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Objective: Suboptimal nutrition in pregnancy is associated with worse offspring cardiometabolic health. DNA methylation may be an underlying mechanism. We meta-analyzed epigenome-wide association studies (EWASs) of maternal dietary glycemic index and load with cord blood DNA methylation. Research Design and Methods: We calculated maternal glycemic index and load from food frequency questionnaires, and ran EWASs on cord blood DNA methylation in 2003 mother-offspring pairs from three cohorts. Analyses were additionally stratified by maternal BMI categories. We looked-up the findings in EWASs of maternal glycemic traits and BMI, and in EWASs of birthweight and child BMI. We examined associations with gene expression in child blood in the online Human Early Life Exposome eQTM catalogue and in 223 adipose tissue samples. Results: Maternal glycemic index and load were associated with cord blood DNA methylation at 41 cytosine-phosphate-guanine sites (CpGs, PPCED1B and PCDHG, respectively, in child blood, and DNA methylation at cg27193519 was associated with expression of TFAP4, ZNF500, PPL and ANKS3 in child subcutaneous adipose tissue. Conclusions: We observed multiple associations of maternal glycemic index and load during pregnancy with cord blood DNA methylation, mostly in mothers with overweight/obesity; some of these CpGs were associated with gene expression. Additional studies are required to further explore functionality, uncover causality, and study pathways to offspring health.

BACKGROUND: Population-based studies generally show J-shaped associations between alcohol intake and mortality from cardiovascular disease (CVD). Little is known about alcohol and long-term mortality risk after myocardial infarction (MI). OBJECTIVES: We examined alcohol intake in relation to all-cause, CVD, and ischemic heart disease (IHD) mortality in Dutch post-MI patients of the Alpha Omega Cohort. METHODS: The analysis comprised 4365 patients (60-80 years; 79% male) with an MI ≤ 10 years before study enrolment. We used a 203-item FFQ to assess alcohol (total ethanol) and dietary intakes over the past month. Patients were classified as nondrinkers (0 g/d; n = 956) or very light (>0 to 2 g/d; n = 385), light (M: >2 to 10 g/d; F: >2 to 5 g/d; n = 1125), moderate (M: >10 to 30 g/d; F: >5 to 15 g/d; n = 1207), or heavy drinkers (M: >30 g/d; F: >15 g/d; n = 692). HRs of mortality for alcohol intake were obtained from Cox models, adjusting for age, sex, education, smoking, BMI, physical activity, and dietary factors. RESULTS: Alcohol was consumed by 83% of males and 61% of females. During ∼12 years of follow-up, 2035 deaths occurred, of which 903 were from CVD and 558 were from IHD. Compared to the (combined) reference group of nondrinkers and very light drinkers, HRs for all-cause mortality were 0.87 (95% CI, 0.78-0.98), 0.85 (95% CI, 0.75-0.96), and 0.91 (95% CI, 0.79-1.04) for light, moderate, and heavy drinkers, respectively. For CVD mortality, corresponding HRs were 0.80 (95% CI, 0.67-0.96), 0.82 (95% CI, 0.69-0.98), and 0.87 (95% CI, 0.70-1.08) for light, moderate, and heavy drinkers, respectively. Findings for IHD mortality were similar. HRs did not materially change when nondrinkers or very light drinkers were taken as the reference, or after exclusion of former drinkers or patients with diabetes or poor/moderate self-rated health. CONCLUSIONS: Light and moderate alcohol intakes were inversely associated with mortality risk in stable post-MI patients. These observational findings should be cautiously interpreted in light of the total evidence on alcohol and health. The Alpha Omega Cohort is registered at clinicaltrials.gov as NCT03192410.

Background Population-based studies generally show neutral associations between dairy consumption and ischemic heart disease (IHD) mortality, whereas weak inverse associations were found for cardiovascular disease (CVD) and stroke mortality. Whether dairy consumption affects long-term survival after myocardial infarction (MI) is unknown. Objectives We studied types of dairy and long-term mortality risk in drug-treated post-MI patients. Methods We included 4365 Dutch patients from the Alpha Omega Cohort aged 60–80 y (21% women) with an MI ≤10 y before enrollment. Dietary data were collected at baseline (2002–2006) using a 203-item FFQ and patients were followed for cause-specific mortality through December 2018. HRs of CVD, IHD, stroke, and all-cause mortality for types of dairy were obtained from Cox models, adjusting for age, sex, energy intake, physical activity, smoking, alcohol intake, diabetes, obesity, and dietary factors. Results Most patients were Dutch, 24% were obese, 20% had diabetes, and 97% used cardiovascular medication. Median intakes were 39 g/d for plain yogurt, 88 g/d for total nonfermented milk, and 17 g/d for hard cheeses. Of the cohort, 10% consumed high-fat milk. During ∼12 y of follow-up (48,473 person-years) 2035 deaths occurred, including 903 from CVD, 558 from IHD, and 170 from stroke. Yogurt was linearly inversely associated with CVD mortality (HR: 0.96; 95% CI: 0.93, 0.99; per 25 g/d) and nonlinearly inversely associated with all-cause mortality. Milk was not associated with any of the outcomes (HRs: ∼1.0 per 100 g/d), except for a higher mortality risk in high-fat milk consumers (HR: 1.30; 95% CI: 1.13, 1.49). Other dairy groups were not associated with mortality risk. Conclusions In Dutch post-MI patients, yogurt consumption was inversely associated with CVD mortality and all-cause mortality. Associations for milk and other dairy products were neutral or inconsistent. This trial was registered at clinicaltrials.gov as NCT03192410.

