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Abstract Background Early life environmental stressors play an important role in the development of multiple chronic disorders. Previous studies that used environmental risk scores (ERS) to assess the cumulative impact of environmental exposures on health are limited by the diversity of exposures included, especially for early life determinants. We used machine learning methods to build early life exposome risk scores for three health outcomes using environmental, molecular, and clinical data. Methods In this study, we analyzed data from 1622 mother-child pairs from the HELIX European birth cohorts, using over 300 environmental, 100 child peripheral, and 18 mother-child clinical markers to compute environmental-clinical risk scores (ECRS) for child behavioral difficulties, metabolic syndrome, and lung function. ECRS were computed using LASSO, Random Forest and XGBoost. XGBoost ECRS were selected to extract local feature contributions using Shapley values and derive feature importance and interactions. Results ECRS captured 13%, 50% and 4% of the variance in mental, cardiometabolic, and respiratory health, respectively. We observed no significant differences in predictive performances between the above-mentioned methods.The most important predictive features were maternal stress, noise, and lifestyle exposures for mental health; proteome (mainly IL1B) and metabolome features for cardiometabolic health; child BMI and urine metabolites for respiratory health. Conclusions Besides their usefulness for epidemiological research, our risk scores show great potential to capture holistic individual level non-hereditary risk associations that can inform practitioners about actionable factors of high-risk children. As in the post-genetic era personalized prevention medicine will focus more and more on modifiable factors, we believe that such integrative approaches will be instrumental in shaping future healthcare paradigms.

Abstract Socioeconomic status (SES) influences the risk of both physical diseases, such as asthma, and neurodevelopmental conditions, including attention-deficit/hyperactivity disorder (ADHD). Using Causal Mediation Analysis on French birth-cohort data, we found a causal pathway from SES to ADHD symptoms, in part mediated by asthma. An increase in family income at age 3 by one unit resulted in lower ADHD symptoms at age 5, by −0.37 [95% CI: −0.50, −0.24] SDQ-score-points, with additional −0.04 [95% CI: −0.08, −0.01] points reduction indirectly via asthma at age 3, both with statistical significance. Importantly, family income at age 3 exerted both direct and indirect (via asthma) negative effects on later ADHD symptoms with much higher magnitudes for the direct effect. Our findings underscore the importance of apprehending ADHD symptoms in the broader context of socioeconomic disparities, along with their comorbidities with asthma, potentially influencing public health interventions and clinical practice in managing ADHD.

Introduction: Phthalates, or dieters of phthalic acid, are a ubiquitous type of plasticizer used in a variety of common consumer and industrial products. They act as endocrine disruptors and are associated with increased risk for several diseases. Once in the body, phthalates are metabolized through partially known mechanisms, involving phase I and phase II enzymes. Objective: In this study we aimed to identify common single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) associated with the metabolism of phthalate compounds in children through genome-wide association studies (GWAS). Methods: The study used data from 1,044 children with European ancestry from the Human Early Life Exposome (HELIX) cohort. Ten phthalate metabolites were assessed in a two-void pooled urine collected at the mean age of 8 years. Six ratios between secondary and primary phthalate metabolites were calculated. Genome-wide genotyping was done with the Infinium Global Screening Array (GSA) and imputation with the Haplotype Reference Consortium (HRC) panel. PennCNV was used to estimate copy number variants (CNVs) and CNVRanger to identify consensus regions. GWAS of SNPs and CNVs were conducted using PLINK and SNPassoc, respectively. Subsequently, functional annotation of suggestive SNPs (p-value

Studies evaluating the benefits and risks of green spaces on children’s health are scarce. The present study aimed to examine the associations between exposure to green spaces during pregnancy and early childhood with respiratory, cardiometabolic, and neurodevelopmental outcomes in school-age children. We performed an Individual-Participant Data (IPD) meta-analysis involving 35,000 children from ten European birth cohorts across eight countries. For each participant, we calculated residential Normalized Difference Vegetation Index (NDVI) within a 300 m buffer and the linear distance to green spaces (meters) during prenatal life and childhood. Multiple harmonized health outcomes were selected: asthma and wheezing, lung function, body mass index, diastolic and systolic blood pressure, non-verbal intelligence, internalizing and externalizing problems, and ADHD symptoms. We conducted a two-stage IPD meta-analysis and evaluated effect modification by socioeconomic status (SES) and sex. Between-study heterogeneity was assessed via random-effects meta-regression. Residential surrounding green spaces in childhood, not pregnancy, was associated with improved lung function, particularly higher FEV1 (β = 0.06; 95 %CI: 0.03, 0.09 I2 = 4.03 %, p

Background: Urban environments are characterized by many factors that may influence children’s energy balance-related behaviors (EBRBs), but there is limited research on the impact of prospective exposure to multiple urban factors in preschoolers. We evaluated prospective associations between various urban exposures and EBRBs in preschoolers across Europe, with EBRBs considered both individually and combined into lifestyle patterns. Methods: We used data from 4,073 preschoolers (aged 3–4 years) participating in three European cohorts from the EU Child Cohort Network: BiB (United Kingdom), EDEN (France), and INMA (Spain). Eighteen built and food environment, green spaces, road traffic and ambient air pollution exposures were characterized at residential addresses. Various EBRBs were considered as the outcomes including screen time, sleep duration and diet (fruit, vegetables, discretionary sweet foods, sweet beverages) individually and combined into unhealthy lifestyle patterns, using principal components analysis. Associations between urban exposures and outcomes were estimated using a single-exposure analysis and the deletion-substitution-addition algorithm was used to construct multi-exposure models. Results: In multi-exposure models, greater walkability and smaller distance to the nearest road were associated with higher scores on the unhealthy lifestyle patterns. Likewise, greater walkability was associated with higher screen time and more frequent discretionary sweet food consumption. A smaller distance to the nearest road was also associated with lower sleep duration and more frequent sweet beverages consumption. On the other hand, higher levels of street connectivity showed an inverse association with the unhealthy lifestyle patterns. In the same vein, greater street connectivity was associated with decreased screen time. Conclusion: This comprehensive examination of multiple urban exposures indicates that residing in walkable environments and in close proximity to roads in densely-populated areas may not be advantageous for children EBRBs, while residing in neighborhoods with higher street connectivity appears to supposedly be beneficial.

