obtained. Multilevel binary logistic regression models were used.Main outcome measuresGestational hypertension, pre‐eclampsia, gestational diabetes, preterm birth, small and large for gestational age at birth.ResultsHigher maternal pre‐pregnancy BMI and gestational weight gain were, across their full ranges, associated with higher risks of gestational hypertensive disorders, gestational diabetes, and large for gestational age at birth. Preterm birth risk was higher at lower and higher BMI and weight gain. Compared with normal weight mothers with medium gestational weight gain, obese mothers with high gestational weight gain had the highest risk of any pregnancy complication (odds ratio 2.51, 95% CI 2.31– 2.74). We estimated that 23.9% of any pregnancy complication was attributable to maternal overweight/obesity and 31.6% of large for gestational age infants was attributable to excessive gestational weight gain.ConclusionsMaternal pre‐pregnancy BMI and gestational weight gain are, across their full ranges, associated with risks of pregnancy complications. Obese mothers with high gestational weight gain are at the highest risk of pregnancy complications. Promoting a healthy pre‐pregnancy BMI and gestational weight gain may reduce the burden of pregnancy complications and ultimately the risk of maternal and neonatal morbidity.Tweetable abstractPromoting a healthy body mass index and gestational weight gain might reduce the population burden of pregnancy complications.

International audience; Objective. Sleep duration may vary inter-individually and intra-individually over time. We aimed at both identifying night-sleep duration (NSD) trajectories among preschoolers and studying associated factors. Methods. NSD were collected within the French birth-cohort study EDEN at ages 2, 3 and 5-6 years through parental questionnaires, and were used to model NSD trajectories among 1205 children. Familial socioeconomic factors, maternal sociodemographic, health and lifestyle characteristics as well as child health, lifestyle, and sleep characteristics at birth and/or at age 2 years were investigated in association with NSD using multinomial logistic regressions. Results. Five distinct NSD trajectories were identified: short (SS

International audience; Background: Growth monitoring of apparently healthy children aims at early detection of serious conditions by use of both clinical expertise and algorithms that define abnormal growth. The seven existing algorithms provide contradictory definitions of growth abnormality and have a low level of validation. Objective: An external validation study with head-to-head comparison of the seven algorithms combined with study of the impact of use of the World Health Organization (WHO) versus national growth charts on algorithm performance. Study design: With a case-referent approach, we retrospectively applied all algorithms to growth data for children with Turner syndrome, growth hormone deficiency, or celiac disease (n= 341) as well as apparently healthy children (n=3,406). Sensitivity, specificity, and theoretical reduction in time to diagnosis for each algorithm were calculated for each condition by using the WHO or national growth charts. Results: Among the two algorithms with high specificity (> 98%), the Grote clinical decision rule had higher sensitivity than the Coventry consensus (4.6% to 54% vs 0% to 8.9%, p

International audience; BACKGROUND:Implementing a patient safety curriculum for medical students requires to identify their needs and current awareness of the topic. Several tools have been developed to measure patient safety culture, but none of them have been developed in the French context. Our objective was to adapt and refine the psychometric properties of the MSSAPS, developed by Liao et al, to use it among general practice (GP) residents.METHODS:1-We conducted a translation and transcultural adaptation of the MSSAPS questionnaire (28 items, 5 dimensions: safety culture, teamwork culture, experiences with professionalism, error disclosure culture and comfort expressing professional concerns) in accordance with the international recommendations. 2-We studied the new questionnaire' psychometric properties on a sample of GP residency students in 2016. This validation comprised 2 steps: a confirmatory factor analysis (CFA) for each dimension of the MSAPPS to explore the adequacy of the structure of the questionnaire; an exploratory factor analysis to refine the instrument, using a principal component analysis and Cronbach's α-coefficients calculation. A final CFA examined the structure validity of the refined questionnaire. 3-We described the items and the safety cultural scores in our sample of residents.RESULTS:Among 391 eligible students, 213 responded (54%). The initial structure was not confirmed by CFAs, showing a poor fit for 3 of the 5 dimensions: safety culture, teamwork culture and professionalism. Exploratory PCA led to 3 dimensions: Safety culture (PVE: 18.5% and 7 of 8 initial items), Experiences with professionalism (PVE: 17.8% and 5 of 7 initial items) and Error disclosure culture (PVE: 13.6% and 3 of 4 original items). Cronbach's α-coefficients were 0.74, 0.78 and 0.76 respectively. The final CFA confirmed the existence of the 3 latent dimensions with a good fit to the and highly significant structural coefficients (P