Background and aims: Age-related kidney function decline is accelerated in patients with coronary heart disease (CHD). CHD and chronic kidney disease may share common etiologies. We examined plasma fatty acids (FAs) as novel biomarkers of kidney function decline after myocardial infarction (MI). Methods and results: The analysis included 2329 Dutch post–MI patients aged 60-80y (Alpha Omega Cohort) most receiving state-of-the-art medications. Plasma FAs (% total FAs) in cholesteryl esters were assessed at baseline (2002–2006), and ∼40 months change in creatinine-cystatin C based glomerular filtration rate was estimated (eGFR, in ml/min per 1.73 m2). Beta coefficients for annual eGFR change in relation to plasma linoleic acid (LA; 50.1% of total FAs in CE), omega-3 FAs (EPA + DHA; 1.7%), odd-chain FAs (C15:0 and C17:0; 0.2%), and C14:0 (0.7%) were obtained from linear regression analyses adjusted for age, sex, smoking, and alcohol intake. Mean baseline eGFR ±SD was 78.5 ± 18.7, which declined by 4.7 ± 13.1 during follow-up, or 1.4 ± 3.9 per year. The annual decline in eGFR was less in patients with higher plasma LA (adjusted beta: 0.40 for LA >47 vs ≤ 47%, 95% CI: 0.01; 0.78; p = 0.046). Associations of plasma LA with annual eGFR decline were stronger in 437 patients with diabetes (1.21, 0.24; 2.19) and in 402 patients with CKD (eGFR

OBJECTIVE Maternal glycemic dysregulation during pregnancy increases the risk of adverse health outcomes in her offspring; a risk thought to be linearly related to maternal hyperglycemia. It is hypothesized that changes in offspring DNA methylation (DNAm) underline these associations. RESEARCH DESIGN AND METHODS To address this hypothesis, we conducted fixed-effect meta-analyses of epigenome-wide association study (EWAS) results from eight birth cohorts investigating relationships between cord blood DNAm and fetal exposure to maternal glucose (Nmax= 3,503), insulin (Nmax= 2,062), and the area under the curve of glucose (AUCgluc) following oral glucose tolerance tests (OGTT, Nmax= 1,505). We performed look-up analyses for identified CpG dinucleotides (CpGs) in independent observational cohorts to examine associations between DNAm and cardiometabolic traits as well as tissue-specific gene expression. RESULTS Greater maternal AUCgluc was associated with lower cord blood DNAm at neighboring CpGs cg26974062 (β= -0.013 [SE=2.1x10-3], PFDR= 5.1x10-3) and cg02988288 (β= -0.013 [SE=2.3x10-3], PFDR =0.031) in TXNIP. These associations were attenuated in women with GDM. Lower blood DNAm at these two CpGs near TXNIP was associated with multiple metabolic traits later in life, including type 2 diabetes. TXNIP DNAm in liver biopsies was associated with hepatic expression of TXNIP. We observed little evidence of associations between either maternal glucose or insulin and cord blood DNAm. CONCLUSION Maternal hyperglycemia, as reflected by AUCgluc, was associated with lower cord blood DNAm at TXNIP. Associations between DNAm at these CpGs and metabolic traits in subsequent look-up analyses suggest that these may be candidate loci to investigate in future causal and mediation analyses.

Objective: Evidence on the impact of leisure time physical activity (LTPA) in pregnancy on birth size is inconsistent. We aimed to examine the association between LTPA during early and late pregnancy and newborn anthropometric outcomes.Design: Individual level meta‐analysis, which reduces heterogeneity across studies.Setting: A consortium of eight population‐based studies (seven European and one US) comprising 72 694 participants.Methods: Generalised linear models with consistent inclusion of confounders (gestational age, sex, parity, maternal age, education, ethnicity, BMI, smoking, and alcohol intake) were used to test associations between self‐reported LTPA at either early (8–18 weeks gestation) or late pregnancy (30+ weeks) and the outcomes. Results were pooled using random effects meta‐analyses.Main outcome measures: Birth weight, large‐for‐gestational age (LGA), macrosomia, small‐for‐gestational age (SGA), % body fat, and ponderal index at birth.Results: Late, but not early, gestation maternal moderate to vigorous physical activity (MVPA), vigorous activity, and LTPA energy expenditure were modestly inversely associated with BW, LGA, macrosomia, and ponderal index, without heterogeneity (all: I2 = 0%). For each extra hour/week of MVPA, RR for LGA and macrosomia were 0.97 (95% CI: 0.96, 0.98) and 0.96 (95% CI: 0.94, 0.98), respectively. Associations were only modestly reduced after additional adjustments for maternal BMI and gestational diabetes. No measure of LTPA was associated with risk for SGA.Conclusions: Physical activity in late, but not early, pregnancy is consistently associated with modestly lower risk of LGA and macrosomia, but not SGA.Tweetable abstract: In an individual participant meta‐analysis, late pregnancy moderate to vigorous physical activity modestly reduced birth size outcomes.

Background Circulating folate, vitamin B12 and homocysteine concentrations during fetal development have been associated with health outcomes in childhood. Changes in fetal DNA methylation may be an underlying mechanism. This may be reflected in altered epigenetic aging of the fetus, as compared to chronological aging. The difference between gestational age derived in clinical practice and gestational age predicted from neonatal DNA methylation data is referred to as gestational age acceleration. Differences in circulating folate, vitamin B12 and homocysteine concentrations during fetal development may be associated with gestational age acceleration. Results Up to 1346 newborns participating in the Generation R Study, a population-based prospective cohort study, had both cord blood DNA methylation data available and information on plasma folate, serum total and active B12 and plasma homocysteine concentrations, measured in early pregnancy and/or in cord blood. A subgroup of 380 newborns had mothers with optimal pregnancy dating based on a regular menstrual cycle and a known date of last menstrual period. For comparison, gestational age acceleration was calculated based the method of both Bohlin and Knight. In the total study population, which was more similar to Bohlin’s training population, one standard deviation score (SDS) higher maternal plasma homocysteine concentrations was nominally associated with positive gestational age acceleration [0.07 weeks, 95% confidence interval (CI) 0.02, 0.13] by Bohlin’s method. In the subgroup with pregnancy dating based on last menstrual period, the method that was also used in Knight’s training population, one SDS higher cord serum total and active B12 concentrations were nominally associated with negative gestational age acceleration [(− 0.16 weeks, 95% CI − 0.30, − 0.02) and (− 0.15 weeks, 95% CI − 0.29, − 0.01), respectively] by Knight’s method. Conclusions We found some evidence to support associations of higher maternal plasma homocysteine concentrations with positive gestational age acceleration, suggesting faster epigenetic than clinical gestational aging. Cord serum vitamin B12 concentrations may be associated with negative gestational age acceleration, indicating slower epigenetic than clinical gestational aging. Future studies could examine whether altered fetal epigenetic aging underlies the associations of circulating homocysteine and vitamin B12 blood concentrations during fetal development with long-term health outcomes.