Background: Precision Health aims to revolutionize disease prevention by leveraging information across multiple omic datasets (multi-omics). However, existing methods generally do not consider personalized environmental risk factors (e.g., environmental pollutants). Objective: To develop and apply a precision health framework which combines multiomic integration (including early, intermediate, and late integration, representing sequential stages at which omics layers are combined for modeling) with mediation approaches (including high-dimensional mediation to identify biomarkers, mediation with latent factors to identify pathways, and integrated/quasi-mediation to identify high-risk subpopulations) to identify novel biomarkers of prenatal mercury induced metabolic dysfunction-associated fatty liver disease (MAFLD), elucidate molecular pathways linking prenatal mercury with MAFLD in children, and identify high-risk children based on integrated exposure and multiomics data. Methods: This prospective cohort study used data from 420 mother–child pairs from the Human Early Life Exposome (HELIX) project. Mercury concentrations were determined in maternal or cord blood from pregnancy. Cytokeratin 18 (CK-18; a MAFLD biomarker) and five omics layers (DNA Methylation, gene transcription, microRNA, proteins, and metabolites) were measured in blood in childhood (age 6–10 years). Results: Each standard deviation increase in prenatal mercury was associated with a 0.11 [95% confidence interval: 0.02–0.21] standard deviation increase in CK-18. High dimensional mediation analysis identified 10 biomarkers linking prenatal mercury and CK-18, including six CpG sites and four transcripts. Mediation with latent factors identified molecular pathways linking mercury and MAFLD, including altered cytokine signaling and hepatic stellate cell activation. Integrated/quasi-mediation identified high risk subgroups of children based on unique combinations of exposure levels, omics profiles (driven by epigenetic markers), and MAFLD. Conclusions: Prenatal mercury exposure is associated with elevated liver enzymes in childhood, likely through alterations in DNA methylation and gene expression. Our analytic framework can be applied across many different fields and serve as a resource to help guide future precision health investigations.

There is growing evidence that in utero imbalance immune activity plays a role in the development of neurodevelopmental and psychiatric disorders in children. Mood dysregulation (MD) is a debilitating transnosographic syndrome whose underlying pathophysiological mechanisms could be revealed by studying its biomarkers using the Research Domain Criteria (RDoC) model. Our aim was to study the association between the network of cord serum cytokines, and mood dysregulation trajectories in offsprings between 3 and 8 years of age. We used the data of a study nested in the French birth cohort EDEN that took place from 2003 to 2014 and followed mother-child dyads from the second trimester of pregnancy until the children were 8 years of age. The 2002 mother-child dyads were recruited from the general population through their pregnancy follow-up in two French university hospitals. 871 of them were included in the nested cohort and cord serum cytokine levels were measured at birth. Children's mood dysregulation symptoms were assessed with the Strengths and Difficulties Questionnaire Dysregulation Profile at the ages 3, 5 and 8 years in order to model their mood dysregulation trajectories. Out of the 871 participating dyads, 53% of the children were male. 2.1% of the children presented a high mood dysregulation trajectory whereas the others were considered as physiological variations. We found a significant negative association between TNF-α cord serum levels and a high mood dysregulation trajectory when considering confounding factors such as maternal depression during pregnancy (adjusted Odds Ratio (aOR) = 0.35, 95% Confidence Interval (CI) [0.18–0.67]). Immune imbalance at birth could play a role in the onset of mood dysregulation symptoms. Our findings throw new light on putative immune mechanisms implicated in the development of mood dysregulation and should lead to future animal and epidemiological studies.

Summary: Background: Early childcare attendance may be related to children's internalizing and externalizing symptoms throughout childhood and young adolescence, however evidence from Europe is limited. We aimed to assess this association across multiple population-based birth cohorts of children recruited in different European countries. Methods: Data come from six parent-offspring prospective birth cohort studies across five European countries within the EU Child Cohort Network. A total of 87,208 parent-child dyads were included in the study. To test associations between childcare attendance (centre-based or informal) anytime between ages 0 and 4 years and children's internalizing and externalizing symptoms in middle childhood and young adolescence (measured at: 5–6 years, 7–9 years, and 10–13 years) a two-stage individual participant data meta-analysis was implemented. Linear regression models were performed in each cohort separately; combined random-effects meta-analysis was then used to obtain overall association estimates. In secondary analyses, we tested interactions between childcare attendance and mother's post-partum depression, low education status, and the child's sex. Findings: Compared to children who were exclusively cared for by their parents prior to school entry, those who attended centre-based childcare had lower levels of internalizing symptoms in all age groups [5–6 years: β: −1.78 (95% CI: −3.39, −0.16); 7–9 years: β: −0.55 (95% CI: −0.88, −0.73); 10–13 years: β: −0.76 (95% CI: −1.15, −0.37)]. Children who attended informal childcare appeared to have elevated levels of internalizing symptoms between 7–9 and 10–13 years, respectively [β: 1.65 (95% CI: 1.25, 2.06); β: 1.25 (95% CI: 0.96, 1.54)]. Informal childcare attendance was also associated with increased levels of children's externalizing symptoms between 7–9 and 10–13 years, respectively [β: 2.84 (95% CI: 1.41, 4.26); β: 2.19 (95% CI: 0.54, 3.84)]. Interpretation: Early centre-based childcare is associated with decreased levels of children's internalizing symptoms compared to exclusive parental care. For informal childcare, opposite associations were observed. Overall, our results suggest that centre-based childcare attendance may be associated with slight positive impacts on children's emotional development and should be encouraged by public policies. In addition, children from socioeconomically disadvantaged families require special attention, as they may not sufficiently benefit from universal early childhood education and care (ECEC). Funding: This research was funded by the ERC Consolidator grant RESEDA (Horizon Europe, 101001420).

Perinatal exposure to omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) can be characterized through biomarkers in maternal or cord blood or breast milk. Objectives were to describe perinatal PUFA status combining multiple biofluids and to investigate how it was influenced by dietary intake during pregnancy and maternal FADS and ELOVL gene polymorphisms. This study involved 1,901 mother–child pairs from the EDEN cohort, with PUFA levels measured in maternal and cord erythrocytes, and colostrum. Maternal dietary PUFA intake during the last trimester was derived from a food frequency questionnaire. Twelve single-nucleotide polymorphisms in FADS and ELOVL genes were genotyped from maternal DNA. Principal component analysis incorporating PUFA levels from the three biofluids identified patterns of perinatal PUFA status. Spearman’s correlations explored associations between patterns and PUFA dietary intake, and linear regression models examined pattern associations with FADS or ELOVL haplotypes. Five patterns were retained: “High omega-3 LC-PUFAs, low omega-6 LC-PUFAs”; “Omega-6 LC-PUFAs”; “Colostrum LC-PUFAs”; “Omega-6 precursor (LA) and DGLA”; “Omega-6 precursor and colostrum ALA”. Maternal omega-3 LC-PUFA intakes were correlated with “High omega-3 LC-PUFAs, low omega-6 LC-PUFAs” (r(DHA) = 0.33) and “Omega-6 LC-PUFAs” (r(DHA) = −0.19) patterns. Strong associations were found between FADS haplotypes and PUFA patterns except for “High omega-3 LC-PUFAs, low omega-6 LC-PUFAs”. Lack of genetic association with the “High omega-3 LC-PUFAs, low omega-6 LC-PUFAs” pattern, highly correlated with maternal omega-3 LC-PUFA intake, emphasizes the importance of adequate omega-3 LC-PUFA intake during pregnancy and lactation. This study offers a more comprehensive assessment of perinatal PUFA status and its determinants.

