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Abstract Study Objectives To identify sleep multi-trajectories in children from age 1 to 5.5 years and their early correlates. Methods We collected early family, maternal, and child characteristics, including children’s nighttime sleep duration (NSD) and daytime sleep duration (DSD), night waking (NW), and sleep-onset difficulties (SOD), by parental phone interviews at age 2 months and 1-, 2-, 3.5-, and 5.5 years. Group-based multi-trajectory modeling identified sleep multi-trajectory groups. Multinomial logistic regression assessed associations with early factors. Results We identified five distinct sleep multi-trajectory groups for NSD, DSD, NW, and SOD in 9273 included children. The “Good sleepers” (31.6%) and “Long sleepers” (31.0%) groups had low NW and SOD prevalence and shorter NSD but longer DSD in “Good sleepers” than in “Long sleepers.” The “Good sleepers but few SOD” group (10.3%) had long NSD and DSD but a SOD peak at age 3.5 years; the “Improving NW and SOD” group (9.6%) showed short but rapidly increasing NSD to a plateau and high but decreasing NW and SOD; the “Persistent NW and SOD” group (17.5%) had persistent high NW and SOD. Maternal depression during pregnancy and sleep habits at age 1 (e.g. parental presence or feeding to fall asleep, sleeping at least part of the night away from own bed) were common risk factors associated with the most disordered sleep multi-trajectory groups. Conclusions We identified distinct sleep multi-trajectory groups and early life-associated factors in preschoolers. Most of the factors associated with the most sleep-disordered multi-trajectory groups are likely modifiable and provide clues for early prevention interventions. Graphical Abstract

Prenatal exposure to air pollution is considered to be associated with adverse effects on child health. This may partly be mediated by mechanisms related to DNA methylation. We investigated associations between exposure to air pollution, using nitrogen dioxide (NO2) as marker, and epigenome-wide cord blood DNA methylation. We meta-analyzed the associations between NO2 exposure at residential addresses during pregnancy and cord blood DNA methylation (Illumina 450K) in four European and North American studies (n = 1,508) with subsequent look-up analyses in children ages 4 (n = 733) and 8 (n = 786) years. Additionally, we applied a literature-based candidate approach for antioxidant and anti-inflammatory genes. To assess influence of exposure at the transcriptomics level, we related mRNA expression in blood cells to NO2 exposure in 4- (n = 111) and 16-year-olds (n = 239). We found epigenome-wide significant associations [false discovery rate (FDR) p < 0.05] between maternal NO2 exposure during pregnancy and DNA methylation in newborns for 3 CpG sites in mitochondria-related genes: cg12283362 (LONP1), cg24172570 (3.8 kbp upstream of HIBADH), and cg08973675 (SLC25A28). The associations with cg08973675 methylation were also significant in the older children. Further analysis of antioxidant and anti-inflammatory genes revealed differentially methylated CpGs in CAT and TPO in newborns (FDR p < 0.05). NO2 exposure at the time of biosampling in childhood had a significant impact on CAT and TPO expression. NO2 exposure during pregnancy was associated with differential offspring DNA methylation in mitochondria-related genes. Exposure to NO2 was also linked to differential methylation as well as expression of genes involved in antioxidant defense pathways. Citation: Gruzieva O, Xu CJ, Breton CV, Annesi-Maesano I, Antó JM, Auffray C, Ballereau S, Bellander T, Bousquet J, Bustamante M, Charles MA, de Kluizenaar Y, den Dekker HT, Duijts L, Felix JF, Gehring U, Guxens M, Jaddoe VV, Jankipersadsing SA, Merid SK, Kere J, Kumar A, Lemonnier N, Lepeule J, Nystad W, Page CM, Panasevich S, Postma D, Slama R, Sunyer J, Söderhäll C, Yao J, London SJ, Pershagen G, Koppelman GH, Melén E. 2017. Epigenome-wide meta-analysis of methylation in children related to prenatal NO2 air pollution exposure. Environ Health Perspect 125:104-110; http://dx.doi.org/10.1289/EHP36.

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

Background: Data concerning the effects of prenatal exposures to phthalates and phenols on fetal growth are limited in humans. Previous findings suggest possible effects of some phenols on male birth weight. Objective: Our aim was to assess the relationships between prenatal exposures to phthalates and phenols and fetal growth among male newborns. Methods: We conducted a case-control study on male malformations of the genitalia nested in two French mother-child cohorts with recruitment between 2002 and 2006. We measured, in maternal urinary samples collected between 6 and 30 gestational weeks, the concentrations (micrograms per liter) of 9 phenol (n = 191 pregnant women) and 11 phthalate metabolites (n = 287). Weight, length, and head circumference at birth were collected from maternity records. Statistical analyses were corrected for the oversampling of malformation cases. Results: Adjusted birth weight decreased by 77 g [95% confidence interval (CI): –129,–25] and by 49 g (95% CI:–86,–13) in association with a 1-unit increase in In-transformed 2,4-dichlorophenol (DCP) and 2,5-DCP urinary concentrations, respectively. Benzophenone-3 (BP3) In-transformed concentrations were positively associated with weight (26 g; 95% CI:–2 , 54) and head circumference at birth (0.1 cm; 95% CI: 0.0, 0.2). Head circumference increased by 0.3 cm (95% CI: 0.0, 0.7) in association with a 1-unit increase in In-transformed BPA concentration. For phthalate metabolites there was no evidence of monotonie associations with birth weight. Conclusions: Consistent with findings of a previous study, we observed evidence of an inverse association of 2,5-DCP and a positive association of BP3 with male birth weight.