Currently, many a priori indexes are being used to assess maternal adherence to the Mediterranean diet (MD) during pregnancy but each with different components, cut-off points, and scoring systems. This narrative review aimed to identify all observational studies utilizing a priori indexes to assess maternal adherence to the MD during pregnancy. A systematic search was conducted in Pubmed until 1 July 2020. Among the 27 studies included, eight different a priori indexes were identified. Studies included a range of 5 to 13 dietary components in their indexes. Only three dietary components—vegetables, fruits, and fish—were common among all indexes. Dairy and alcohol were the only two components modified for pregnancy. All but one study either excluded alcohol from their index or reversed its scoring to contribute to decreased adherence to the MD. Approximately half of the studies established cut-off points based on the distribution of the study population; the others utilized fixed criteria. This review emphasizes the incongruent definitions of the MD impairing effective comparison among studies relating to maternal or offspring health outcomes. Future research should carefully consider the heterogeneous definitions of the MD in a priori indexes and the relevance of incorporating pregnancy-specific nutritional requirements.

Background Hypertension and atherosclerosis may partly originate in early life. Altered epigenetic aging may be a mechanism underlying associations of early-life exposures and the development of cardiovascular risk factors in childhood. A discrepancy between chronological age and age predicted from neonatal DNA methylation data is referred to as age acceleration. It may either be positive, if DNA methylation age is older than clinical age, or negative, if DNA methylation age is younger than chronological age. We examined associations of age acceleration at birth (‘gestational age acceleration’), and of age acceleration at school-age, with blood pressure and with intima-media thickness and distensibility of the common carotid artery, as markers of vascular structure and function, respectively, measured at age 10 years. Results This study was embedded in the Generation R Study, a population-based prospective cohort study. We included 1115 children with information on cord blood DNA methylation and blood pressure, carotid intima-media thickness or carotid distensibility. Gestational age acceleration was calculated using the Bohlin epigenetic clock, which was developed specifically for cord blood DNA methylation data. It predicts gestational age based on methylation levels of 96 CpGs from HumanMethylation450 BeadChip. We observed no associations of gestational age acceleration with blood pressure, carotid intima-media thickness or carotid distensibility at age 10 years. In analyses among children with peripheral blood DNA methylation measured at age 6 (n = 470) and 10 (n = 449) years, we also observed no associations of age acceleration at these ages with the same cardiovascular outcomes, using the ‘skin and blood clock,’ which predicts age based on methylation levels at 391 CpGs from HumanMethylation450 BeadChip. Conclusions Our findings do not provide support for the hypothesis that altered epigenetic aging during the earliest phase of life is involved in the development of cardiovascular risk factors in childhood.

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15–18%, at least p, Associations between of omega-3 fatty acids and mortality are not clear. Here the authors report that, based on a pooled analysis of 17 prospective cohort studies, higher blood omega-3 fatty acid levels correlate with lower risk of all-cause mortality.

Background Habitual intake of long‐chain omega‐3 fatty acids, especially eicosapentaenoic and docosahexaenoic acid (EPA+DHA) from fish, has been associated with a lower risk of fatal coronary heart disease (CHD) in population‐based studies. Whether that is also the case for patients with CHD is not yet clear. We studied the associations of dietary and circulating EPA+DHA and alpha‐linolenic acid, a plant‐derived omega‐3 fatty acids, with long‐term mortality risk after myocardial infarction. Methods and Results We analyzed data from 4067 Dutch patients with prior myocardial infarction aged 60 to 80 years (79% men, 86% on statins) enrolled in the Alpha Omega Cohort from 2002 to 2006 (baseline) and followed through 2018. Baseline intake of fish and omega‐3 fatty acids were assessed through a validated 203‐item food frequency questionnaire and circulating omega‐3 fatty acids were assessed in plasma cholesteryl esters. Hazard ratios (HRs) with 95% CIs were obtained from Cox regression analyses. During a median follow‐up period of 12 years, 1877 deaths occurred, of which 515 were from CHD and 834 from cardiovascular diseases. Dietary intake of EPA+DHA was significantly inversely associated with only CHD mortality (HR, 0.69 [0.52–0.90] for >200 versus ≤50 mg/d; HR, 0.92 [0.86–0.98] per 100 mg/d). Similar results were obtained for fish consumption (HR CHD , 0.74 [0.53–1.03] for >40 versus ≤5 g/d; P trend : 0.031). Circulating EPA+DHA was inversely associated with CHD mortality (HR, 0.71 [0.53–0.94] for >2.52% versus ≤1.29%; 0.85 [0.77–0.95] per 1‐SD) and also with cardiovascular diseases and all‐cause mortality. Dietary and circulating alpha‐linolenic acid were not significantly associated with mortality end points. Conclusions In a cohort of Dutch patients with prior myocardial infarction, higher dietary and circulating EPA+DHA and fish intake were consistently associated with a lower CHD mortality risk. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03192410.

Background DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits. Methods We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment. Results DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P −7, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth Penrichment = 1; childhood Penrichment = 2.00 × 10−4; adolescence Penrichment = 2.10 × 10−7). Conclusions There were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.