Green space exposure has been associated with improved mental, physical and general health. However, the underlying biological mechanisms remain largely unknown. The aim of this study was to investigate the association between green space exposure and cord and child blood DNA methylation.Data from eight European birth cohorts with a total of 2,988 newborns and 1,849 children were used. Two indicators of residential green space exposure were assessed: (i) surrounding greenness (satellite-based Normalized Difference Vegetation Index (NDVI) in buffers of 100 m and 300 m) and (ii) proximity to green space (having a green space ≥ 5,000 m2 within a distance of 300 m). For these indicators we assessed two exposure windows: (i) pregnancy, and (ii) the period from pregnancy to child blood DNA methylation assessment, named as cumulative exposure. DNA methylation was measured with the Illumina 450K or EPIC arrays. To identify differentially methylated positions (DMPs) we fitted robust linear regression models between pregnancy green space exposure and cord blood DNA methylation and between cumulative green space exposure and child blood DNA methylation. Two sensitivity analyses were conducted: (i) without adjusting for cellular composition, and (ii) adjusting for air pollution. Cohort results were combined through fixed-effect inverse variance weighted meta-analyses. Differentially methylated regions (DMRs) were identified from meta-analysed results using the Enmix-combp and DMRcate methods.There was no statistical evidence of pregnancy or cumulative exposures associating with any DMP (False Discovery Rate, FDR, p-value

Abstract An inverse social gradient in early childhood overweight has been consistently described in high-income countries; however, less is known about the role of migration status. We studied the social patterning of overweight in preschool children according to the mother’s socio-economic and migration background. For 9250 children of the French ELFE birth cohort with body mass index collected at age 3.5 years, we used nested logistic regression to investigate the association of overweight status in children with maternal educational level, occupation, household income and migration status. Overall, 8.3% (95%CI [7.7–9.0]) of children were classified as overweight. The odds of overweight was increased for children from immigrant mothers (OR 2.22 [95% CI 1.75–2.78]) and descendants of immigrant mothers (OR 1.35 [1.04–2.78]) versus non-immigrant mothers. The highest odds of overweight was also observed in children whose mothers had low education, were unemployed or students, or were from households in the lowest income quintile. Our findings confirm that socio-economic disadvantage and migration status are risk factors for childhood overweight. However, the social patterning of overweight did not apply uniformly to all variables. These new and comprehensive insights should inform future public health interventions aimed at tackling social inequalities in childhood overweight.

Abstract Background Attention-deficit/hyperactivity disorder (ADHD) is a prevalent and highly heritable neurodevelopmental disorder of major societal concern. Diagnosis can be challenging and there are large knowledge gaps regarding its etiology, though studies suggest an interplay of genetic and environmental factors involving epigenetic mechanisms. MicroRNAs (miRNAs) show promise as biomarkers of human pathology and novel therapies, and here we aimed to identify blood miRNAs associated with traits of ADHD as possible biomarker candidates and further explore their biological relevance. Methods Our study population consisted of 1126 children (aged 5–12 years, 46% female) from the Human Early Life Exposome study, a study spanning six ongoing population-based European birth cohorts. Expression profiles of miRNAs in whole blood samples were quantified by microarray and tested for association with ADHD-related measures of behavior and neuropsychological functions from questionnaires (Conner’s Rating Scale and Child Behavior Checklist) and computer-based tests (the N-back task and Attention Network Test). Results We identified 29 miRNAs significantly associated (false discovery rate

Abstract Background Perinatal maternal depression and anxiety are associated with adverse maternal outcomes, and nutrition may play an important role in their emergence. Previous research shows that certain micro and macronutrients found in different dietary patterns may associate with perinatal mood disorders. This study aims to explore relationships between nutrition during pregnancy and perinatal maternal depression and anxiety symptoms using network analyses. Methods Using data from the French EDEN mother-child cohort, the sample consisted of 1438 women with available mental health outcomes (CES-D, STAI and EPDS) and nutritional markers collected from food frequency questionnaires. Four networks were constructed to explore the relationships between prenatal nutrient status, dietary patterns, and perinatal mental health, while accounting for important confounders. Results The Healthy dietary pattern was associated with the presence of vital micronutrients, while the Western dietary pattern was consistently associated with poorer intake of specific micronutrients and contained an excess of certain macronutrients. Western dietary pattern and symptoms of postnatal depression were connected by a positive edge in both the macronutrient and micronutrient networks. Lower education levels were associated with higher Western dietary pattern scores, from which a positive edge linked to postnatal depression symptoms in both models. Conclusions A Western dietary pattern was associated with increased symptoms of postnatal depression in our adjusted network models; The Healthy dietary pattern was associated with essential micronutrients but not with symptoms of depression or anxiety. Perinatal mental health might be impacted by specific dietary patterns in the context of psychosocial and physical stress associated with pregnancy.

Abstract Background Early-life environmental exposures are suspected to be involved in the development of chronic diseases later in life. Most studies conducted so far considered single or few exposures and single-health parameter. Our study aimed to identify a childhood general health score and assess its association with a wide range of pre- and post-natal environmental exposures. Methods The analysis is based on 870 children (6–12 years) from six European birth cohorts participating in the Human Early-Life Exposome project. A total of 53 prenatal and 105 childhood environmental factors were considered, including lifestyle, social, urban and chemical exposures. We built a general health score by averaging three sub-scores (cardiometabolic, respiratory/allergy and mental) built from 15 health parameters. By construct, a child with a low score has a low general health status. Penalized multivariable regression through Least Absolute Shrinkage and Selection Operator (LASSO) was fitted in order to identify exposures associated with the general health score. Findings The results of LASSO show that a lower general health score was associated with maternal passive and active smoking during pregnancy and postnatal exposure to methylparaben, copper, indoor air pollutants, high intake of caffeinated drinks and few contacts with friends and family. Higher child’s general health score was associated with prenatal exposure to a bluespace near residency and postnatal exposures to pets, cobalt, high intakes of vegetables and more physical activity. Against our hypotheses, postnatal exposure to organochlorine compounds and perfluorooctanoate were associated with a higher child’s general health score. Conclusion By using a general health score summarizing the child cardiometabolic, respiratory/allergy and mental health, this study reinforced previously suspected environmental factors associated with various child health parameters (e.g. tobacco, air pollutants) and identified new factors (e.g. pets, bluespace) warranting further investigations.

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.

