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Background: Growth monitoring of apparently healthy children aims at early detection of serious conditions through the use of both clinical expertise and algorithms that define abnormal growth. Optimization of growth monitoring requires standardization of the definition of abnormal growth, and the selection of the priority target conditions is a prerequisite of such standardization., Objective: To obtain a consensus about the priority target conditions for algorithms monitoring children's growth., Methods: We applied a formal consensus method with a modified version of the RAND/UCLA method, based on three phases (preparatory, literature review, and rating), with the participation of expert advisory groups from the relevant professional medical societies (ranging from primary care providers to hospital subspecialists) as well as parent associations. We asked experts in the pilot (n = 11), reading (n = 8) and rating (n = 60) groups to complete the list of diagnostic classification of the European Society for Paediatric Endocrinology and then to select the conditions meeting the four predefined criteria of an ideal type of priority target condition., Results: Strong agreement was obtained for the 8 conditions selected by the experts among the 133 possible: celiac disease, Crohn disease, craniopharyngioma, juvenile nephronophthisis, Turner syndrome, growth hormone deficiency with pituitary stalk interruption syndrome, infantile cystinosis, and hypothalamic-optochiasmatic astrocytoma (in decreasing order of agreement)., Conclusion: This national consensus can be used to evaluate the algorithms currently suggested for growth monitoring. The method used for this national consensus could be re-used to obtain an international consensus.

Objectives: To assess the predictive value of the 36-month Ages & Stages Questionnaire (ASQ) score for IQ score at age 5 to 6 years in the general population and to identify factors associated with IQ <85 once the ASQ score is taken into account., Methods: Data were collected from 939 children enrolled in a population-based prospective cohort study. Developmental outcomes at 36 months were assessed via the ASQ and at 5 to 6 years via the Wechsler Preschool and Primary Scale of Intelligence. The ASQ threshold was identified via the receiver operating characteristic curve. Additional predictive factors to obtain an IQ <85 were investigated, and their interaction with ASQ score was studied., Results: Sixty-nine children (7.3%) had an IQ <85. A 36-month ASQ score threshold of 270 was optimal to identify children with an IQ <85 at 5 to 6 years, with a 0.77 ± 0.11 sensitivity and 0.68 ± 0.03 specificity. Maternal educational level and occupational activity at the time of ASQ completion were associated with the risk of an IQ <85 at a given ASQ level. In the multivariate model, no interaction between the studied factors and ASQ score reached significance., Conclusions: In the general pediatric population, 36-month ASQ parental reports could be used to identify children at later risk of cognitive delay. Low maternal education level should also be considered as a major risk factor for lower IQ in preschool children regardless of ASQ score., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)

Objective: To examine the relationship of polyunsaturated fatty acid (PUFA) in breast milk with children's IQ., Study Design: In the French Etude des Déterminants pré- et postnatals précoces du développement et de la santé de l'Enfant (EDEN) mother-child cohort, colostrum samples were collected at the maternity unit. Colostrum omega-6 and omega-3 PUFA were analyzed by gas chromatography. At age 5-6 years, the IQs of 1080 children were assessed using the Wechsler Preschool and Primary Scale of Intelligence-III. The relationships of breastfeeding duration and PUFA levels with children's IQs were examined by linear regression., Results: Full scale IQ of ever breastfed children was 4.5 (95% CI: 2.7, 6.2) higher than never breastfed children in the unadjusted model, but this was not statistically significant in the adjusted model (1.3 points higher [-0.4, 3.0]). Any breastfeeding duration was associated with full scale (0.20 [0.00, 0.41] points/month) and verbal (0.31 [0.09, 0.52]) IQ. Colostrum linoleic acid (LA) levels were negatively associated with Verbal IQ (-0.6 [-1.1, 0.0] points per 1% level increase). Children exposed to colostrum high in LA and low in docosahexaenoic acid (DHA) had lower IQs than those exposed to colostrum high in DHA (3.0 [0.5, 5.5] points) and those exposed to colostrum low in LA and DHA (4.4 [1.6, 7.3] points). Finally, the association between breastfeeding duration and child IQ was stronger when LA levels were high., Conclusions: Duration of breastfeeding and colostrum PUFA levels were associated with children's IQs in the EDEN cohort. These data support breastfeeding and add evidence for the role of early PUFA exposure on childhood cognition., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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 < 70) and gifted children (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-Lézine 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., (Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Atmospheric pollutants and meteorological conditions are suspected to be causes of preterm birth. We aimed to characterize their possible association with the risk of preterm birth (defined as birth occurring before 37 completed gestational weeks). We pooled individual data from 13 birth cohorts in 11 European countries (71,493 births from the period 1994-2011, European Study of Cohorts for Air Pollution Effects (ESCAPE)). City-specific meteorological data from routine monitors were averaged over time windows spanning from 1 week to the whole pregnancy. Atmospheric pollution measurements (nitrogen oxides and particulate matter) were combined with data from permanent monitors and land-use data into seasonally adjusted land-use regression models. Preterm birth risks associated with air pollution and meteorological factors were estimated using adjusted discrete-time Cox models. The frequency of preterm birth was 5.0%. Preterm birth risk tended to increase with first-trimester average atmospheric pressure (odds ratio per 5-mbar increase = 1.06, 95% confidence interval: 1.01, 1.11), which could not be distinguished from altitude. There was also some evidence of an increase in preterm birth risk with first-trimester average temperature in the -5°C to 15°C range, with a plateau afterwards (spline coding, P = 0.08). No evidence of adverse association with atmospheric pollutants was observed. Our study lends support for an increase in preterm birth risk with atmospheric pressure., (© The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background/objectives: Few studies have examined the factors explaining the variability in fat and carbohydrate intake during infancy. We aimed to describe infants' fat and carbohydrate intake and analyse the associations with infant and maternal characteristics and feeding practices., Subjects/methods: This study included 1275 infants aged 8 months from the French EDEN mother-child cohort. Carbohydrate intake, fat intake, added fat (vegetable oils and animal fats) and added sugar (honey, white sugar, brown sugar, jam and sweetened beverages) consumption were calculated at 8 and 12 months. Associations between these variables and infant and maternal characteristics as well as maternal dietary patterns during pregnancy, breast-feeding duration and age at complementary feeding introduction were analysed using multivariable linear and logistic regressions., Results: Less than 5% of non-breast-fed infants reached the recommendation of consuming at least 40% of total energy from fat, whereas more than 95% of them reached 45% of energy from carbohydrates. Overall, infant and maternal characteristics and maternal diet during pregnancy were marginally associated with both carbohydrate/added sugar and fat/added fat intake. Nevertheless, age at complementary feeding introduction was associated with all outcomes., Conclusions: Our results suggest that only a small proportion of non-breast-fed infants at 8 and 12 months reached the recommendations for fat intake, whereas a majority of them reached the recommendations for carbohydrate intake. As subgroups of infants with a higher risk of inadequate diet were not identified, the present results call for an improved dissemination of information regarding infant-specific dietary fat needs in the entire population.

Background: This study assessed the association between timing and course of maternal depression from pregnancy onwards and children's cognitive development at ages 5 to 6. Potential interaction effects with child sex and family socioeconomic status were explored., Methods: One thousand thirty-nine mother-child pairs from the French EDEN mother-child birth cohort were followed from 24 to 28 weeks of pregnancy onwards. Based on Center for Epidemiological Studies Depression (CES-D) and Edinburgh Postnatal Depression Scale (EPDS) scores assessed at six timepoints, longitudinal maternal depressive symptom trajectories were calculated with a group-based semiparametric method. Children's cognitive function was assessed at ages 5 to 6 by trained interviewers with the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III), resulting in three composite scores: Verbal IQ (VIQ), Performance IQ (PIQ), and Full-Scale IQ (FSIQ)., Results: Five trajectories of maternal symptoms of depression could be distinguished: no symptoms, persistent intermediate-level depressive symptoms, persistent high depressive symptoms, high symptoms in pregnancy only, and high symptoms in the child's preschool period only. Multiple linear regression analyses showed that, compared to children of mothers who were never depressed, children of mothers with persistent high levels of depressive symptoms had reduced VIQ, PIQ, and FSIQ scores. This association was moderated by the child's sex, boys appearing especially vulnerable in case of persistent maternal depression., Conclusions: Chronicity of maternal depression predicts children's cognitive development at school entry age, particularly in boys. As maternal mental health is an early modifiable influence on child development, addressing the treatment needs of depressed mothers may help reduce the associated burden on the next generation., (© 2016 Wiley Periodicals, Inc.)