A series of epidemiological studies conducted in the United States have consistently shown an increased risk of autism spectrum disorder (ASD) in children associated with pre- and postnatal exposure to ambient particulate matter (PM). In Europe, studies are scarce and results are inconsistent. We aimed to investigate the association between prenatal exposure to PM and the risk of ASD in France. ASD cases were participants from the ELENA cohort. Controls children from the ELFE cohort were matched by sex, year (± 2) and region of birth. Prenatal exposures to PM10 and to PM2.5 were estimated between 2008 and 2013 using innovative hybrid spatio-temporal models developed for France. Conditional logistic regression models adjusted for birth season, parent's age at the child birth and parental education level were run. We included 125 ASD cases and 500 controls. Prenatal PM2.5 and PM10 median (IQR) concentration estimates were respectively 16.3 (3.9) µg/m and 22.9 (6.6) µg/m in the whole sample. The conditional logistic regression models showed Odds Ratios (ORs) (Confidence Interval 95%) for ASD risk of 0.72 (0.52-1.01) and 0.84 (0.58-1.22) for an IQR increase in PM2.5 and PM10 prenatal levels, respectively. When restricting population of ASD cases to children born the same year of controls, ORs were 1.79 (0.80-4.01) and 2.23 (0.71-9.04), respectively. Our results did not show that prenatal exposures to PM2.5 and PM10 were associated with the risk of ASD in children in France.Trial Registration Number NCT02625116.

Evidence from literature is mixed regarding a possible association of maternal gestational diabetes mellitus (GDM) and overweight in the offspring. Sexual dimorphism, or sex disparities in the pathogenesis linking GDM exposure to overweight, could be at play. The objective of this study was to investigate the association between GDM and child overweight at 5-7 years. Six hundred pairs (1:1) of Reunionese liveborn singletons selected from a hospital-based birth registry, matched for sex, gestational age, and birth period, underwent a prospective in-home follow-up and were analyzed with respect to their exposure to GDM. The primary outcome was child overweight at 5-7 years, as defined by the International Obesity Task Force. The association between GDM exposure and child overweight was estimated by the odds ratio (OR) using conditional logistic regression models. For the subset of children exposed to GDM with available maternal glycemic data, we analyzed the relationship between maternal glycemic levels during pregnancy and child body mass index (BMI) at 5-7 years with a linear regression model. In light of the significant interaction between sex and GDM, all statistical analyses were then stratified by sex. After controlling for pre-pregnancy BMI and maternal sociodemographic characteristics, the risk of overweight increased with exposure to GDM for boys (adjusted OR: 2.34; 95% confidence interval = 1.26-4.34, P = 0.007) but not for girls (adjusted OR: 0.56; 95%CI = 0.28-1.10, P = 0.093). Consistent with this, the linear increase of boys' BMI at 5-7 years with maternal blood glucose levels during pregnancy, in the exposed group, displayed a dose-response relationship. Our findings indicate that exposure to GDM is a risk factor for childhood overweight in boys but not in girls, which adds to the growing body of evidence suggesting greater sensitivity of male offspring to intrauterine hyperglycemia.

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.

While breast-feeding is the recommended feeding mode in infancy, rates are low in some Western societies, and infants are widely fed formula. France, in particular, shows high rates of infant formula use, including formulas with protein hydrolysates. The degree of protein hydrolysis has previously been associated with neurodevelopmental outcomes. The present study examines the associations between the protein’s hydrolysis degree in infant formula and child neurodevelopment up to 3·5 years of age in the French nationwide Étude Longitudinale Française depuis l’Enfance (ELFE study). Parents reported on brand and name of the formula used at 2 months, and protein hydrolysis degree was derived from the ingredient list. Analyses were based on 6979 infants (92·2, 6·8 and 1 % consuming non-hydrolysed, partially and extensively hydrolysed formulas, respectively). Neurodevelopment was assessed at age 1 and 3·5 years with the Child Development Inventory (CDI), at age 2 years with the MacArthur-Bates Communicative Development Inventories and at age 3·5 years with the Picture Similarities sub-scale (British Ability Scales). Associations between protein hydrolysis degree and child neurodevelopment were assessed using linear and logistic regression for overall scores and poor CDI sub-domain scores (<25th centile), respectively. Among formula-fed infants, protein hydrolysis degree in infant formula was not associated with overall neurodevelopmental scores up to 3·5 years. Some associations were found with the motor skills CDI sub-domain, but they were not consistent at 1 and 3·5 years as well as across sensitivity analyses. The use of hydrolysed formula appears safe in terms of overall neurodevelopment, and research should further investigate specific neurodevelopmental domains.