Outcome-wide analysis can offer several benefits, including increased power to detect weak signals and the ability to identify exposures with multiple effects on health, which may be good targets for preventive measures. Recently, advanced statistical multivariate techniques for outcome-wide analysis have been developed, but they have been rarely applied to exposome analysis. In this work, we provide an overview of a selection of methods that are well-suited for outcome-wide exposome analysis and are implemented in the R statistical software. Our work brings together six different methods presenting innovative solutions for typical problems arising from outcome-wide approaches in the context of the exposome, including dependencies among outcomes, high dimensionality, mixed-type outcomes, missing data records, and confounding effects. The identified methods can be grouped into four main categories: regularized multivariate regression techniques, multi-task learning approaches, dimensionality reduction approaches, and bayesian extensions of the multivariate regression framework. Here, we compare each technique presenting its main rationale, strengths, and limitations, and provide codes and guidelines for their application to exposome data. Additionally, we apply all selected methods to a real exposome dataset from the Human Early-Life Exposome (HELIX) project, demonstrating their suitability for exposome research. Although the choice of the best method will always depend on the challenges to be faced in each application, for an exposome-like analysis we find dimensionality reduction and bayesian methods such as reduced rank regression (RRR) or multivariate bayesian shrinkage priors (MBSP) particularly useful, given their ability to deal with critical issues such as collinearity, high-dimensionality, missing data or quantification of uncertainty.

Introduction: Maternal exposure to food chemicals may increase the risk of allergy and respiratory disorders in offspring. We aimed to assess the association of prenatal dietary exposure to single chemicals and chemical mixtures with allergy or respiratory events reported before age 8 y in children. Methods: We included 1428 mother–child pairs enrolled in the EDEN mother–child cohort. Maternal dietary exposure to 209 chemicals and eight associated mixtures was investigated. Allergic and respiratory diseases (wheezing, asthma, allergic rhinitis, eczema and food allergy) were reported by parents between birth and age 8 y. Associations with the studied outcomes were evaluated with three approaches based on adjusted logistic regression, estimating odds ratios (ORs) and 95 % confidence intervals (CIs). First, food chemicals were considered individually, with correction for multiple testing. Second, chemicals selected by elastic net regression were considered simultaneously in a multiple exposure model. Third, predefined mixtures were introduced in the same adjusted logistic regression. Results are expressed as odds ratio (OR[95 % CI]). Results: Prenatal single exposure to 74 food chemicals was associated with higher risk of allergic rhinitis. Prenatal single exposure to 11 chemicals was associated with higher risk of wheezing. In the multi-exposure approach, risk of wheezing was associated with the pesticides diazinon and triadimenol, and polycyclic aromatic hydrocarbon 5-methylchrysene. Phytoestrogen resveratrol was negatively associated with lower risk of both wheezing and allergic rhinitis, and mycotoxin monoacetoxyscirpenol was negatively associated with risk of eczema. Finally, a chemical mixture composed mainly of trace elements, furans and polycyclic aromatic hydrocarbons, was associated with higher risk of allergic rhinitis (1.33 [1.02;1.73]). Conclusion: Prenatal dietary exposure to chemicals was associated with risk of allergic rhinitis or wheezing up to age 8 y. A few chemicals were associated with other allergic and respiratory diseases. Larger prospective studies are needed to confirm these findings.

Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder that results from a complex interaction between genes and environment. Breastfeeding (BF) is thought to promote healthy cognitive development, and a body of research has suggested that it may also protect against ASD. Our objectives were to identify the relationship between the initiation and duration of BF and the severity of clinical presentation in ASD. Data were collected from 243 children with a confirmed diagnosis of ASD followed in the ELENA cohort. Clinical severity was measured according to multiple dimensions using standardised tools. The frequency of the initiation of BF was comparable to that of the general population and the rate of children still being breastfed at six months of age was higher. Our results did not indicate a contribution of initiation or duration of BF to the prevention of clinical severity of ASD. We discuss our results in the light of possible methodological limitations of previous reports of an association between BF and ASD. Clinical Trial Registration: NCT02625116.

A meta-analysis of pre-pregnancy maternal body mass index (ppBMI) and placental DNA methylation from 2631 mother-child pairs identifies 27 CpG sites associated with ppBMI, providing insight into how maternal obesity could be associated with metabolic health outcomes in offspring.

Environmental exposures in early life can have lasting health effects, but the molecular mechanisms are not well understood. Here, the authors discover >1000 associations between exposure factors and child multi-omics profiles, revealing signatures for diet, toxic chemical compounds, essential trace elements, and weather conditions.

Abstract Background Maternal blood pressure levels reflect cardiovascular adaptation to pregnancy and proper maternal-fetal exchanges through the placenta and are very sensitive to numerous environmental stressors. Maternal hypertension during pregnancy has been associated with impaired placental functions and with an increased risk for children to suffer from cardiovascular and respiratory diseases later on. Investigating changes in placental DNA methylation levels and cell-type composition in association with maternal blood pressure could help elucidate its relationships with placental and fetal development. Methods Taking advantage of a large cohort of 666 participants, we investigated the association between epigenome-wide DNA methylation patterns in the placenta, measured using the Infinium HumanMethylation450 BeadChip, placental cell-type composition, estimated in silico, and repeated measurements of maternal steady and pulsatile blood pressure indicators during pregnancy. Results At the site-specific level, no significant association was found between maternal blood pressure and DNA methylation levels after correction for multiple testing (false discovery rate < 0.05), but 5 out of 24 previously found CpG associations were replicated (p-value < 0.05). At the regional level, our analyses highlighted 64 differentially methylated regions significantly associated with at least one blood pressure component, including 35 regions associated with mean arterial pressure levels during late pregnancy. These regions were found enriched for genes implicated in lung development and diseases. Further mediation analyses show that a significant part of the association between steady blood pressure—but not pulsatile pressure—and placental methylation can be explained by alterations in placental cell-type composition. In particular, elevated blood pressure levels are associated with a decrease in the ratio between mesenchymal stromal cells and syncytiotrophoblasts, even in the absence of preeclampsia. Conclusions This study provides the first evidence that the association between maternal steady blood pressure during pregnancy and placental DNA methylation is both direct and partly explained by changes in cell-type composition. These results could hint at molecular mechanisms linking maternal hypertension to lung development and early origins of childhood respiratory problems and at the importance of controlling maternal blood pressure during pregnancy.

Abstract The objective of this study was to determine the relationship between maternal pre-pregnancy body mass index (BMI) and child hyperactivity-inattention symptoms (HIS) at 5 years, including preterm and term-born children, and to determine whether this association varied with gestational age. Maternal pre-pregnancy BMI and offspring HIS were assessed in 10,898 participants born ≥ 33 weeks of gestation from the ELFE cohort and 2646 children born between 23 and 34 weeks from the EPIPAGE 2 cohort. Reported pre-pregnancy weight (kg) and measured height (m) were collected from mothers at inclusion and used to classify BMI (kg/m2). Child HIS were evaluated using the Strengths and Difficulties Questionnaire around 5 years of age. Logistic regression estimated odds ratios (OR) of a high HIS score (≥ 90th percentile) in the ELFE cohort and generalized estimated equations were used in EPIPAGE 2 to account for non-independence of multiple births. As a negative control, paternal BMI was also considered as an exposure of interest in sensitivity analyses. Maternal pre-pregnancy obesity and overweight were associated with child HIS at 5 years in ELFE (adjusted OR [aOR] for obesity 1.27 [1.06, 1.53]; overweight aOR 1.16 [1.00, 1.36]) and pre-pregnancy obesity was associated with high HIS scores in preterm infants of EPIPAGE 2 (aOR 1.48 [1.06, 2.08]). In ELFE, the magnitude of the association increased with decreasing gestational age (interaction p = 0.02). High maternal pre-pregnancy BMI is associated with greater likelihood of high HIS scores in both at-term and preterm children at 5 years of age.