Background/objectives: Sedentary behavior, physical activity and dietary behavior are formed early during childhood and tend to remain relatively stable into later life. No longitudinal studies have assessed the independent influence of these three energy balance-related behaviors during toddlerhood on later adiposity. We aimed to analyze the associations between TV/DVD watching time, outdoor play time and dietary patterns at the age of 2 years and child adiposity at the age of 5 years, in boys and girls separately., Subjects/methods: This study included 883 children from the French EDEN mother-child cohort. TV/DVD watching time, outdoor play time and dietary intakes were reported by parents in questionnaires when the child was aged 2 years. Two dietary patterns, labeled 'Guidelines' and 'Processed, fast foods', were identified in a previous study. The percentage of body fat (%BF) based on bioelectrical impedance analysis and body mass index were measured at the age of 5 years., Results: In boys, TV/DVD watching time at the age of 2 years was positively associated with %BF at the age of 5 years (β=0.50 (95% confidence interval: 0.001, 1.00) for those boys with ⩾60 min per day of TV/DVD watching time vs those with ⩽15 min per day, P-value for trend 0.05). In girls, outdoor play was inversely associated with %BF (β=-0.96 (95% confidence interval: -1.60, -0.32) for those in the highest tertile of outdoor play time vs those in the lowest tertile, P=0.001). Overall, at the age of 2 years, dietary patterns were associated with both TV/DVD watching time and outdoor play time, but no significant and independent association was observed between dietary patterns and later adiposity., Conclusion: This study shows longitudinal and gender-differentiated relations between both TV/DVD watching time and outdoor play time in toddlerhood and later adiposity, whereas evidence for a relation between dietary patterns and subsequent fat development was less conclusive. Early childhood-by the age of 2 years-should be targeted as a critical time for promoting healthy energy balance-related behaviors.

Background: Breastfeeding is associated with multiple domains of health for both mothers and children. Nevertheless, breastfeeding initiation is low within certain developed countries. Furthermore, comparative studies of initiation rates using harmonised data across multiple regions is scarce., Objective: The aim of the present study was to investigate and compare individual-level determinants of breastfeeding initiation using two French-speaking cohorts., Methods: Participants included ~ 3,900 mothers enrolled in two cohort studies in Canada and France. Interviews, questionnaires, and medical records were utilised to collect information on maternal, family, and medical factors associated with breastfeeding initiation., Results: Rates of breastfeeding initiation were similar across cohorts, slightly above 70%. Women in both Canada and France who had higher levels of maternal education, were born outside of their respective countries and who did not smoke during pregnancy were more likely to initiate breastfeeding with the cohort infant. Notably, cohort effects of maternal education at the university level were found, whereby having 'some university' was not statistically significant for mothers in France. Further, younger mothers in Canada, who delivered by caesarean section and who had previous children, had reduced odds of breastfeeding initiation. These results were not found for mothers in France., Conclusions and Implications for Practice: While some similar determinants were observed, programming efforts to increase breastfeeding initiation should be tailored to the characteristics of specific geographical regions which may be heavily impacted by the social, cultural and political climate of the region, in addition to individual and family level factors., Competing Interests: The authors have declared that no competing interests exist.

Night waking in preschoolers has been associated with adverse health outcomes in cross-sectional studies, but has rarely been analyzed in a longitudinal setting. Therefore, little is known about the evolution of night waking in early childhood. The objectives of the present study were: to identify night-waking trajectories in preschoolers, and to examine the risk factors associated with those trajectories. Analyses were based on the French birth-cohort study EDEN, which recruited 2002 pregnant women between 2003 and 2006. Data on a child's night waking at the ages of two, three, and five, six years, and potential confounders, were collected through parental self-reported questionnaires. Night-waking trajectories were computerized using group-based trajectory modeling on 1346 children. Two distinct developmental patterns were identified: the "2-5 rare night-waking" (77% of the children) and the "2-5 common night-waking" pattern. Logistic regressions were performed to identify the factors associated with the trajectories. Risk factors for belonging to the "2-5 common night-waking" trajectory were: exposure to passive smoking at home, daycare in a collective setting, watching television for extended periods, bottle feeding at night, high emotionality, and low shyness. This approach allowed identification of risk factors associated with night waking during a critical age window, and laid the groundwork for identifying children at higher risk of deleterious sleep patterns. Those risk factors were mainly living habits, which indicated that prevention and intervention programs could be highly beneficial in this population., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Evidence from animal studies suggests maternal caffeine intake during pregnancy has detrimental effects on subsequent brain development in offspring. However, human data in this area are limited. The aim of this study was to assess whether caffeine intake by women during pregnancy is associated with impaired cognitive development in offspring at age 5.5 years., Methods: Multivariate modeling was conducted using data of 1083 mother-child pairs from a population-based birth cohort in France followed from pregnancy to age 5.5 years of the children. Measures included an estimate of maternal caffeine intake during pregnancy, children's IQ at age 5.5, and individual and family characteristics., Results: Prenatal caffeine exposure was common in the sample (91%) with 12% displaying an intake ≥200 mg/day (high). Multivariable modeling showed a significant negative relationship between caffeine intake and children's IQ at 5.5 years (-.94 [95% confidence interval = -1.70, -.17] full IQ unit per 100 mg daily caffeine intake). In particular, children of mothers consuming ≥200 mg/day were more likely to have borderline or lower IQ compared with children of mothers consuming <100 mg/day (13.5% vs. 7.3%; odds ratio = 2.30, 95% confidence interval = 1.13, 4.69)., Conclusions: We found an association between caffeine intake during pregnancy and impaired cognitive development in offspring, a result in line with animal data. More epidemiologic and biologically grounded research is needed to determine whether this association is causal. This finding suggests that conservative guidelines regarding the maximum caffeine intake recommended in pregnancy (i.e., 200 mg/day) should be maintained., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Physiological evidence suggests that birth weight (BW) and postnatal growth affect blood pressure (BP) level, independently or in interaction. Their respective roles are difficult to disentangle in epidemiological studies, however, especially when adjusting for final weight. We assessed the portion of the effect of BW on BP at 5 years that was not attributable to postnatal growth and investigated potential interactions between BW and postnatal growth velocity at different time points in the EDEN mother-child study. Collecting a median of 19 weight measurements for each of the 1119 children who completed follow-up enabled us to model instantaneous growth velocity at any age. After computing a BP SD-score at 5 years, adjusted for age, sex, current body mass index, and height, we used multiple linear regression to study its association with age- and sex-specific BW z score, adjusting for several maternal and pregnancy risk factors. We tested interactions between BW categories (small-, appropriate-, and large-for-gestational-age) and weight growth velocities at different ages. The BW z score was negatively and significantly correlated with the systolic BP SD-score at the age of 5 years (r=-0.07, P=0.02). Interactions were found between BW categories and weight growth velocities from 1 to 4 months (P from 0.002 to 0.08) but not at older ages; specifically, children born small for gestational age with a fast weight growth velocity in their first few months of life had the highest absolute systolic BP and SD score values at 5 years. They may need monitoring for cardiovascular risks., (© 2016 American Heart Association, Inc.)