To examine the validity of the Recent Physical Activity Questionnaire (RPAQ) which assesses physical activity (PA) in 4 domains (leisure, work, commuting, home) during past month. 580 men and 1343 women from 10 European countries attended 2 visits at which PA energy expenditure (PAEE), time at moderate-to-vigorous PA (MVPA) and sedentary time were measured using individually-calibrated combined heart-rate and movement sensing. At the second visit, RPAQ was administered electronically. Validity was assessed using agreement analysis. RPAQ significantly underestimated PAEE in women [median(IQR): 34.9 (22.3, 52.8) vs. 40.6 (32.4, 50.9) kJ/kg/day, 95%LoA: -44.4, 66.1 kJ/kg/day) and overestimated PAEE in men [45.9 (30.6, 71.1) vs. 45.5 (34.1, 57.6) kJ/kg/day, 95%LoA: -44.8, 102.6 kJ/kg/day]. Using individualised definition of 1MET, RPAQ significantly underestimated MVPA in women [median(IQR): 63.7 (30.5, 126.9) vs. 73.6 (47.8, 107.2) min/day, 95%LoA: -127.4, 311.9 min/day] and overestimated MVPA in men [90.0 (42.3, 188.6) vs. 83.3 (55.1, 125.0) min/day, 95%LoA: -134.8, 427.3 min/day]. Correlations (95%CI) between subjective and objective estimates were statistically significant [PAEE: women, rho = 0.20 (0.15-0.26); men, rho = 0.37 (0.30-0.44); MVPA: women, rho = 0.18 (0.13-0.24); men, rho = 0.31 (0.24-0.38)]. When using non-individualised definition of 1MET (3.5 mlO2/kg/min), MVPA was substantially overestimated (16 min/day, and 32 min/day in women and men, respectively). Revisiting occupational intensity assumptions in questionnaire estimation algorithms with occupational group-level empirical distributions reduced median PAEE-bias in manual (38.8 kJ/kg/day vs. 6.8 kJ/kg/day, p<0.001) and heavy manual workers (63.6 vs. -2.8 kJ/kg/day, p<0.001) in an independent hold-out sample [corrected]. Relative validity of RPAQ-derived PAEE and MVPA is comparable to previous studies but underestimation of PAEE is smaller. Electronic RPAQ may be used in large-scale epidemiological studies including surveys, providing information on all domains of PA.

Weight-control interventions in pregnant women with overweight or obesity have limited effectiveness for fetal growth and birth outcomes. Interventions or prevention programs aiming at the pre-pregnancy period should be considered. However, how the woman's weight change before pregnancy affects fetal growth is not known. We investigated the association between weight change over the year before pregnancy and birth weight. We used the inclusion data of 16,395 women from the ELFE French national birth cohort, a nationally representative cohort in which infants were enrolled at birth with their families in 2011. Maternal weight change was self-reported and classified into 3 groups: moderate weight variation or stable weight, weight loss > 5 kg, and weight gain > 5 kg or both weight loss and gain > 5 kg. Multiple linear regression models were used to investigate the association between pre-pregnancy weight change and a birth weight z-score calculated according to the French Audipog reference, adjusted for a large set of maternal characteristics. The analyses were stratified by maternal body mass index (BMI) at conception (<25 versus ≥25 kg/m2) and adjusted for BMI within these categories. We used the MacKinnon method to test the mediating effect of gestational weight gain (GWG) on these associations. Mother's mean age was 30.5 years, 87% were born in France, and 26% had overweight or obesity. For women in either BMI category at conception, GWG was more than 2 kg higher, on average, for women with weight loss before pregnancy than for women with stable weight or moderate weight variation. For women with BMI < 25 kg/m2 at conception, birth weight was significantly higher with weight loss than stable weight before pregnancy (β = 0.08 [95% CI 0.02; 0.14], p = 0.01), and this total effect was explained by a significant mediating effect through GWG. For women with BMI ≥ 25 kg/m2 at conception, birth weight was not associated with pre-pregnancy weight loss during the year before pregnancy. Mediation analysis revealed that in these women, the direct effect of pre-pregnancy weight loss that would have resulted in a smaller birth weight z-score (β = -0.11 [95% CI -0.19; -0.03], p = 0.01) was cancelled out by the GWG. The mediating effect of GWG was even higher when weight loss resulted from a restrictive diet in the year before pregnancy. Weight gain before pregnancy was not associated with birth weight. Although we included a large number of women and had extensive data, the only potential cause of pre-pregnancy weight loss that was investigated was dieting for intentional weight loss. We have no information on other potential causes but did however exclude women with a history of pre-pregnancy chronic disease. Another limitation is declaration bias due to self-reported data. Health professionals should be aware that GWG may offset the expected effect of weight loss before conception on fetal growth in overweight and obese women. Further studies are required to understand the underlying mechanisms in order to develop weight-control interventions and improve maternal periconceptional health and developmental conditions for the fetus.