Currently, many a priori indexes are being used to assess maternal adherence to the Mediterranean diet (MD) during pregnancy but each with different components, cut-off points, and scoring systems. This narrative review aimed to identify all observational studies utilizing a priori indexes to assess maternal adherence to the MD during pregnancy. A systematic search was conducted in Pubmed until 1 July 2020. Among the 27 studies included, eight different a priori indexes were identified. Studies included a range of 5 to 13 dietary components in their indexes. Only three dietary components—vegetables, fruits, and fish—were common among all indexes. Dairy and alcohol were the only two components modified for pregnancy. All but one study either excluded alcohol from their index or reversed its scoring to contribute to decreased adherence to the MD. Approximately half of the studies established cut-off points based on the distribution of the study population; the others utilized fixed criteria. This review emphasizes the incongruent definitions of the MD impairing effective comparison among studies relating to maternal or offspring health outcomes. Future research should carefully consider the heterogeneous definitions of the MD in a priori indexes and the relevance of incorporating pregnancy-specific nutritional requirements.

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N=15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha=1.2×10−7; Bonferroni correction). In cord blood samples of 2,425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r=0.74, p=0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripherl blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range=3-82%) of the aggression–methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.

BackgroundAccumulating evidence links paternal adiposity in the peri-conceptional period to offspring health outcomes. DNA methylation has been proposed as a mediating mechanism, but very few studies have explored this possibility in humans.Methods and findingsIn the Pregnancy And Childhood Epigenetics (PACE) consortium, we conducted a meta-analysis of co-ordinated epigenome-wide association studies (EWAS) of paternal prenatal Body Mass Index (BMI) (with and without adjustment for maternal BMI) in relation to DNA methylation in offspring blood at birth (13 datasets; total n= 4,894) and in childhood (six datasets; total n = 1,982). We found little evidence of association at either time point: for all CpGs, the False Discovery Rate-adjusted P-values were >0.05. In sex-stratified analyses, we found just four CpGs where there was robust evidence of association in female offspring. To compare our findings to those of other studies, we conducted a systematic review, which identified seven studies, including five candidate gene studies showing associations between paternal BMI/obesity and offspring or sperm DNA methylation at imprinted regions. However, in our own study, we found very little evidence of enrichment for imprinted genes.ConclusionOur findings do not support the hypothesis that paternal BMI around the time of pregnancy is associated with offspring blood DNA methylation, even at imprinted regions.Author SummaryPrevious small, mostly candidate gene studies have shown associations between paternal pre-pregnancy BMI and offspring blood DNA methylation. However, in our large meta-analysis of co-ordinated EWAS results from a total of 19 datasets across two timepoints, we found little evidence to support these findings, even at imprinted regions. This does not rule out the possibility of a paternal epigenetic effect in different tissues, at regions not covered by the 450k array, via different mechanisms, or in populations with greater extremes of paternal BMI. More research is warranted to help understand the size and nature of contributions of paternal adiposity to offspring epigenetics and health outcomes.

Background: Several recent studies have linked higher blood levels of the long-chain omega-3 polyunsaturated fatty acids (PUFAs) with lower risk of certain disease outcomes, in particular cardiovascular disease (CVD). Limited studies have evaluated associations between n-3 PUFA levels and total and cause-specific mortality. Methods: We meta-analyzed the association of circulating omega-3 PUFAs with total and cause-specific mortality from 15 distinct cohorts in 10 countries following a total of 36,840 individuals (baseline average age 66 yrs; 47% female; median follow-up 13.7 yrs), with 11,635 deaths. Total mortality, and 3 cause-specific mortalities (CVD, cancer or other), were separately predicted by levels of the long chain omega-3 PUFAs eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA) and the Omega-3 index (EPA+DHA), as well as levels of alpha-linolenic acid (ALA, an intermediate chain n-3 PUFA). Using cohort-specific fatty acid levels (range from 10 th to 90 th percentiles), each cohort fit a Cox regression model adjusting for demographics, health related covariates, and n-6 PUFA levels. Cohort-specific estimates were pooled with inverse-variance weighted meta-analysis. Results: Higher levels of EPA, DPA, DHA and the Omega-3 index were all associated with lower all-cause mortality [EPA meta-analysis Hazard Ratio (HR)=0.90 (95% CI: 0.85, 0.95), DPA HR=0.84 (95% CI: 0.77, 0.91), DHA HR=0.84 (95% CI: 0.75, 0.93), Omega-3 index HR = 0.84 (95% CI 0.77, 0.92) (Figure)], as well as for each cause-specific mortality (CVD, cancer and other; HRs from 0.85 to 0.92). ALA showed no association with total-mortality or cause-specific mortality [HRs from 0.97 to 1.00)]. Conclusions: We have found strong evidence of inverse associations between long-chain omega-3 PUFA levels and all-cause and cause-specific mortality. Further controlled studies are needed in order to determine the extent to which these observations represent a causal or coincidental relationships.

Background: Little is known about alcohol consumption in relation to long-term mortality risk after myocardial infarction (MI). We examined alcohol consumption in relation to total, coronary heart disease (CHD) and cardiovascular disease (CVD) mortality in the Alpha Omega Cohort of Dutch post-MI patients. Methods: We included 4,365 patients (60-80y, 79% male) with MI ≤10y before enrolment. Heavy alcohol users (≥6 glasses/d) were excluded from cohort participation. Dietary intake and alcohol consumption were assessed using a 203-item validated food-frequency questionnaire. Patients were classified as non-drinkers (0 g/d, n=956), very light (>0-≤2 g/d, n=385), light (M: >2-≤10, F: >2-≤5 g/d, n=1,125), moderate (M: >10-≤30, F: >5-≤15 g/d, n=1,207) or heavy drinkers (M :>30, F: >15 g/d, n=692). Hazard ratios (HRs) for total, CHD and CVD mortality were obtained, adjusting for age, sex, education, smoking, BMI, physical activity, energy intake and other dietary factors. Results: Alcohol was consumed by 83% of men and 61% of women. During 11.1y follow up, 2,035 deaths occurred of which 575 from CHD and 801 from CVD. Compared to the reference group of very light drinkers, HRs (95%CI) for total mortality were 1.01 (0.85, 1.19) in non-drinkers, and 0.88 (0.74, 1.04), 0.85 (0.72, 1.01) and 0.91 (0.76, 1.10) in light, moderate and heavy drinkers respectively. Adding non-drinkers to the reference group did not affect HRs: 0.87 (0.78, 0.98), 0.85 (0.76, 0.96) and 0.91 (0.79, 1.05) for light, moderate and heavy drinkers. Associations were slightly stronger but non-significant for CVD and CHD mortality. Findings were roughly similar after exclusion of former drinkers (n=385), diabetics (n=883) and patients with poor health (n=1,010). Conclusion: Light to moderate alcohol consumption was weakly inversely associated with total, CVD and CHD mortality risk in post-MI patients. In this observational study, potential bias and confounding cannot be ruled out and findings should be interpreted cautiously in light of the totality of evidence.