Objective: To investigate risk factors specific to posterior crossbite and anterior open bite at the age of 3 years., Materials and Methods: The study included 422 children of the French EDEN mother-child cohort. The main outcomes were the presence of posterior crossbite and anterior open bite assessed by dentists at 3 years. Social characteristics (collected during pregnancy), neonatal characteristics (collected at birth), duration of breast-feeding (collected prospectively), sucking habits at 3 years, and open lips (as a proxy for mouth breathing) were studied and two logistic regressions conducted., Results: Preterm birth appears to be a risk factor specific for posterior crossbite (OR: 3.13; 95% CI: 1.13-8.68), whereas small for gestational age seems to be associated with a lower risk of posterior crossbite (OR: 0.32; 95% CI: 0.12-0.87). Ongoing pacifier or thumb sucking at 3 years is a risk factor for both posterior crossbite and anterior open bite., Conclusions: Children born preterm seem to be more at risk for posterior crossbite than those born at term. Different mechanisms may be involved in posterior crossbite and anterior open bite.

During pregnancy, the placenta ensures multiple functions, which are directly involved in the initiation, fetal growth and outcome of gestation. The placental tissue involved in maternal-fetal exchanges and in synthesis of pregnancy hormones is the mononucleated villous cytotrophoblast (VCT) which aggregates and fuses to form and renew the syncytiotrophoblast (ST). Knowledge of the gene expression pattern specific to this endocrine and exchanges tissue of human placenta is of major importance to understand functions of this heterogeneous and complex tissue. Therefore, we undertook a global analysis of the gene expression profiles of primary cultured-VCT (n = 6) and in vitro-differentiated-ST (n = 5) in comparison with whole term placental tissue from which mononucleated VCT were isolated. A total of 880 differentially expressed genes (DEG) were observed between VCT/ST compared to whole placenta, and a total of 37 and 137 genes were significantly up and down-regulated, respectively, in VCT compared to ST. The 37 VCT-genes were involved in cellular processes (assembly, organization, and maintenance), whereas the 137 ST-genes were associated with lipid metabolism and cell morphology. In silico, all networks were linked to 3 transcriptional regulators (PPARγ, RARα and NR2F1) which are known to be essential for trophoblast differentiation. A subset of six DEG was validated by RT-qPCR and four by immunohistochemistry. To conclude, recognition of these pathways is fundamental to increase our understanding of the molecular basis of human trophoblast differentiation. The present study provides for the first time a gene expression signature of the VCT and ST compared to their originated term human placental tissue., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: The aim of the study was to examine the relationship between social withdrawal behaviour at one year and motor and language milestones., Materials and Methods: One-year old children from the EDEN French population-based birth cohort study (Study on the pre- and postnatal determinants of the child's development and prospective health Birth Cohort Study) were included. Social withdrawal at one year was assessed by trained midwives using the Alarm Distress BaBy (ADBB) scale. Midwives concurrently examined infants' motor and language milestones. Parents reported on child's psychomotor and language milestones, during the interview with the midwife., Results: After adjusting for potential confounding factors, social withdrawal behaviour was significantly associated with concurrent delays in motor and language milestones assessed by the midwife or the parents., Discussion: Higher scores on social withdrawal behaviour as assessed with the ADBB were associated with delays in reaching language milestones, and to a lesser extent with lower motor ability scores. Taking the contribution of social withdrawal behaviour into account may help understand the unfolding of developmental difficulties in children.

Background: Accurately characterizing children's body mass index (BMI) trajectories and studying their determinants is a statistical challenge. There is a need to identify early public health measures for obesity prevention. We describe a method that allows studies of the determinants of height, weight and BMI growth up to five years of age. We illustrated this method using maternal smoking during pregnancy as one of the early-life factors that is potentially involved in prenatal programming of obesity., Methods: Individual height and weight trajectories were fitted using the Jenss-Bayley model on 28,381 and 30,515 measurements, respectively, from 1,666 children to deduce BMI trajectories. We assessed global associations between smoking and growth trajectories and cross-sectional associations at specific ages., Results: Children exposed in late pregnancy had a 0.24 kg/m2 (95% confidence interval: 0.07, 0.41) higher BMI at 5 years of age compared with non-exposed children. Although the BMIs of children exposed during late pregnancy became significantly higher compared with those of non-exposed children from 2 years onwards, the trajectories began to diverge during the first weeks of life., Conclusion: Our method is relevant for studies on the relationships between individual-level exposures and the dynamics and shapes of BMI growth during childhood, including key features such as instantaneous growth velocities and the age or BMI value at the BMI infancy peak that benefit from the monotonic pattern of height and weight growth.

Growth monitoring of apparently healthy children aims at early detection of serious underlying disorders. However, existing growth-monitoring practices are mainly based on suboptimal methods, which can result in delayed diagnosis of severe diseases and inappropriate referrals. We did a systematic review to address two key and interconnected questions underlying growth monitoring: which conditions should be targeted, and how should abnormal growth be defined? We systematically searched for studies reporting algorithms for growth monitoring in children and studies comparing the performance of new WHO growth charts with that of other growth charts. Among 1556 identified citations, 69 met the inclusion criteria. Six target conditions have mainly been studied: Turner syndrome, coeliac disease, cystic fibrosis, growth hormone deficiency, renal tubular acidosis, and small for gestational age with no catch-up after 2 or 3 years. Seven algorithms to define abnormal growth have been proposed in the past 20 years, but their level of validation is low, and their overall sensitivities and specificities vary substantially; however, the Grote and Saari clinical decision rules seem the most promising. Two studies reported that WHO growth charts had poorer performance compared with other existing growth charts for early detection of target conditions. Available data suggest a large gap between the widespread implementation of growth monitoring and its level of evidence or the clinical implications of early detection of serious disorders in children. Further investigations are needed to standardise the practice of growth monitoring, with a consensus on a few priority target conditions and with internationally validated clinical decision rules to define abnormal growth, including the selection of appropriate growth charts., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure., (Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Children born preterm or with a small size for gestational age are at increased risk for childhood asthma., Objective: We sought to assess the hypothesis that these associations are explained by reduced airway patency., Methods: We used individual participant data of 24,938 children from 24 birth cohorts to examine and meta-analyze the associations of gestational age, size for gestational age, and infant weight gain with childhood lung function and asthma (age range, 3.9-19.1 years). Second, we explored whether these lung function outcomes mediated the associations of early growth characteristics with childhood asthma., Results: Children born with a younger gestational age had a lower FEV1, FEV1/forced vital capacity (FVC) ratio, and forced expiratory volume after exhaling 75% of vital capacity (FEF75), whereas those born with a smaller size for gestational age at birth had a lower FEV1 but higher FEV1/FVC ratio (P < .05). Greater infant weight gain was associated with higher FEV1 but lower FEV1/FVC ratio and FEF75 in childhood (P < .05). All associations were present across the full range and independent of other early-life growth characteristics. Preterm birth, low birth weight, and greater infant weight gain were associated with an increased risk of childhood asthma (pooled odds ratio, 1.34 [95% CI, 1.15-1.57], 1.32 [95% CI, 1.07-1.62], and 1.27 [95% CI, 1.21-1.34], respectively). Mediation analyses suggested that FEV1, FEV1/FVC ratio, and FEF75 might explain 7% (95% CI, 2% to 10%) to 45% (95% CI, 15% to 81%) of the associations between early growth characteristics and asthma., Conclusions: Younger gestational age, smaller size for gestational age, and greater infant weight gain were across the full ranges associated with childhood lung function. These associations explain the risk of childhood asthma to a substantial extent., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Importance: Maternal fish intake in pregnancy has been shown to influence fetal growth. The extent to which fish intake affects childhood growth and obesity remains unclear., Objective: To examine whether fish intake in pregnancy is associated with offspring growth and the risk of childhood overweight and obesity., Design, Setting, and Participants: Multicenter, population-based birth cohort study of singleton deliveries from 1996 to 2011 in Belgium, France, Greece, Ireland, Italy, the Netherlands, Norway, Poland, Portugal, Spain, and Massachusetts. A total of 26,184 pregnant women and their children were followed up at 2-year intervals until the age of 6 years., Exposures: Consumption of fish during pregnancy., Main Outcomes and Measures: We estimated offspring body mass index percentile trajectories from 3 months after birth to 6 years of age. We defined rapid infant growth as a weight gain z score greater than 0.67 from birth to 2 years and childhood overweight/obesity at 4 and 6 years as body mass index in the 85th percentile or higher for age and sex. We calculated cohort-specific effect estimates and combined them by random-effects meta-analysis., Results: This multicenter, population-based birth cohort study included the 26,184 pregnant women and their children. The median fish intake during pregnancy ranged from 0.5 times/week in Belgium to 4.45 times/week in Spain. Women who ate fish more than 3 times/week during pregnancy gave birth to offspring with higher body mass index values from infancy through middle childhood compared with women with lower fish intake (3 times/week or less). High fish intake during pregnancy (>3 times/week) was associated with increased risk of rapid infant growth, with an adjusted odds ratio (aOR) of 1.22 (95% CI, 1.05-1.42) and increased risk of offspring overweight/obesity at 4 years (aOR, 1.14 [95% CI, 0.99-1.32]) and 6 years (aOR, 1.22 [95% CI, 1.01-1.47]) compared with an intake of once per week or less. Interaction analysis showed that the effect of high fish intake during pregnancy on rapid infant growth was greater among girls (aOR, 1.31 [95% CI, 1.08-1.59]) than among boys (aOR, 1.11 [95% CI, 0.92-1.34]; P = .02 for interaction)., Conclusions and Relevance: High maternal fish intake during pregnancy was associated with increased risk of rapid growth in infancy and childhood obesity. Our findings are in line with the fish intake limit proposed by the US Food and Drug Administration and Environmental Protection Agency., Competing Interests: Disclosures: None reported.