The preconception period represents an important window for foetal 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. We investigated whether intake of OCM nutrients in the year before pregnancy was associated with placental DNA methylation in the EDEN mother–child cohort. 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. 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. In mainly well-nourished French women without major deficiencies, OCM intake before pregnancy was not associated with major variation in DNA methylation.

IntroductionHigh prevalence of overweight and obesity already observed in preschool children suggests the involvement of early-life risk factors. Preconception period and pregnancy are crucial windows for the implementation of child obesity prevention interventions with parental lifestyle factors as relevant targets. So far, most studies have evaluated their role separately, with only a few having investigated their potential synergistic effect on childhood obesity. Our objective was to investigate parental lifestyle patterns in the preconception and pregnancy periods and their association with the risk of child overweight after 5 years.Materials and methodsWe harmonized and interpreted results from four European mother-offspring cohorts participating in the EndObesity Consortium [EDEN, France; Elfe, France; Lifeways, Ireland; and Generation R, Netherlands] with data available for 1,900, 18,000, 1,100, and 9,500 families, respectively. Lifestyle factors were collected using questionnaires and included parental smoking, body mass index (BMI), gestational weight gain, diet, physical activity, and sedentary behavior. We applied principal component analyses to identify parental lifestyle patterns in preconception and pregnancy. Their association with risk of overweight (including obesity; OW-OB) and BMI z-scores between 5 and 12 years were assessed using cohort-specific multivariable logistic and linear and regression models (adjusted for potential confounders including parental age, education level, employment status, geographic origin, parity, and household income).ResultsAmong the various lifestyle patterns derived in all cohorts, the two explaining the most variance were characterized by (1) “high parental smoking, low maternal diet quality (and high maternal sedentary behavior in some cohorts)” and, (2) “high parental BMI and low gestational weight gain.” Patterns characterized by high parental BMI, smoking, low diet quality or high sedentary lifestyle before or during pregnancy were associated with higher risk of OW-OB in children, and BMI z-score at any age, with consistent strengths of associations in the main cohorts, except for lifeways.ConclusionThis project provides insight into how combined parental lifestyle factors in the preconception and pregnancy periods are associated with the future risk of child obesity. These findings are valuable to inform family-based and multi-behavioural child obesity prevention strategies in early life.

[This corrects the article DOI: 10.1371/journal.pmed.1004036.].

BackgroundPreterm birth is the leading cause of perinatal morbidity and mortality and is associated with adverse developmental and long-term health outcomes, including several cardiometabolic risk factors and outcomes. However, evidence about the association of preterm birth with later body size derives mainly from studies using birth weight as a proxy of prematurity rather than an actual length of gestation. We investigated the association of gestational age (GA) at birth with body size from infancy through adolescence.Methods and findingsWe conducted a two-stage individual participant data (IPD) meta-analysis using data from 253,810 mother-child dyads from 16 general population-based cohort studies in Europe (Denmark, Finland, France, Italy, Norway, Portugal, Spain, the Netherlands, United Kingdom), North America (Canada), and Australasia (Australia) to estimate the association of GA with body mass index (BMI) and overweight (including obesity) adjusted for the following maternal characteristics as potential confounders: education, height, prepregnancy BMI, ethnic background, parity, smoking during pregnancy, age at child's birth, gestational diabetes and hypertension, and preeclampsia. Pregnancy and birth cohort studies from the LifeCycle and the EUCAN-Connect projects were invited and were eligible for inclusion if they had information on GA and minimum one measurement of BMI between infancy and adolescence. Using a federated analytical tool (DataSHIELD), we fitted linear and logistic regression models in each cohort separately with a complete-case approach and combined the regression estimates and standard errors through random-effects study-level meta-analysis providing an overall effect estimate at early infancy (>0.0 to 0.5 years), late infancy (>0.5 to 2.0 years), early childhood (>2.0 to 5.0 years), mid-childhood (>5.0 to 9.0 years), late childhood (>9.0 to 14.0 years), and adolescence (>14.0 to 19.0 years). GA was positively associated with BMI in the first decade of life, with the greatest increase in mean BMI z-score during early infancy (0.02, 95% confidence interval (CI): 0.00; 0.05, p < 0.05) per week of increase in GA, while in adolescence, preterm individuals reached similar levels of BMI (0.00, 95% CI: -0.01; 0.01, p 0.9) as term counterparts. The association between GA and overweight revealed a similar pattern of association with an increase in odds ratio (OR) of overweight from late infancy through mid-childhood (OR 1.01 to 1.02) per week increase in GA. By adolescence, however, GA was slightly negatively associated with the risk of overweight (OR 0.98 [95% CI: 0.97; 1.00], p 0.1) per week of increase in GA. Although based on only four cohorts (n = 32,089) that reached the age of adolescence, data suggest that individuals born very preterm may be at increased odds of overweight (OR 1.46 [95% CI: 1.03; 2.08], p < 0.05) compared with term counterparts. Findings were consistent across cohorts and sensitivity analyses despite considerable heterogeneity in cohort characteristics. However, residual confounding may be a limitation in this study, while findings may be less generalisable to settings in low- and middle-income countries.ConclusionsThis study based on data from infancy through adolescence from 16 cohort studies found that GA may be important for body size in infancy, but the strength of association attenuates consistently with age. By adolescence, preterm individuals have on average a similar mean BMI to peers born at term.

Abstract Background Integrated patterns of energy balance-related behaviours of preschool children in Asia are sparse, with few comparative analyses. Purpose Using cohorts in Singapore (GUSTO) and France (EDEN), we characterized lifestyle patterns of children and investigated their associations with family-focused contextual factors. Methods Ten behavioural variables related to child’s diet, walking, outdoor play and screen time were ascertained by parental questionnaires at age 5–6 years. Using principal component analysis, sex-specific lifestyle patterns were derived independently for 630 GUSTO and 989 EDEN children. Contextual variables were organised into distal (family socio-economics, demographics), intermediate (parental health, lifestyle habits) and proximal (parent-child interaction factors) levels of influence and analysed with hierarchical linear regression. Results Three broadly similar lifestyle patterns were identified in both cohorts: “discretionary consumption and high screen time”, “fruit, vegetables, and low screen time” and “high outdoor playtime and walking”. The latter two patterns showed small differences between cohorts and sexes. The “discretionary consumption and high screen time” pattern was consistently similar in both cohorts; distal associated factors were lower maternal education (EDEN boys), no younger siblings (GUSTO boys) and Malay/Indian ethnicity (GUSTO), while intermediate and proximal associated factors in both cohorts and sexes were poor maternal diets during pregnancy, parents allowing high child control over food intake, snacking between meals and having television on while eating. Conclusions Three similar lifestyle patterns were observed among preschool children in Singapore and France. There were more common associated proximal factors than distal ones. Cohort specific family-focused contextual factors likely reflect differences in social and cultural settings. Findings will aid development of strategies to improve child health.