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

Purpose of Review The burden of chronic kidney disease (CKD) is increasing worldwide. For CKD prevention, it is important to gain insight in commonly consumed foods and beverages in relation to kidney function. Recent Findings We included 21 papers of prospective cohort studies with 3–24 years of follow-up. We focused on meat, fish, dairy, vegetables, fruit, coffee, tea, soft drinks, and dietary patterns. There was convincing evidence that a healthy dietary pattern may lower CKD risk. Plant-based foods, coffee, and dairy may be beneficial. Unhealthy diets and their components, such as red (processed) meat and sugar-sweetened beverages, may promote kidney function loss. For other foods and beverages, associations with CKD were neutral and/or the number of studies was too limited to draw conclusions. Summary Healthy dietary patterns are associated with a lower risk of CKD. More research is needed into the effects of specific food groups and beverages on kidney function.

OBJECTIVE To study plasma and dietary linoleic acid (LA) in relation to type 2 diabetes risk in post–myocardial infarction (MI) patients. RESEARCH DESIGN AND METHODS We included 3,257 patients aged 60–80 years (80% male) with a median time since MI of 3.5 years from the Alpha Omega Cohort and who were initially free of type 2 diabetes. At baseline (2002–2006), plasma LA was measured in cholesteryl esters, and dietary LA was estimated with a 203-item food-frequency questionnaire. Incident type 2 diabetes was ascertained through self-reported physician diagnosis and medication use. Hazard ratios (with 95% CIs) were calculated by Cox regressions, in which dietary LA isocalorically replaced the sum of saturated (SFA) and trans fatty acids (TFA). RESULTS Mean ± SD circulating and dietary LA was 50.1 ± 4.9% and 5.9 ± 2.1% energy, respectively. Plasma and dietary LA were weakly correlated (Spearman r = 0.13, P < 0.001). During a median follow-up of 41 months, 171 patients developed type 2 diabetes. Plasma LA was inversely associated with type 2 diabetes risk (quintile [Q]5 vs. Q1: 0.44 [0.26, 0.75]; per 5%: 0.73 [0.62, 0.86]). Substitution of dietary LA for SFA+TFA showed no association with type 2 diabetes risk (Q5 vs. Q1: 0.78 [0.36, 1.72]; per 5% energy: 1.18 [0.59, 2.35]). Adjustment for markers of de novo lipogenesis attenuated plasma LA associations. CONCLUSIONS In our cohort of post-MI patients, plasma LA was inversely related to type 2 diabetes risk, whereas dietary LA was not related. Further research is needed to assess whether plasma LA indicates metabolic state rather than dietary LA in these patients.

Background Age at menarche has been associated with various health outcomes. We aimed to identify potential causal effects of age at menarche on health-related traits in a hypothesis-free manner. Methods We conducted a Mendelian randomization phenome-wide association study (MR-pheWAS) of age at menarche with 17,893 health-related traits in UK Biobank (n = 181,318) using PHESANT. The exposure of interest was the genetic risk score for age at menarche. We conducted a second MR-pheWAS after excluding SNPs associated with BMI from the genetic risk score, to examine whether results might be due to the genetic overlap between age at menarche and BMI. We followed up a subset of health-related traits to investigate MR assumptions and seek replication in independent study populations. Results Of the 17,893 tests performed in our MR-pheWAS, we identified 619 associations with the genetic risk score for age at menarche at a 5% false discovery rate threshold, of which 295 were below a Bonferroni-corrected P value threshold. These included potential effects of younger age at menarche on lower lung function, higher heel bone-mineral density, greater burden of psychosocial/mental health problems, younger age at first birth, higher risk of childhood sexual abuse, poorer cardiometabolic health, and lower physical activity. After exclusion of variants associated with BMI, the genetic risk score for age at menarche was related to 37 traits at a 5% false discovery rate, of which 29 were below a Bonferroni-corrected P value threshold. We attempted to replicate findings for bone-mineral density, lung function, neuroticism, and childhood sexual abuse using 5 independent cohorts/consortia. While estimates for lung function, higher bone-mineral density, neuroticism, and childhood sexual abuse in replication cohorts were consistent with UK Biobank estimates, confidence intervals were wide and often included the null. Conclusions The genetic risk score for age at menarche was related to a broad range of health-related traits. Follow-up analyses indicated imprecise evidence of an effect of younger age at menarche on greater bone-mineral density, lower lung function, higher neuroticism score, and greater risk of childhood sexual abuse in the smaller replication samples available; hence, these findings need further exploration when larger independent samples become available.

Aim: Cigarette smoking influences DNA methylation genome wide, in newborns from pregnancy exposure and in adults from personal smoking. Whether a unique methylation signature exists for in utero exposure in newborns is unknown. Materials & methods: We separately meta-analyzed newborn blood DNA methylation (assessed using Illumina450k Beadchip), in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers). Results & conclusion: Comparing meta-analyses, we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways. Our findings may provide insights into specific health impacts of prenatal exposure on offspring.