Epidemiological researches in the field of DOHaD are in favor of a role of early environment, including chemical (pesticides), physical (air pollution), nutritional or psychosocial environment, on child and adult health. Disentangling the different factors of environment that may affect health, especially over time, and identifying critical periods of exposure remains a major challenge. The biological mechanisms involved remain elusive in human beings. Nevertheless, it seems that whatever the nature of the exposure, epigenetic mechanisms are currently discussed to explain how the environment may alter biological systems over time., (© 2016 médecine/sciences – Inserm.)

Total sleep duration has been decreasing among children in the last decades. Short sleep duration (SSD) has been associated with deleterious health consequences, such as excess weight/obesity. Risk factors for SSD have already been studied among school-aged children and adolescents, but inconsistent results have been reported regarding possible gender differences. Studies reporting such relationships are scarce in preschoolers, despite the importance of this period for adopting healthy behaviour. We aimed to investigate factors associated with SSD in 3-year-old boys (n = 546) and girls (n = 482) in a French Mother-Child Cohort (EDEN Study). Children were born between 2003 and 2006 in two French university hospitals. Clinical examinations and parent self-reported questionnaires allowed us to collect sociodemographic (e.g. income, education, family situation, child-minding system), maternal [e.g. body mass index (BMI), parity, depression, breastfeeding duration] and child's characteristics (e.g. gender, birth weight, term, physical activity and TV viewing duration, food consumption, usual sleep time). Sleep duration/24-h period was calculated and SSD was defined as <12 h. Analyses were performed using logistic regression. The mean sleep duration was 12 h 35 ± 56 min, with 91% of the children napping. Patterns of risk factors associated with SSD differed according to gender. In addition to parental presence when falling asleep, short sleep duration was associated strongly positively with high BMI Z-score and TV viewing duration among boys and with familial home child-minding and lower scores on the 'fruits and vegetables' dietary pattern among girls. These results suggest either a patterning of parental behaviours that differs according to gender, or a gender-specific sleep physiology, or both., (© 2015 European Sleep Research Society.)

The prevalence of childhood obesity has increased dramatically in the second half of the 20th century even in children before the age of 5 years. Many factors may interfere with early development, from the prenatal period to the first two years of life, and modulate susceptibility to subsequent obesity. Regarding the prenatal period, maternal BMI before pregnancy is a factor associated with adult obesity in a very reproducible way. Many studies are also consistent for gestational maternal weight gain and maternal smoking during pregnancy, after adjustment for major potential confounders. More recently, a meta-analysis concluded that caesarean delivery is also a risk marker. For the post natal period, the marker most consistently associated with adult obesity is rapid weight gain during the first months of life. Most studies are negative for breastfeeding. Advances in the genetics of obesity, epigenetics and new knowledge on intestinal microbiota should help decipher the mechanisms behind these associations. Many of these early markers become more frequent during the second half of the 20th century and they may have feed the obesity epidemic in children.

Background: The association between socioeconomic position and diet in early childhood has mainly been addressed based on maternal education and household income. We aimed to assess the influence of a variety of social factors from different socio-ecological levels (parents, household and child-care) on multi-time point dietary patterns identified from 2 to 5 y., Method: This study included 974 children from the French EDEN mother-child cohort. Two multi-time point dietary patterns were derived in a previous study: they correspond to consistent exposures to either core- or non-core foods across 2, 3 and 5 y and were labelled "Guidelines" and "Processed, fast-foods". The associations of various social factors collected during pregnancy (age, education level) or at 2-y follow-up (mother's single status, occupation, work commitments, household financial disadvantage, presence of older siblings and child-care arrangements) with each of the two dietary patterns, were assessed by multivariable linear regression analysis., Results: The adherence to a diet close to "Guidelines" was positively and independently associated with both maternal and paternal education levels. The adherence to a diet consistently composed of processed and fast-foods was essentially linked with maternal variables (younger age and lower education level), household financial disadvantage, the presence of older sibling (s) and being cared for at home by someone other than the mother., Conclusions: Multiple social factors operating at different levels (parents, household, and child-care) were found to be associated with the diet of young children. Different independent predictors were found for each of the two longitudinal dietary patterns, suggesting distinct pathways of influence. Our findings further suggest that interventions promoting healthier dietary choices for young children should involve both parents and take into account not only household financial disadvantage but also maternal age, family size and options for child-care.

Objectives: To evaluate the performance of screening for small-for-gestational-age (SGA) fetuses by ultrasound biometry at 30-35 weeks' gestation, and to determine the impact of screening on obstetric and neonatal outcomes., Methods: For this prospective cohort study, pregnant women were recruited from two French university maternity centers between 2003 and 2006. Performance measures of third-trimester biometry for the prediction of SGA, defined as estimated fetal weight < 10(th) centile, were analyzed. Obstetric outcomes and neonatal health status were compared, first, between SGA neonates diagnosed correctly at ultrasound examination (true positive (TP); n = 45) and SGA neonates that went undiagnosed (false negative (FN); n = 110) and, second, between non-SGA neonates identified as normal at ultrasound examination (true negative (TN); n = 1641) and non-SGA neonates diagnosed incorrectly as SGA (false positive (FP); n = 101)., Results: In the prediction of SGA, third-trimester ultrasound had a sensitivity of 29.0% (95% CI, 22.5-36.6%) and specificity of 94.2% (95% CI, 93.0-95.2%). Positive and negative predictive values were 30.8% (95% CI, 23.9-38.7%) and 93.7% (95% CI, 92.5-94.8%), respectively. One hundred and ten SGA neonates went undiagnosed at ultrasound. Compared to the TN neonates considered as of normal weight at ultrasound, planned preterm delivery (before 37 weeks) and elective Cesarean section for a fetal growth indication were 2.4 (P = 0.01) and 2.85 (P = 0.003) times more likely to occur, respectively, in the FP group of non-SGA neonates, diagnosed incorrectly as SGA during the antenatal period. There was no statistically significant difference in 5-min Apgar score < 7, cord blood pH at birth < 7.15 and need for neonatal resuscitation between the two subgroups (TN vs FP and TP vs FN)., Conclusions: The performance of third-trimester ultrasound screening for SGA seems poor, as it misses the diagnosis of a large number of SGA neonates. The consequences of routine screening for SGA in a low-risk population may lead to unnecessary planned preterm deliveries and elective Cesarean sections in FP pregnancies, without improved neonatal outcome in the FN pregnancies., (Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.)