The placenta is a key organ for fetal and brain development. Its epigenome can be regarded as a biochemical record of the prenatal environment and a potential mechanism of its association with the future health of the fetus. We investigated associations between placental DNA methylation levels and child behavioral and emotional difficulties, assessed at 3 years of age using the Strengths and Difficulties Questionnaire (SDQ) in 441 mother–child dyads from the EDEN cohort. Hypothesis-driven and exploratory analyses (on differentially methylated probes (EWAS) and regions (DMR)) were adjusted for confounders, technical factors, and cell composition estimates, corrected for multiple comparisons, and stratified by child sex. Hypothesis-driven analyses showed an association of cg26703534 (AHRR) with emotional symptoms, and exploratory analyses identified two probes, cg09126090 (intergenic region) and cg10305789 (PPP1R16B), as negatively associated with peer relationship problems, as well as 33 DMRs, mostly positively associated with at least one of the SDQ subscales. Among girls, most associations were seen with emotional difficulties, whereas in boys, DMRs were as much associated with emotional than behavioral difficulties. This study provides the first evidence of associations between placental DNA methylation and child behavioral and emotional difficulties. Our results suggest sex-specific associations and might provide new insights into the mechanisms of neurodevelopment.

Research suggests that maternal exposure to natural environments (i.e., green and blue spaces) promotes healthy fetal growth. However, the available evidence is heterogeneous across regions, with very few studies on the effects of blue spaces. This study evaluated associations between maternal exposure to natural environments and birth outcomes in 11 birth cohorts across nine European countries. This study, part of the LifeCycle project, was based on a total sample size of 69,683 newborns with harmonised data. For each participant, we calculated seven indicators of residential exposure to natural environments: surrounding greenspace in 100m, 300m, and 500m using Normalised Difference Vegetation Index (NDVI) buffers, distance to the nearest green space, accessibility to green space, distance to the nearest blue space, and accessibility to blue space. Measures of birth weight and small for gestational age (SGA) were extracted from hospital records. We used pooled linear and logistic regression models to estimate associations between exposure to the natural environment and birth outcomes, controlling for the relevant covariates. We evaluated the potential effect modification by socioeconomic status (SES) and region of Europe and the influence of ambient air pollution on the associations. In the pooled analyses, residential surrounding greenspace in 100m, 300m, and 500m buffer was associated with increased birth weight and lower odds for SGA. Higher residential distance to green space was associated with lower birth weight and higher odds for SGA. We observed close to null associations for accessibility to green space and exposure to blue space. We found stronger estimated magnitudes for those participants with lower educational levels, from more deprived areas, and living in the northern European region. Our associations did not change notably after adjustment for air pollution. These findings may support implementing policies to promote natural environments in our cities, starting in more deprived areas.

Maternal smoking during pregnancy contributes to poor birth outcomes. Here the authors perform a meta-analysis of the associations between maternal smoking during pregnancy and placental DNA methylation and identify links between these and poor birth outcomes, which may better inform the mechanisms through which smoking impacts placental function and fetal growth.

Abstract 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.

Background: Urban environmental design is increasingly considered influential for health and wellbeing, but evidence is mostly based on adults and single exposure studies. We evaluated the association between a wide range of urban environment characteristics and health behaviours in childhood. Methods: We estimated exposure to 32 urban environment characteristics (related to the built environment, traffic, and natural spaces) for home and school addresses of 1,581 children aged 6–11 years from six European cohorts. We collected information on health behaviours including total amount of overall moderate-to-vigorous physical activity, physical activity outside school hours, active transport, sedentary behaviours and sleep duration, and developed patterns of behaviours with principal component analysis. We used an exposure-wide association study to screen all exposure-outcome associations, and the deletion-substitution-addition algorithm to build a final multi-exposure model. Results: In multi-exposure models, green spaces (Normalized Difference Vegetation Index, NDVI) were positively associated with active transport, and inversely associated with sedentary time (22.71 min/day less (95 %CI −39.90, −5.51) per interquartile range increase in NDVI). Residence in densely built areas was associated with more physical activity and less sedentary time, and densely populated areas with less physical activity outside school hours and more sedentary time. Presence of a major road was associated with lower sleep duration (-4.80 min/day (95 %CI −9.11, −0.48); compared with no major road). Results for the behavioural patterns were similar. Conclusions: This multicohort study suggests that areas with more vegetation, more building density, less population density and without major roads are associated with improved health behaviours in childhood.

Abstract Studies in children have reported associations of screen time and background TV on language skills as measured by their parents. However, few large, longitudinal studies have examined language skills assessed by trained psychologists, which is less prone to social desirability. We assessed screen time and exposure to TV during family meals at ages 2, 3 and 5–6 years in 1562 children from the French EDEN cohort. Language skills were evaluated by parents at 2 years (Communicative Development Inventory, CDI) and by trained psychologists at 3 (NEPSY and ELOLA batteries) and 5–6 years (verbal IQ). Cross-sectional and longitudinal associations were assessed by linear regression adjusted for important confounders. Overall, daily screen time was not associated with language scores, except in cross-sectional at age 2 years, where higher CDI scores were observed for intermediate screen time. Exposure to TV during family meals was consistently associated with lower language scores: TV always on (vs never) at age 2 years was associated with lower verbal IQ (− 3.2 [95% IC: − 6.0, − 0.3] points), independent of daily screen time and baseline language score. In conclusion, public health policies should better account for the context of screen watching, not only its amount.

Abstract Refractive errors are common, especially in children and adolescents, leading to global health issues, academic implications and economic costs. Circadian rhythm and sleep habits may play a role. The study included 1130 children from the EDEN birth-cohort. Data were collected through parental questionnaires at age 2 and 5 for sleep duration and timing, and at age 5 for refractive error. At 5 years, 20.4% were prescribed glasses (2% for myopia, 11.9% for hyperopia and 6.8% for unknown reason). Children slept on average (SD) 11h05/night (± 30 min) and 10h49/night (± 48 min) at age 2 and 5, respectively. Average bedtime and midsleep was 8.36 pm (± 30 min), 2.06 am (± 36 min), and 8.54 pm (± 30 min), 2.06 am (± 24 min) at age 2 and 5, respectively. A U-shaped association was observed between sleep duration at age 2 and eyeglass prescription at age 5. Later midsleep and bedtime at age 2 were associated with an increased risk of eyeglass prescription at age 5. Associations became borderline significant after adjustment for confounding factors. Sleep duration and timing at age 2 were associated with subsequent refractive errors in preschoolers from general population. Sleep hygiene might be a target for refractive errors prevention.