Background: Odd-chain fatty acids (OCFA) pentadecanoic (15:0) and heptadecanoic acid (17:0) are considered to reflect dairy intakes in studies on cardiometabolic outcomes. A recent randomized controlled trial on dietary fiber showed that circulating proportions of these OCFA may also be related to fiber intake, which may result from fermentation by gut microbes. Objective: To examine the associations between circulating OCFA and dairy and fiber intake in patients with a history of myocardial infarction. Methods: We performed cross-sectional analyses in a subsample of 896 Dutch post-MI patients of the Alpha Omega Cohort. Proportions of OCFA (as % of total fatty acids) were measured in plasma phospholipids (PL) and cholesterol esters (CE). Dietary intakes (g/d) were assessed using a 203-item validated food frequency questionnaire. Spearman correlations ( r ) were computed between circulating OCFA in PL and CE and intakes of total dairy, types of dairy products, dietary fiber and total meat. Results: Patients were on average 69 years old, 78% was male and 89% used statins. Dairy intake was predominantly from milk and yogurt. PL 15:0 was positively correlated with total dairy intake ( r =0.16, pr =0.01, p=0.75). For CE 15:0, correlations were similar. PL 17:0 was positively correlated with total dairy ( r =0.15, pr =0.13, pr =0.10, p=0.003; fiber: r =0.09, p=0.009). OCFA were not significantly correlated with meat intake. Conclusions: Plasma PL 15:0 and CE 15:0 were related to dairy and not to fiber intake. PL 17:0 and CE 17:0 were equally related to dairy and fiber intake. Cardiometabolic health benefits attributed to biomarkers of dairy intake, especially 17:0, may be (partly) attributable to fiber intake. Further research is needed into endogenous OCFA synthesis as a result of fermentation of dietary fiber by gut microbes.

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from −183 to 178 grams per 10% increase in methylation (PBonferroni, Birthweight has been found to associate with later-life health outcomes. Here the authors perform a meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, identifying differentially methylated CpGs in neonatal blood that associate with birthweight.

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

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

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

Background Circulating odd-chain fatty acids pentadecanoic (15:0) and heptadecanoic acid (17:0) are considered to reflect dairy intake. In cohort studies, higher circulating 15:0 and 17:0 were associated with lower type 2 diabetes risk. A recent randomized controlled trial in humans suggested that fiber intake also increased circulating 15:0 and 17:0, potentially resulting from fermentation by gut microbes. We examined the associations of dairy and fiber intake with circulating 15:0 and 17:0 in patients with a history of myocardial infarction (MI). Methods We performed cross-sectional analyses in a subsample of 869 Dutch post-MI patients of the Alpha Omega Cohort who had data on dietary intake and circulating fatty acids. Dietary intakes (g/d) were assessed using a 203-item food frequency questionnaire. Circulating 15:0 and 17:0 (as % of total fatty acids) were measured in plasma phospholipids (PL) and cholesteryl esters (CE). Spearman correlations (rs) were computed between intakes of total dairy, dairy fat, fiber, and circulating 15:0 and 17:0. Results Patients were on average 69 years old, 78% was male and 21% had diabetes. Total dairy intake comprised predominantly milk and yogurt (69%). Dairy fat was mainly derived from cheese (47%) and milk (15%), and fiber was mainly from grains (43%). Circulating 15:0 in PL was significantly correlated with total dairy and dairy fat intake (both rs = 0.19, p rs = 0.05, p = 0.11). Circulating 17:0 in PL was correlated both with dairy intake (rs = 0.14 for total dairy and 0.11 for dairy fat, p rs = 0.19, p rs = 0.11, p = 0.001). Circulating 15:0 was highest in those with high dairy intake irrespective of fiber intake, while circulating 17:0 was highest in those with high dairy and fiber intake. Conclusions In our cohort of post-MI patients, circulating 15:0 was associated with dairy intake but not fiber intake, whereas circulating 17:0 was associated with both dairy and fiber intake. These data suggest that cardiometabolic health benefits previously attributed to 17:0 as a biomarker of dairy intake may partly be explained by fiber intake.