Background: Breastfeeding has been associated with improved cognitive development. This may be explained by polyunsaturated fatty acid (PUFA) content of breast milk, especially long-chain (LC) PUFA that are needed for postnatal brain growth., Methods: Using data from the French EDEN cohort, we aimed to study whether the PUFA content of colostrum may explain observed associations between breastfeeding duration and cognitive scores at 2 and 3 y. A total of 709 breastfed children with available data on PUFA composition of milk were assessed using parent-reported questionnaires for motor and language at 2 y of age, or global cognition at 3 y. Multiple linear regressions were used to examine associations between PUFA levels and child cognitive scores, after controlling for many confounders., Results: We found no association between LCPUFA levels in colostrum and child development. However, levels of linoleic acid (LA) were negatively associated with motor and cognitive scores, independently of breastfeeding duration. Children breastfed with the highest levels of LA tended to score closer to the never breastfed children than children breastfed with the lowest levels of LA., Conclusion: Our findings suggest that too high levels of LA in colostrum are associated with poorer child development at 2 and 3 y.

Background: Although it has been suggested that dietary patterns emerge early in life, less is known about the extent to which they track through the toddler and preschool ages., Objectives: The objectives of this study were to derive cross-sectional dietary patterns at 2, 3, and 5 y of age and assess their correlations and to derive multi-time point dietary patterns from ages 2-5 y and assess their associations with sociodemographic factors and infant feeding patterns., Methods: Depending on the age considered, analyses included 989-1422 children from the EDEN (Étude des Déterminants pré- et postnatals précoces du développement et de la santé de l'ENfant) mother-child cohort. Dietary intake was collected with the use of food-frequency questionnaires at 2, 3, and 5 y of age. Principal component analyses were applied to these data, first cross-sectionally at each age, then longitudinally accounting for the data collected at all 3 ages. Tracking between patterns was estimated by Spearman correlation coefficients and associations with either the infant feeding patterns or the demographic and socioeconomic factors were assessed with the use of multivariable linear regression analyses., Results: Overall, we derived 2 main cross-sectional patterns labeled "Processed and fast foods" and "Guidelines," the latter being characterized by intakes approximating age-specific dietary guidelines; and 2 multi-time point dietary patterns that corresponded to consistent exposures to similar foods across the 3 ages. The first, labeled "Processed and fast foods at 2, 3, and 5 y," was inversely associated with maternal education and age, and positively associated with the presence of older siblings. The second, called "Guidelines at 2, 3, and 5 y," was predicted by maternal education. Moderate tracking was observed between similar patterns assessed at different ages., Conclusions: Our findings confirmed the emergence of dietary profiles socially differentiated early in life as well as a moderate tracking of the diet. The promotion of healthy dietary trajectories should be encouraged as early as infancy, in particular in the presence of older siblings and among the most socially disadvantaged population groups., (© 2015 American Society for Nutrition.)

Background: Growth charts are an essential clinical tool for evaluating a child's health and development. The current French reference curves, published in 1979, have recently been challenged by the 2006 World Health Organization (WHO) growth charts., Objective: To evaluate and compare the growth of French children who were born between 1981 and 2007, with the WHO growth charts and the French reference curves currently used., Design: Anthropometric measurements from French children, who participated in 12 studies, were analyzed: 82,151 measurements were available for 27,257 children in different age groups, from birth to 18 years. We calculated and graphically compared mean z-scores based on the WHO and French curves, for height, weight and Body Mass Index (BMI) according to age and sex. The prevalence of overweight using the WHO, the French and International Obesity Task Force definitions were compared., Results: Our population of children was on average 0.5 standard deviations taller than the French reference population, from the first month of life until puberty age. Mean z-scores for height, weight and BMI were closer to zero based on the WHO growth charts than on the French references from infancy until late adolescence, except during the first six months. These differences not related to breastfeeding rates. As expected, the prevalence of overweight depended on the reference used, and differences varied according to age., Conclusion: The WHO growth charts may be appropriate for monitoring growth of French children, as the growth patterns in our large population of French children were closer to the WHO growth charts than to the French reference curves, from 6 months onwards. However, there were some limitations in the use of these WHO growth charts, and further investigation is needed.

Importance: Patterns of body size and body composition associated with genetic obesity susceptibility inform the mechanisms that increase obesity risk., Objective: To test associations between genetic obesity susceptibility, represented by a combined obesity risk-allele score, and body size or body composition at birth to age 5 years., Design, Setting, and Participants: A total of 3031 children from 4 birth cohort studies in England, France, and Spain were included in a meta-analysis., Exposures: A combined obesity risk-allele score was calculated from genotypes at 16 variants identified by genome-wide association studies of adult body mass index (BMI)., Main Outcomes and Measures: Outcomes were age- and sex-adjusted SD scores (SDS) for weight, length/height, BMI, fat mass, lean mass, and percentage of body fat at birth as well as at ages 1, 2 to 3, and 4 to 5 years., Results: The obesity risk-allele score was not associated with infant size at birth; at age 1 year it was positively associated with weight (β [SE], 0.020 [0.008] SDS per allele; P = .009) and length (β [SE], 0.020 [0.008] SDS per allele; P = .01), but not with BMI (β [SE], 0.013 [0.008] SDS per allele; P = .11). At age 2 to 3 years these associations were stronger (weight: β [SE], 0.033 [0.008] SDS per allele; P < .001; height: β [SE], 0.025 [0.008] SDS per allele; P < .001) and were also seen for BMI (β [SE], 0.024 [0.008] SDS per allele; P = .003). The obesity risk-allele score was positively associated with both postnatal fat mass (1 year: β [SE], 0.032 [0.017] SDS per allele; P = .05; 2-3 years: β [SE], 0.049 [0.018] SDS per allele; P = .006; and 4-5 years: β [SE], 0.028 [0.011] SDS per allele; P = .009) and postnatal lean mass (1 year: β [SE], 0.038 [0.014] SDS per allele; P = .008; 2-3 years: β [SE], 0.064 [0.017] SDS per allele; P < .001; and 4-5 years: β [SE], 0.047 [0.011] SDS per allele; P < .001), but not with the percentage of body fat (P > .15 at all ages)., Conclusions and Relevance: Genetic obesity susceptibility appears to promote a normally partitioned increase in early postnatal, but not prenatal, growth. These findings suggest that symmetrical rapid growth may identify infants with high life-long susceptibility for obesity.

Background: Accumulating evidence from laboratory animal and human studies suggests that air pollution exposure during pregnancy affects cognitive and psychomotor development in childhood., Methods: We analyzed data from 6 European population-based birth cohorts-GENERATION R (The Netherlands), DUISBURG (Germany), EDEN (France), GASPII (Italy), RHEA (Greece), and INMA (Spain)-that recruited mother-infant pairs from 1997 to 2008. Air pollution levels-nitrogen oxides (NO2, NOx) in all regions and particulate matter (PM) with diameters of <2.5, <10, and 2.5-10 μm (PM2.5, PM10, and PMcoarse, respectively) and PM2.5 absorbance in a subgroup-at birth addresses were estimated by land-use regression models, based on monitoring campaigns performed primarily between 2008 and 2011. Levels were back-extrapolated to exact pregnancy periods using background monitoring sites. Cognitive and psychomotor development was assessed between 1 and 6 years of age. Adjusted region-specific effect estimates were combined using random-effects meta-analysis., Results: A total of 9482 children were included. Air pollution exposure during pregnancy, particularly NO2, was associated with reduced psychomotor development (global psychomotor development score decreased by 0.68 points [95% confidence interval = -1.25 to -0.11] per increase of 10 μg/m in NO2). Similar trends were observed in most regions. No associations were found between any air pollutant and cognitive development., Conclusions: Air pollution exposure during pregnancy, particularly NO2 (for which motorized traffic is a major source), was associated with delayed psychomotor development during childhood. Due to the widespread nature of air pollution exposure, the public health impact of the small changes observed at an individual level could be considerable.