Background: Maternal smoking during pregnancy has adverse health effects on the offspring, including lower birth weight and increased risk for obesity. These outcomes are also influenced by common genetic polymorphisms. We aimed to investigate the combined effect of maternal smoking during pregnancy and genetic predisposition on birth weight and body mass index (BMI)-related traits in 1,086 children of the Human Early Life Exposome (HELIX) project.Methods: Maternal smoking during pregnancy was self-reported. Phenotypic traits were assessed at birth or at the age of 8 years. Ten polygenic risk scores (PRSs) per trait were calculated using the PRSice v2 program. For birth weight, we estimated two sets of PRSs based on two different base GWAS summary statistics: PRS-EGG, which includes HELIX children, and PRS-PanUK, which is completely independent. The best PRS per trait (highest R2) was selected for downstream analyses, and it was treated in continuous or categorized into three groups. Multivariate linear regression models were applied to evaluate the association of the explanatory variables with the traits of interest. The combined effect was evaluated by including an interaction term in the regression models and then running models stratified by the PRS group.Results: BMI-related traits were correlated among them but not with birth weight. A similar pattern was observed for their PRSs. On average, the PRSs explained ∼4% of the phenotypic variation, with higher PRS values related to higher trait values (p-value 0.237).Conclusion: Sustained maternal smoking and the PRSs were independently associated with birth weight and childhood BMI-related traits. There was low evidence of GxE interactions.

Sleep is essential for optimal child development and health during the life course. However, sleep disturbances are common in early childhood and increase the risk of cognitive, metabolic and inflammatory disorders throughout life. Sleep and immunity are mutually linked, and cytokines secreted by immune cells could mediate this interaction. The sleep modulation of cytokines has been studied mostly in adults and adolescents; few studies have focused on school-aged children and none on preschoolers. We hypothesized that night sleep duration affects cytokine levels in preschoolers. In a sample of 687 children from the EDEN French birth cohort, we studied the associations between night sleep duration trajectories from age to 2–5 years old and serum concentrations of four cytokines (Tumor necrosis factor α [TNF-α], Interleukin 6 [IL-6], IL-10, Interferon γ [IFN)-γ] at age 5, adjusting for relevant covariates. As compared with the reference trajectory (≈11h30/night sleep, 37.4% of children), a shorter sleep duration trajectory (

BackgroundEarly childhood may represent an opportune time to commence primordial prevention of cardiovascular disease (CVD, i.e., prevention of risk factors onset), but epidemiological evidence is scarce. We aimed to examine the distribution and parental and early life determinants of ideal cardiovascular health (CVH) in children up to 5 years and to compare the level of cognitive development between children with and without ideal CVH at age 5 years.MethodsUsing data from the Etude sur les déterminants pré et post natals précoces du Développement psychomoteur et de la santé de l'Enfant (EDEN) study, a French population-based mother–child cohort study, CVH was examined in children at 5 years of age based on the American Heart Association CVH metrics (ideal body mass index, physical activity, diet, blood pressure, cholesterol and glucose levels, and passive smoking, considered in sensitivity analysis only). Children were categorized as having ideal (five to six ideal metrics) or non-ideal CVH (

During human childhood, brain development and body growth compete for limited metabolic resources, resulting in a trade-off where energy allocated to brain development can decrease as body growth accelerates. This preregistered study explores the relationship between language skills, serving as a proxy for brain development, and body mass index at three distinct developmental stages, representing different phases of body growth. Longitudinal data from 2002 children in the EDEN mother-child cohort were analyzed using structural equation modeling. Our findings reveal a compelling pattern of associations: girls with a delayed adiposity rebound, signaling slower growth rate, demonstrated better language proficiency at ages 5-6. Importantly, this correlation appears to be specific to language skills and does not extend to nonverbal cognitive abilities. Exploratory analyses show that early environmental factors contributing to enhanced cognitive development, such as higher parental socio-economic status and increased cognitive stimulation, are positively associated with both language skills and the timing of adiposity rebound in girls. Overall, our findings lend support to the existence of an energy allocation trade-off mechanism that appears to prioritize language function over body growth investment in girls.

Abstract 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

Few studies have investigated longitudinal trajectories of child socioemotional and behavioural development in relation to maternal prenatal mental health exposure or taken into consideration of the potential buffering effects of psychological intervention during pregnancy. Using data from 1135 mother–child dyads from the EDEN cohort from the general French population, Group-based trajectory modelling was used to model trajectories of behavioural and emotional characteristics measured at four timepoints via a parent-administered Strengths and Difficulties Questionnaire. Using propensity scores and inverse probability weighting to account for confounding factors, multinomial logistic regressions were used to quantify the associations with maternal symptoms of prenatal depression and anxiety. Stratified analyses were conducted by reporting psychologist and psychiatrist consultations during pregnancy. Compared to those without psychological problems, children of mothers with comorbid anxiety and depression retained a higher probability of following high and intermediate trajectories of emotional problems and a high trajectory of conduct problems throughout childhood. This increased risk was not present in the children of mothers who sought support through a prenatal psychologist or psychiatrist consultation. This article adds to a body of evidence underlining the importance of mental health care for expecting mothers.

Abstract Background Although exposure to cigarette smoking during pregnancy has been associated with alterations of DNA methylation in the cord blood or placental cells, whether such exposure before pregnancy could induce epigenetic alterations in the placenta of former smokers has never been investigated. Methods Our approach combined the analysis of placenta epigenomic (ENCODE) data with newly generated DNA methylation data obtained from 568 pregnant women, the largest cohort to date, either actively smoking during their pregnancy or formerly exposed to tobacco smoking. Results This strategy resulted in several major findings. First, among the 203 differentially methylated regions (DMRs) identified by the epigenome-wide association study, 152 showed “reversible” alterations of DNA methylation, only present in the placenta of current smokers, whereas 26 were also found altered in former smokers, whose placenta had not been exposed directly to cigarette smoking. Although the absolute methylation changes were smaller than those observed in other contexts, such as in some congenital diseases, the observed alterations were consistent within each DMR. This observation was further supported by a demethylation of LINE-1 sequences in the placentas of both current (beta-coefficient (β) (95% confidence interval (CI)), − 0.004 (− 0.008; 0.001)) and former smokers (β (95% CI), − 0.006 (− 0.011; − 0.001)) compared to nonsmokers. Second, the 203 DMRs were enriched in epigenetic marks corresponding to enhancer regions, including monomethylation of lysine 4 and acetylation of lysine 27 of histone H3 (respectively H3K4me1 and H3K27ac). Third, smoking-associated DMRs were also found near and/or overlapping 10 imprinted genes containing regions (corresponding to 16 genes), notably including the NNAT, SGCE/PEG10, and H19/MIR675 loci. Conclusions Our results pointing towards genomic regions containing the imprinted genes as well as enhancers as preferential targets suggest mechanisms by which tobacco could directly impact the fetus and future child. The persistence of significant DNA methylation changes in the placenta of former smokers supports the hypothesis of an “epigenetic memory” of exposure to cigarette smoking before pregnancy. This observation not only is conceptually revolutionary, but these results also bring crucial information in terms of public health concerning potential long-term detrimental effects of smoking in women.