Background: Gestational diabetes and gestational hypertensive disorders are associated with offspring obesity, but the role of maternal adiposity in these associations remains unclear. We aimed to investigate whether these pregnancy complications affect the odds of offspring obesity independently of maternal obesity. Methods: We did an individual participant data (IPD) meta-analysis of mother–offspring pairs from prospective birth cohort studies that had IPD on mothers with singleton liveborn children born from 1989 onwards and had information available about maternal gestational diabetes, gestational hypertension or pre-eclampsia, and childhood body-mass index (BMI). We applied multilevel mixed-effects models to assess associations of gestational diabetes, gestational hypertension, and pre-eclampsia with BMI SD scores and the odds of overweight and obesity throughout childhood, adjusting for lifestyle characteristics (offspring's sex, maternal age, educational level, ethnicity, parity, and smoking during pregnancy). We then explored the extent to which any association was explained by maternal pre-pregnancy or early-pregnancy BMI. Findings: 160 757 mother–offspring pairs from 34 European or North American cohorts were analysed. Compared with uncomplicated pregnancies, gestational diabetes was associated with increased odds of overweight or obesity throughout childhood (odds ratio [OR] 1·59 [95% CI 1·36 to 1·86] for early childhood [age 2·0–4·9 years], 1·41 [1·26 to 1·57] for mid childhood [5·0–9·9 years], and 1·32 [0·97 to 1·78] for late childhood [10·0–17·9 years]); however, these associations attenuated towards the null following adjustment for maternal BMI (OR 1·35 [95% CI 1·15 to 1·58] for early childhood, 1·12 [1·00 to 1·25] for mid childhood, and 0·96 [0·71 to 1·31] for late childhood). Likewise, gestational hypertension was associated with increased odds of overweight throughout childhood (OR 1·19 [95% CI 1·01 to 1·39] for early childhood, 1·23 [1·15 to 1·32] for mid childhood, and 1·49 [1·30 to 1·70] for late childhood), but additional adjustment for maternal BMI largely explained these associations (1·01 [95% CI 0·86 to 1·19] for early childhood, 1·02 [0·95 to 1·10] for mid childhood, and 1·18 [1·03 to 1·36] for late childhood). Pre-eclampsia was associated with decreased BMI in early childhood only (difference in BMI SD score −0·05 SD score [95% CI −0·09 to −0·01]), and this association strengthened following additional adjustment for maternal BMI. Interpretation: Although lowering maternal risk of gestational diabetes, gestational hypertension, and pre-eclampsia is important in relation to maternal and fetal pregnancy outcomes, such interventions are unlikely to have a direct impact on childhood obesity. Preventive strategies for reducing childhood obesity should focus on maternal BMI rather than on pregnancy complications. Funding: EU's Horizon 2020 research and innovation programme (LifeCycle Project). This study has received support from the US National Institute of Health (R01 DK10324) and European Research Council under the European Union’s Seventh 22 Framework Programme (FP7/2007-2013) / ERC grant agreement no 669545. The Swedish Research Council, The Swedish Heart and Lung Foundation, The Swedish Research Council for Working Life and Social Welfare, the Swedish Asthma and Allergy Association Research Foundation, The Swedish Research Council Formas, Stockholm County Council, and the European Commission’s Seventh Framework 29 Program MeDALL under grant agreement No. 261357. This study has received support from the British Heart Foundation (CS/16/4/32482), US National Institute of Health (R01 DK10324) and European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) / ERC grant agreement no 669545. The general design of the Generation R Study is made possible by financial support from the Erasmus MC, University Medical Center, Rotterdam, Erasmus University Rotterdam, Netherlands Organization for Health Research and Development (ZonMw), Netherlands Organisation for Scientific Research (NWO), Ministry of Health, Welfare and Sport and Ministry of Youth and Families. Research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007- 2013), project EarlyNutrition under grant agreement n°289346, the European Union’s Horizon 2020 research and innovation programme under grant agreement No 633595 (DynaHEALTH) and the European Union’s Horizon 2020 research and innovation programme under grant agreement 733206 (LifeCycle Project). European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreements Early Nutrition n° 289346 and by funds from the Norwegian Research Council's MILPAAHEL programme, project No.213148. This study was funded by Grants from UE (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), Spain: ISCIII (G03/176; FIS-FEDER: PI09/02647, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, and PI16/1288; Miguel Servet-FEDER CP11/00178, CP15/00025, and CPII16/00051), and Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, and UGP-15-249). The "Rhea" project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211250 Escape, EU FP7-2008-ENV-28.1.2.1.4 envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226285 ENRIECO, EU- FP7- HEALTH-2012 Proposal No 308333 HELIX) and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011-2014; “Rhea Plus”: Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012-15). ROLO is supported by the Health Research Board Ireland, the Health Research Centre for Health and Diet Research, and the European Union's Seventh Framework Programme (FP7/2007-2013), project EarlyNutrition under grant agreement no. 289346. The SWS is supported by grants from the Medical Research Council, National Institute for Health Research Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton National Health Service Foundation Trust, and the European Union’s Seventh Framework Programme (FP7/2007-2013), project EarlyNutrition (grant 289346). Study participants were drawn from a cohort study funded by the Medical Research Council and the Dunhill Medical Trust.

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. The BAMSE cohort was supported by The Swedish Research Council, The Swedish Heart-Lung Foundation, Freemason Child House Foundation in Stockholm, MeDALL (Mechanisms of the Development of ALLergy), a collaborative project conducted within the European Union (grant agreement No. 261357), Centre for Allergy Research, Stockholm County Council (ALF), Swedish foundation for strategic research (SSF, RBc08-0027, EpiGene project), the Strategic Research Programme (SFO) in Epidemiology at Karolinska Institutet, The Swedish Research Council Formas and the Swedish Environment Protection Agency.

Summary The increasing popularity of epigenome-wide association studies (EWAS) has led to the establishment of several large international meta-analysis consortia. However, when using data originating from multiple sources, a thorough and centralized quality control is essential. To facilitate this, we developed the QCEWAS R package. QCEWAS enables automated quality control of results files of EWAS. QCEWAS produces cohort-specific statistics and graphs to interpret the quality of the results files, graphs comparing results of multiple cohorts, as well as cleaned input files ready for meta-analysis. Availability and Implementation https://cran.r-project.org/web/packages/QCEWAS