The specific role of weight change in the first weeks of gestation in fetal growth has not been fully explored in humans. Our aims were to investigate: (1) the specific association between weight change in the first trimester of pregnancy (WCT1) and size at birth in term pregnancies; and (2) the role of placental weight in this relationship. From 2002 women included in the French EDEN study, 1744 mother-child pairs reached term, had pre-pregnancy weight available and at least five measures of weight in pregnancy. We extrapolated women's weight at each week of gestation with a three-degree polynomial model and estimated weight change during each trimester of gestation. We used a multivariate linear model to investigate the associations between WCT1 and birth size after taking into account potential confounders (age, parity, BMI, tobacco use, educational level, length of gestation, newborn gender, weight change after the first trimester and centre of study). Then, we performed path analysis to investigate whether the relation between WCT1 and birth size could be mediated by placental weight. After taking into account weight gain in later gestation, WCT1 was positively associated with birthweight. Results of path analysis showed that there was no direct association between WCT1 and birth size, but that this association was mediated by placental weight. Weight change during the first weeks of pregnancy may impact on fetal growth independently of weight change later in pregnancy through its effects on placental growth and function., (© 2012 John Wiley & Sons Ltd.)

Background: Preterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results., Objectives: We performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years)., Methods: First, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma. Second, we performed an adjusted 2-stage random-effect meta-analysis to assess the associations of preterm birth (gestational age <37 weeks) and low birth weight (<2500 g) with childhood asthma outcomes., Results: Younger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma (P < .05). The inverse associations of birth weight with childhood asthma were explained by gestational age at birth. Compared with term-born children with normal infant weight gain, we observed the highest risks of school-age asthma in children born preterm with high infant weight gain (odds ratio [OR], 4.47; 95% CI, 2.58-7.76). Preterm birth was positively associated with an increased risk of preschool wheezing (pooled odds ratio [pOR], 1.34; 95% CI, 1.25-1.43) and school-age asthma (pOR, 1.40; 95% CI, 1.18-1.67) independent of birth weight. Weaker effect estimates were observed for the associations of low birth weight adjusted for gestational age at birth with preschool wheezing (pOR, 1.10; 95% CI, 1.00-1.21) and school-age asthma (pOR, 1.13; 95% CI, 1.01-1.27)., Conclusion: Younger gestational age at birth and higher infant weight gain were associated with childhood asthma outcomes. The associations of lower birth weight with childhood asthma were largely explained by gestational age at birth., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Objective. To examine the factors predicting changes in language skills between 2 and 3 years. Methods. By using longitudinal data concerning 1002 children from the EDEN study, linear regression was used to predict 3-year language performance from 2-year language performance and the risk factors associated with language delays. Logistic regressions were performed to examine two change trajectories: children who fall below the 10th percentile of language skills between 2 and 3 years (declining trajectory), and those who rose above the 10th percentile (resilient trajectory). Results. The final linear model accounted for 43% of the variance in 3-year language scores, with 2-year language scores accounting for 22%. Exposure to alcohol during pregnancy, earlier birth term, lower level of parental education and lower frequency of maternal stimulation were associated with the declining trajectory. Breastfeeding was associated with the resilient trajectory. Conclusions. This study provides a better understanding of the natural history of early language delays by identifying biological and social factors that predict changes in language skills between the ages of 2 and 3 years.

Background: Fish is a rich source of essential nutrients for fetal development, but in contrast, it is also a well-known route of exposure to environmental pollutants., Objective: We assessed whether fish intake during pregnancy is associated with fetal growth and the length of gestation in a panel of European birth cohort studies., Design: The study sample of 151,880 mother-child pairs was derived from 19 population-based European birth cohort studies. Individual data from cohorts were pooled and harmonized. Adjusted cohort-specific effect estimates were combined by using a random- and fixed-effects meta-analysis., Results: Women who ate fish >1 time/wk during pregnancy had lower risk of preterm birth than did women who rarely ate fish (≤ 1 time/wk); the adjusted RR of fish intake >1 but <3 times/wk was 0.87 (95% CI: 0.82, 0.92), and for intake ≥ 3 times/wk, the adjusted RR was 0.89 (95% CI: 0.84, 0.96). Women with a higher intake of fish during pregnancy gave birth to neonates with a higher birth weight by 8.9 g (95% CI: 3.3, 14.6 g) for >1 but <3 times/wk and 15.2 g (95% CI: 8.9, 21.5 g) for ≥ 3 times/wk independent of gestational age. The association was greater in smokers and in overweight or obese women. Findings were consistent across cohorts., Conclusion: This large, international study indicates that moderate fish intake during pregnancy is associated with lower risk of preterm birth and a small but significant increase in birth weight.

Weight, height and body mass index (BMI) growth trajectories have been associated with several chronic diseases in later life. Our aim was to describe a method to model individual weight and height growth curves during infancy and to show how it can be used to study their determinants and relationships with later health outcomes as well as to predict BMI trajectories. In the EDEN mother-child cohort, we collected 17 measurements of weight and 16 of length/height per child between birth and 3 years of age in 1,900 infants from their health care booklet and during the study clinical examinations at 1 and 3 years; 1,436 (76%) had at least 1 measurement between 2 and 3 years. We fitted individual weight and height growth trajectories using the Jenss nonlinear model including random effects using the 'SAEMIX' package (R software). We studied whether individual growth model parameters were associated with gender in one- and two-step approaches. We indirectly calculated BMI increase against time from both weight and height growth models combined and compared the fit with a direct multilevel spline model. By modeling observed growth data, we homogenized the data in terms of number and age of measurements and were able to calculate other specific parameters as growth velocities., (© 2014 S. Karger AG, Basel.)

Background: Ambient air pollution has been associated with restricted fetal growth, which is linked with adverse respiratory health in childhood. We assessed the effect of maternal exposure to low concentrations of ambient air pollution on birthweight., Methods: We pooled data from 14 population-based mother-child cohort studies in 12 European countries. Overall, the study population included 74 178 women who had singleton deliveries between Feb 11, 1994, and June 2, 2011, and for whom information about infant birthweight, gestational age, and sex was available. The primary outcome of interest was low birthweight at term (weight <2500 g at birth after 37 weeks of gestation). Mean concentrations of particulate matter with an aerodynamic diameter of less than 2·5 μm (PM2·5), less than 10 μm (PM10), and between 2·5 μm and 10 μm during pregnancy were estimated at maternal home addresses with temporally adjusted land-use regression models, as was PM2·5 absorbance and concentrations of nitrogen dioxide (NO2) and nitrogen oxides. We also investigated traffic density on the nearest road and total traffic load. We calculated pooled effect estimates with random-effects models., Findings: A 5 μg/m(3) increase in concentration of PM2·5 during pregnancy was associated with an increased risk of low birthweight at term (adjusted odds ratio [OR] 1·18, 95% CI 1·06-1·33). An increased risk was also recorded for pregnancy concentrations lower than the present European Union annual PM2·5 limit of 25 μg/m(3) (OR for 5 μg/m(3) increase in participants exposed to concentrations of less than 20 μg/m(3) 1·41, 95% CI 1·20-1·65). PM10 (OR for 10 μg/m(3) increase 1·16, 95% CI 1·00-1·35), NO2 (OR for 10 μg/m(3) increase 1·09, 1·00-1·19), and traffic density on nearest street (OR for increase of 5000 vehicles per day 1·06, 1·01-1·11) were also associated with increased risk of low birthweight at term. The population attributable risk estimated for a reduction in PM2·5 concentration to 10 μg/m(3) during pregnancy corresponded to a decrease of 22% (95% CI 8-33%) in cases of low birthweight at term., Interpretation: Exposure to ambient air pollutants and traffic during pregnancy is associated with restricted fetal growth. A substantial proportion of cases of low birthweight at term could be prevented in Europe if urban air pollution was reduced., Funding: The European Union., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Long-chain polyunsaturated fatty acids (LC-PUFAs) of the n6 (ω6) and n3 series are essential for the development of a child's brain. Fetal LC-PUFA exposure as well as infant exposure via breast milk depend on the maternal intake of these LC-PUFAs and of their respective dietary precursors (PUFAs). We aimed to investigate the associations between maternal LC-PUFA and PUFA [(LC)PUFA] dietary intake during pregnancy and child neurodevelopment at ages 2 and 3 y. In 1335 mother-child pairs from the EDEN cohort, we evaluated associations between daily maternal (LC)PUFA intake during the last 3 months of pregnancy with the child's language at age 2 y and with different assessments of development at age 3 y. Associations were investigated separately in breastfed and never-breastfed children. We examined interactions between the ratios of n6 and n3 (LC)PUFA intakes (n6:n3 fatty acid ratio) and duration of breastfeeding. Breastfeeding mothers had a lower n6:n3 fatty acid ratio (8.4 vs. 8.8; P = 0.02). Among never-breastfed children (n = 338), we found negative associations between maternal dietary n6:n3 fatty acid ratios and neurodevelopment, as reflected by the child's language at age 2 y (β ± SE = -2.1 ± 0.7; P = 0.001) and development assessed with the Ages and Stages Questionnaire at age 3 y (-1.5 ± 0.8; P = 0.05). Among mothers with a high n6:n3 fatty acid ratio only, breastfeeding duration was positively associated with language at age 2 y (P-interaction < 0.05). This suggests that the ratio between maternal dietary n6 and n3 (LC)PUFA intake possibly influences the child's brain development during fetal life but not during or by breastfeeding. However, breastfeeding might compensate for prenatal imbalance in maternal dietary n6:n3 fatty acid ratio.