Although an early adiposity rebound (AR) is an established risk factor for later obesity, little is known regarding its determinants, especially modifiable ones. Using data from the French EDEN mother–child cohort (1903 children born in 2003–2006), we aimed to examine the association between diet and activity-related behaviors at 2 years of age and the timing of the AR. Two-year-old children (n = 1138) with parent-reported data on their foods/drinks intake, TV/DVD watching time, outdoor playtime, and with an estimated (via growth modelling) age at AR were included in the present study. Two dietary patterns, labelled 'Nutrient-dense foods' and 'Processed and fast foods', were identified in a previous study. Multivariable linear and logistic regression models were used to assess the association between dietary patterns and activity-related behaviors and, respectively, the age at AR (continuous) and the likelihood of having a very early AR (before 3.6 years for girls and 3.8 years for boys, i.e., below the 10th percentile of sex-specific distribution). A higher score on the ‘Processed and fast foods’ dietary pattern was associated with a higher likelihood of having a very early AR (OR = 1.23; 95% CI: 1.00 to 1.50). No significant association was observed between the ‘Nutrient-dense foods’ dietary pattern, TV/DVD watching and outdoor playing times and the timing of the AR. This finding emphasizes the importance of reducing nutrient-dense and processed foods from the early years of life, and provides further support for early interventions aimed at helping parents establish healthy eating habits for their growing child from the complementary period.

Background: Exposure to phthalates during pregnancy may alter DNA methylation in the placenta, a crucial organ for the growth and development of the fetus. Objectives: We studied associations between urinary concentrations of phthalate biomarkers during pregnancy and placental DNA methylation. Methods: We measured concentrations of 11 phthalate metabolites in maternal spot urine samples collected between 22 and 29 gestational weeks in 202 pregnant women. We analyzed DNA methylation levels in placental tissue (fetal side) collected at delivery. We first investigated changes in global DNA methylation of repetitive elements Alu and LINE-1. We then performed an adjusted epigenome-wide association study using IlluminaHM450 BeadChips and identified differentially methylated regions (DMRs) associated with phthalate exposure. Results: Monobenzyl phthalate concentration was inversely associated with placental methylation of Alu repeats. Moreover, all phthalate biomarkers except for monocarboxy-iso-octyl phthalate and mono(2-ethyl-5-hydroxyhexyl) phthalate were associated with at least one DMR. All but three DMRs showed increased DNA methylation with increased phthalate exposure. The largest identified DMR (22 CpGs) was positively associated with monocarboxy-iso-nonyl phthalate and encompassed heat shock proteins (HSPA1A, HSPA1L). The remaining DMRs encompassed transcription factors and nucleotide exchange factors, among other genes. Conclusions: This is the first description of genome-wide modifications of placental DNA methylation in association with pregnancy exposure to phthalates. Our results suggest epigenetic mechanisms by which exposure to these compounds could affect fetal development. Of interest, four identified DMRs had been previously associated with maternal smoking, which may suggest particular sensitivity of these genomic regions to the effect of environmental contaminants.

Detecting SGA (small for gestational age) during pregnancy improves the fetal and neonatal prognosis. To date, there is no valid antenatal biomarker of SGA used in clinical practice. Maternal circulating DLK1 (delta-like non-canonical notch ligand 1) levels have been shown to be significantly lower in pregnant women at 36 weeks of gestation (WG) who delivered a SGA newborn than in controls. Data in the literature are contradictory on the association between maternal circulating DLK1 levels and placental vascular dysfunction. The objective was to determine if maternal DLK1 levels in the second trimester of pregnancy are predictive of SGA, and to assess whether the measurement of DLK1 levels in maternal blood could be a means to distinguish SGA with placental vascular dysfunction from that due to other causes. We conducted a nested cased-control study within the EDEN mother-child cohort. 193 SGA (birth weight < 10th percentile) and 370 mother-child control (birth weight between the 25th and 75th percentile) matched pairs were identified in the EDEN cohort. Maternal circulating DLK1 levels at 26 WG were significantly lower for children born SGA than for controls (27.7 ± 8.7 ng/mL vs 30.4 ± 10.6 ng/mL, p = 0.001). Maternal blood DLK1 levels in the first quartile (DLK1 < 22.85 ng/mL) were associated with an odds ratio for SGA of 1.98 [1.15 - 3.37]. DLK1 was less predictive of SGA than ultrasound, with an area under the curve of 0.578. Maternal circulating DLK1 levels were not significantly different in cases of SGA with signs of placental vascular dysfunction (n = 63, 27.1 ± 9.2 ng/mL) than in those without placental dysfunction (n = 129, 28.0 ± 8.5 ng/mL, p = 0.53). The level of circulating DLK1 is reduced in the second trimester of pregnancy in cases of SGA at birth, independently of signs of placental vascular dysfunction. However, DLK1 alone cannot predict the risk of SGA.

Background Fetal growth restriction is a major complication of pregnancy and is associated with stillbirth, infant death and child morbidity. Ultrasound monitoring of pregnancy is becoming more common in Africa for fetal growth monitoring in clinical care and research, but many countries have no national growth charts. We evaluated the new international fetal growth standards from INTERGROWTH-21st and WHO in a cohort from southern Benin. Methods Repeated ultrasound and clinical data were collected in women from the preconceptional RECIPAL cohort (241 women with singleton pregnancies, 964 ultrasounds). We modelled fetal biometric parameters including abdominal circumference (AC) and estimated fetal weight (EFW) and compared centiles to INTERGROWTH-21st and WHO standards, using the Bland and Altman method to assess agreement. For EFW, we used INTERGROWTH-21st standards based on their EFW formula (IG21st) as well as a recent update using Hadlock’s EFW formula (IG21hl). Proportions of fetuses with measurements under the 10th percentile were compared. Results Maternal malaria and anaemia prevalence was 43% and 69% respectively and 11% of women were primigravid. Overall, the centiles in the RECIPAL cohort were higher than that of INTERGROWTH-21st and closer to that of WHO. Consequently, the proportion of fetuses under 10th percentile thresholds was systematically lower when applying IG21st compared to WHO standards. At 27–31 weeks and 33–38 weeks, respectively, 7.4% and 5.6% of fetuses had EFW Conclusion Despite high anemia and malaria prevalence in the cohort, IG21st and WHO standards did not identify higher than expected proportions of fetuses under the 10th percentiles of ultrasound parameters or EFW. The proportions of fetuses under the 10th percentile threshold for IG21st charts were particularly low, raising questions about its use to identify growth-restricted fetuses in Africa.

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.

Abstract 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

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.

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.