During pregnancy, the fetus is exposed to contaminants from its mother's diet. This work provides an assessment of the dietary exposure of pregnant women to inorganic contaminants (aluminum, mercury, lead, inorganic arsenic, cobalt), polychlorodibenzodioxins, polychlorodibenzofurans, dioxin-like and non-dioxin-like polychlorobiphenyls (DL-PCBs, NDL-PCBs), polybromodiphenyl ethers (PBDEs), perfluoroalkyl acids, mycotoxins (zearalenone, patulin, trichothecenes), and heat-generated compounds (acrylamide and polycyclic aromatic hydrocarbons). Consumption data of 2002 pregnant women aged 18 to 45 from the EDEN cohort study were combined with contamination data from the second French total diet study to assess the exposure before pregnancy (n=1861) and during the third trimester of pregnancy (n=1775). Exposure was also assessed considering the season during which the third trimester of pregnancy occurred. Significant changes in consumptions during pregnancy and between seasons were associated with differences in exposures for some substances. Some contaminant exposures appeared to be of health concern. Margins of exposure to acrylamide (635 to 1094 for mean), inorganic arsenic, lead, and BDE-99 (≤100) were too low to exclude all risks. For NDL-PCBs, T-2 and HT-2 toxins, and deoxynivalenol, significant exceedings of toxicological reference values were found before pregnancy, but there was no significant exceeding in the third trimester., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: To investigate the dose-response relationship between breastfeeding duration and cognitive development in French preschool children., Study Design: In the French EDEN Mother-Child Cohort Study, we evaluated language ability with the Communicative Development Inventory (CDI) in 1387 2-year-old children and overall development with the Ages and Stages Questionnaire (ASQ) in 1199 3-year-old children. Assessments were compared between breastfed and non-breastfed children and also according to breastfeeding duration in multivariable linear models, controlling for a wide range of potential confounders. We tested departure from linearity., Results: After adjustments, ever-breastfed children scored 3.7 ± 1.8 (P = .038) points higher than never-breastfed children on the CDI and 6.2 ± 1.9 (P = .001) points higher on the ASQ. Among breastfed children, exclusive and any-breastfeeding durations were positively associated with both CDI and ASQ scores. The fine motor domain of ASQ was associated with any-breastfeeding duration, and the problem solving domain with exclusive-breastfeeding duration. We did not observe significant departures from linearity. No interactions were found between the child's sex, parental education or socioeconomic status, and breastfeeding duration., Conclusion: Longer breastfeeding duration was associated with better cognitive and motor development in 2- and 3-year-old children and a dose-response relationship was suggested., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Background: During the past 25 years, many pregnancy and birth cohorts have been established. Each cohort provides unique opportunities for examining associations of early-life exposures with child development and health. However, to fully exploit the large amount of available resources and to facilitate cross-cohort collaboration, it is necessary to have accessible information on each cohort and its individual characteristics. The aim of this work was to provide an overview of European pregnancy and birth cohorts registered in a freely accessible database located at http://www.birthcohorts.net., Methods: European pregnancy and birth cohorts initiated in 1980 or later with at least 300 mother-child pairs enrolled during pregnancy or at birth, and with postnatal data, were eligible for inclusion. Eligible cohorts were invited to provide information on the data and biological samples collected, as well as the timing of data collection., Results: In total, 70 cohorts were identified. Of these, 56 fulfilled the inclusion criteria encompassing a total of more than 500,000 live-born European children. The cohorts represented 19 countries with the majority of cohorts located in Northern and Western Europe. Some cohorts were general with multiple aims, whilst others focused on specific health or exposure-related research questions., Conclusion: This work demonstrates a great potential for cross-cohort collaboration addressing important aspects of child health. The web site, http://www.birthcohorts.net, proved to be a useful tool for accessing information on European pregnancy and birth cohorts and their characteristics., (© 2013 John Wiley & Sons Ltd.)

Background/objectives: Early eating patterns and behaviors can determine later eating habits and food preferences and they have been related to the development of childhood overweight and obesity. We aimed to identify patterns of feeding in the first year of life and to examine their associations with family characteristics., Subjects/methods: Our analysis included 1004 infants from the EDEN mother-child cohort. Feeding practices were assessed through maternal self-report at birth, 4, 8 and 12 months. Principal component analysis was applied to derive patterns from breastfeeding duration, age at complementary food (CF) introduction and type of food used at 1 year. Associations between patterns and family characteristics were analyzed by linear regressions., Results: The main source of variability in infant feeding was characterized by a pattern labeled 'late CF introduction and use of ready-prepared baby foods'. Older, more educated, primiparous women with high monthly income ranked high on this pattern. The second pattern, labeled 'longer breastfeeding, late CF introduction and use of home-made foods' was the closest to infant feeding guidelines. Mothers ranking high on this pattern were older and more educated. The third pattern, labeled 'use of adults' foods' suggests a less age-specific diet for the infants. Mothers ranking high on this pattern were often younger and multiparous. Recruitment center was related to all patterns., Conclusions: Not only maternal education level and age, but also parity and region are important contributors to the variability in patterns. Further studies are needed to describe associations between these patterns and infant growth and later food preferences.

Aims: The importance of reducing sedentary time is increasingly being recognized in the prevention of diabetes and cardiovascular disease. Despite this, the prospective association between sedentary time and physical activity with insulin sensitivity and cardiometabolic risk factors has been little studied., Methods: In an analysis of data from the European RISC study, sedentary time and time spent in activity of moderate or vigorous intensity were assessed by accelerometry at baseline in 313 men and 414 women, aged 30-60 years, with insulin sensitivity as measured by euglycaemic-hyperinsulinaemic clamp. Three years later, cardiometabolic risk factors (anthropometry, glucose, insulin, lipids) were available for 549 participants., Results: In cross-sectional analyses using baseline data, after adjusting for age, gender, recruitment centre and time spent in activity of moderate or vigorous intensity, significant unfavourable associations were observed between higher sedentary time with body weight, HDL cholesterol, triglycerides, clamp-measured insulin sensitivity and insulin secretion (all P(trend)<0.002). Sedentary time remained significantly associated with insulin secretion after adjusting for insulin sensitivity (P(trend)=0.02). In longitudinal analyses, higher baseline sedentary time was associated with 3-year increases in fasting glucose, fasting insulin and the HOMA insulin-resistance index score for the 50% of the study population who increased their BMI by at least 0.3 kg/m(2) (all P(trend)<0.01); these relationships remained significant after adjusting for time spent in activity of moderate or vigorous intensity. The 3-year increase in insulin secretion was lower in those spending more time doing activity of moderate or vigorous intensity (P(trend)=0.03)., Conclusion: These prospective data suggest that less sedentary behaviour may partly counteract some of the negative effects of increasing body weight on glucose-insulin homoeostasis., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

The objective of this study is to investigate the potential effect of maternal environmental cadmium (Cd) exposure on birth weight and fetal growth restriction (FGR). A total of 901 pregnant women from the EDEN cohort study were enrolled from two maternity units. Blood Cd was measured at mid-pregnancy and associations with birth weight and FGR were analyzed. Maternal Cd levels were associated with reduced birth weight in the offspring of women who smoked during pregnancy (b=-113.7; p=0.001). Smoking during pregnancy and maternal blood Cd concentrations had comparable effects on FGR incidence (OR 1.89; 95% CI: 1.00-3.58 and OR=1.41; 95% CI: 1.00-1.99, respectively). This study highlights the effect of Cd toxicity on fetal growth through the probable accumulation and transmission of this metal through the placenta. The close relationship between blood Cd levels and smoking habits indicates that Cd may be a relevant biomarker for smoking toxicity on fetal development., (Copyright © 2012 Elsevier Inc. All rights reserved.)

To study the relationship between pre-pregnancy body mass index (BMI) and weight gain during pregnancy with pregnancy and birth outcomes, with a focus on gestational diabetes and hypertension and their role in the association with fetal growth. We studied 1,884 mothers and offspring from the Eden mother-child cohort. Weight before pregnancy (W1) and weight after delivery (W2) were collected and we calculated BMI and net gestational weight gain (netGWG = (W2 - W1)/(weeks of gestation)). Gestational diabetes, hypertension gestational age and birth weight were collected. We used multivariate linear or logistic models to study the association between BMI, netGWG and pregnancy and birth outcomes, adjusting for center, maternal age and height, parity and average number of cigarettes smoked per day during pregnancy. High BMI was more strongly related to the risk of giving birth to a large-for-gestational-age (LGA) baby than high netGWG (odds ratio OR [95% CI] of 3.23 [1.86-5.60] and 1.61 [0.91-2.85], respectively). However, after excluding mothers with gestational diabetes or hypertension the ORs for LGA, respectively weakened (OR 2.57 [1.29-5.13]) for obese women and strengthened for high netGWG (OR 2.08 [1.14-3.80]). Low in comparison to normal netGWG had an OR of 2.18 [1.20-3.99] for pre-term birth, which became stronger after accounting for blood pressure and glucose disorders (OR 2.70 [1.37-5.34]). Higher net gestational weight gain was significantly associated with an increased risk of LGA only after accounting for blood pressure and glucose disorders. High gestational weight gain should not be neglected in regard to risk of LGA in women without apparent risk factors.

It has recently been suggested that the low-frequency c.136-14&#95;136-13insC variant in high-mobility group A1 (HMGA1) may strongly contribute to insulin resistance and type 2 diabetes risk. In our study, we attempted to confirm that HMGA1 is a novel type 2 diabetes locus in French Caucasians. The gene was sequenced in 368 type 2 diabetic case subjects with a family history of type 2 diabetes and 372 normoglycemic control subjects without a family history of type 2 diabetes. None of the 41 genetic variations identified were associated with type 2 diabetes. The lack of association between the c.136-14&#95;136-13insC variant and type 2 diabetes was confirmed in an independent French group of 4,538 case subjects and 4,015 control subjects and in a large meta-analysis of 16,605 case subjects and 46,179 control subjects. Finally, this variant had no effects on metabolic traits and was not involved in variations of HMGA1 and insulin receptor (INSR) expressions. The c.136-14&#95;136-13insC variant was not associated with type 2 diabetes in individuals of European descent. Our study emphasizes the need to analyze a large number of subjects to reliably assess the association of low-frequency variants with the disease.

Maternal weight change before pregnancy can be considered as an indicator of maternal energy balance and nutritional status before conception, and may be involved in early life programming. We aimed to investigate the association of maternal Weight Change Before Pregnancy (WCBP) with fetal growth and adverse pregnancy outcomes. Data are from the French EDEN mother-child cohort where 1,756 mother-child pairs had information on mother's weight at 20 years, weight just before pregnancy, fetal anthropometry at second and third trimesters, infant's birthweight and pregnancy complications. The average annual WCBP between 20 years and start of pregnancy (in kg/year) was categorized as: "Weight Loss" (n = 320), "Moderate weight gain" (n = 721) and "High weight gain" (n = 715). The associations of WCBP with fetal and newborn characteristics and with adverse pregnancy outcomes were analyzed, adjusting for maternal and pregnancy characteristics, including the mother's prepregnancy BMI. Interactions between WCBP and prepregnancy BMI were tested. Birthweight and estimated fetal weight in the third trimester increased significantly with increasing WCBP in mothers with BMI <25 kg/m(2). In these mothers, weight loss before pregnancy was associated with a higher risk of newborns small for gestational age (SGA). Whatever the prepregnancy BMI, WCBP was positively associated with a maternal risk of gestational diabetes and hypertension. The ponderal history of mothers before pregnancy can impact on fetal growth and on pregnancy outcomes such as gestational diabetes or hypertension. Our analysis is the first to report that in non-overweight women, those who lost weight before pregnancy are at higher risk of having SGA newborns.

Background: The protective role of the Ala allele in the Pro12Ala polymorphism of PPARγ on type 2 diabetes has been well established but not confirmed in the context of pregnancy, for gestational diabetes, a known predictor of later type 2 diabetes onset. Another PPARγ polymorphism, the C1431T, is in strong linkage disequilibrium with Pro12Ala and has been shown to be associated with body weight, but its association with diabetes is controversial., Research Design and Methods: In 1708 women of the EDEN mother-child cohort, the PPARγ Pro12Ala and C1431T polymorphisms were genotyped and analyzed in association with maternal prepregnancy body mass index, obesity before pregnancy, and gestational diabetes, separately and also combined in haplotypes., Results: The prevalence of obesity was significantly higher in mothers with the Ala/Ala genotype compared with carriers of the Pro allele (35 vs. 9%, P < 0.0001), but there was no cases of gestational diabetes in Ala/Ala mothers. Mothers homozygous for the T allele of C1431T were also more obese (24 vs. 9%, P = 0.035), and three times more had gestational diabetes (18 vs. 6%, P = 0.044). Frequencies of haplotypes for these two single-nucleotide polymorphisms differed significantly in mothers with and without gestational diabetes; in comparison with the Pro-C haplotype, the Pro-T haplotype conferred the highest risk [odds ratio (95% CI) = 1.89 (1.05-3.40)], and the Ala-C the lowest risk [odds ratio (95% CI) = 0.12 (0.52-1.70)]., Conclusions: These results from a haplotype analysis, show for the first time that genetic variations in the PPARγ gene could play a role in the susceptibility to develop gestational diabetes.

Objective: To understand the relationships between maternal glycemia during pregnancy and prenatal and early postnatal growth by evaluating cord C-peptide and IGF-I as mediating biomarkers in boys and girls separately., Research Design and Methods: We evaluated 342 neonates within the EDEN mother-child cohort study born to mothers without diabetes diagnosis before pregnancy. We measured maternal glycemia at 24-28 weeks of gestation and neonates' cord blood C-peptide (used as a proxy for fetal insulin) and IGF-I at birth. Reported maternal prepregnancy BMI and all measured infant weights and lengths in the 1st year were recorded. Growth modeling was used to obtain an individual growth curve for each infant in the 1st year. Path models, a type of structural equation modeling, were used for statistical analysis. Path analysis is a multivariate method associated with a graphical display that allows evaluation of mediating factors and distinguishes direct, indirect, and total effects., Results: Cord C-peptide at birth was positively correlated with maternal prepregnancy BMI and maternal glycemia and was higher in girls. In a path model that represented prenatal growth, there was no significant direct effect of maternal glycemia on birth weight, but the effect of maternal glycemia on birth weight was mediated by fetal insulin and IGF-I in both girls and boys. However, in girls only, higher concentrations of cord C-peptide (but not cord IGF-I or maternal glucose) were associated with slower weight growth in the first 3 months of life., Conclusions: Our study underlines the role of the fetal insulin-IGF-I axis in the relationship between maternal glycemia during pregnancy and birth weight. We also show for the first time that high insulin concentration in female fetuses is associated with slower early postnatal growth. This slow, early growth pattern may be programmed by fetal hyperinsulinemia, and girls may be more susceptible than boys to its consequences.