BackgroundGestational weight gain differs according to pre-pregnancy body mass index and is related to the risks of adverse maternal and child health outcomes. Gestational weight gain charts for women in different pre-pregnancy body mass index groups enable identification of women and offspring at risk for adverse health outcomes. We aimed to construct gestational weight gain reference charts for underweight, normal weight, overweight, and grades 1, 2 and 3 obese women and to compare these charts with those obtained in women with uncomplicated term pregnancies.MethodsWe used individual participant data from 218,216 pregnant women participating in 33 cohorts from Europe, North America, and Oceania. Of these women, 9065 (4.2%), 148,697 (68.1%), 42,678 (19.6%), 13,084 (6.0%), 3597 (1.6%), and 1095 (0.5%) were underweight, normal weight, overweight, and grades 1, 2, and 3 obese women, respectively. A total of 138, 517 women from 26 cohorts had pregnancies with no hypertensive or diabetic disorders and with term deliveries of appropriate for gestational age at birth infants. Gestational weight gain charts for underweight, normal weight, overweight, and grade 1, 2, and 3 obese women were derived by the Box-Cox t method using the generalized additive model for location, scale, and shape.ResultsWe observed that gestational weight gain strongly differed per maternal pre-pregnancy body mass index group. The median (interquartile range) gestational weight gain at 40weeks was 14.2kg (11.4-17.4) for underweight women, 14.5kg (11.5-17.7) for normal weight women, 13.9kg (10.1-17.9) for overweight women, and 11.2kg (7.0-15.7), 8.7kg (4.3-13.4) and 6.3kg (1.9-11.1) for grades 1, 2, and 3 obese women, respectively. The rate of weight gain was lower in the first half than in the second half of pregnancy. No differences in the patterns of weight gain were observed between cohorts or countries. Similar weight gain patterns were observed in mothers without pregnancy complications.ConclusionsGestational weight gain patterns are strongly related to pre-pregnancy body mass index. The derived charts can be used to assess gestational weight gain in etiological research and as a monitoring tool for weight gain during pregnancy in clinical practice., ABCDr This work was supported by the Netherlands Organization for Health Research and Development (ZonMw) (TOP grant, 40-00812-98-11010).r ALSPACr The UK Medical Research Council and Wellcome (Grant ref.: 102215/2/13/2) and the University of Bristol provide core support fog ALSPAC. This study has received support from the US National Institute of Health (R01 DK10324) and European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no 669545. DA Lawlor works in a unit that receives UK MRC funding (MQ_UU_12013/5) and is an NIHR senior investigator (NF-Sl-0611-10196).r AOB/Fr All Our Families is funded through Alberta Innovates Interdisciplinary Team Grant 4200700595, the Alberta Children's Hospital Foundation, and the Max Bell Foundation.r DNBCr The Danish National Research Foundation has established the Danish Epidemiology Science Centre that initiated and created the Danish National Birth Cohort. The cohort is furthermore a result of a major grant from this foundation. Additional support for the Danish National Birth Cohort is obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. The DNBC 7-year follow-up is supported by the Lundbeck Foundation (195/04) and the Danish Medical Research Council (SWF 0646).r EDENr The EDEN Study was supported by Foundation for medical research (FRM), National Agency for Research (ANR), National Institute for Research in Public health (IRESP: TGIR cohorte sante 2008 program), French Ministry of Health (DGS), French Ministry of Research, INSERM Bone and Joint Diseases National Research (PRO-A) and Human Nutrition National Research Programs, Paris-Sud LJniversity, Nestle, French National Institute for Population Health Surveil lance (InVS), French National Institute for h-lealth Education (APES), the European Union FP7 programmes (FP7/2007-2013, HELIX, ESCAPE, ENRIECO, Medall projects), Diabetes National Re.search Program (through a collaboration with the French Association of Diabetic Patients (AFD)), French Agency for Environmental Health Safety (now ANSES), Mutuelle Generale de l'Education Nationale a complementary health inswance (MGEN), French national agency for food security, French-speaking association for the study of diabetes and metabolism (ALFEDIAM).r FCOUr FCOU study is supported by the US National Institutes of Health Fogarty International Center, US NIEHS, US CDC, US PA, and National Academy of Medical Sciences of Ukraine.r GASPIIr Ministry of Health.r GECKO Drenther The GECKO Drenthe birth cohort was funded by an unrestricted grant of Hutchison Whampoa Ld, Hong Kong and supported by the University of Groningen, Well Baby Clinic Foundation Icare, Noodlease, Paediatric Association Of The Netherlands and Youth Health Care Drenthe.r Generation Rr The general design of the Generation R Study is made possible by financial support from the Erasmus MC, University Medical Center, Rotterdam, Erasmus University Rotterdam, Netherlands Organization for Health Research and Development (ZonMw), Netherlands Organisation for Scientific Research (NWO), Ministry of Health, Welfare and Sport and Ministry of Youth and Families. Research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013), project ErlyNutrition under grant agreement no. 289346, the European Union's Horizon 2020 research and innovation programme under grant agreement no.; 633595 (DynalHEALTH)and the European Union's Horzon 2020 research and Innovation programme under grant agreement 733206 (LifeCycle Project). Romy Gaillard received funding from the Dutch Heart Foundation (grant number 2017T013) and the Dutch Diabetes Foundation (grant number 2017.81.002). Vincent Jaddoe received grants from the Netherlands Organization for Health Research and Development (VIDI 016.136.361) and the European Research Council (Consolidator Grant, ERC-2014-CoG-648916).r Generation XXIr Generation XX: was funded by Pmgrama Operational de Saude-Saude XXI, Quadro Comunitario de Apoio III and Administracao Regional de Saude Norte (Regional Department of Ministry of Health). This study was funded by FEDER through the Operational Programme Competitiveness and Internationalization and national funding from the Foundation for Science and Technology FCT (Portuguese Minstry of Science, Technology and Higher Education) (POCI-01-0145-FEDER-016837), under the project PathMOB.: Risco cardiomwtabolico na infancia: desde o inicio da vida ao fim da infancia (Ref. FCT PIDc/DTP-EP1/3306/2014) and the Unidade de Investigacao em Epiclemiologia-Instituto de Saude Publica da Universidade do Porte (EPIUnit) (POCI-01-0145-FEDER-006862; Ref. UlD/DTP/04750/2013). AC Santos holds a FG Investigator contract IF/01060/2015.r GENESISr The study was supported by a research grant from Friesland Foods Hellas. Gen3G Gen3G was supported by a Fonds de recherche du Quebec en sante (FRQ-S) operating grant (grant 4206971; a Canadian Institute of Health Reseach (CIHR) Operating grant (grant WOE) 115071); a Diabete Quebec grant and a Canadian Diabetes Association operating grant (grant #OG-3-08-2622-JA).r GINIplusr The GINIplus study was mainly supported for the first 3 years of the Federal Ministry for Education, Science, Research and Technology I:interventional arm) and Helmholtz Zentrum Munich (former GSF) (observational arm). The 4-year, 6-year, 10-year, and 15-year follow-up examinations of the GINIplus Study were covered from the respective budgets of the 5 study centers Helmoltz Zentrum Munich (former GSF), Research Institute at Marien-Hospital Wesel, LMU Munich, TU Munich and from 6 years onwards also from IUF-Leibniz Research-Institute for Environmental Medicine at the University of Dusseldorp and a grant from the Federal Ministry for Environment (IUF Dus seldoit FKZ 20462296). Further, the 15 year follow-up examination of the GINIplus study was supported by the Commission of the European Communities, the 7th Framework Program: MeDALL project, and as well by the companies Mead Johnson and Nestle.r HUMISr European Community's Seventh Framework Programme (P7/2007-2013) under grant agreements Early Nutrition no. 289346 and by funds from the Norwegian Research Council's MILPAAHEL programme, project no. 213148. INMA-Sabadellr This study was funded by grants from the Institute de Salad Carlos III (Red INMA G03/176) and the Genera tat de Catalunya-CIRIT (1999SGR 00241).r INMA-Valenciar This study was funded by Grants from UE (P7-ENV-2011 cod 282957 and HEALTH2010.2.4.5-1), Spain: ISCIII (G03/176; FIS-FEDER: P109/02647, PI11/01007, PI11/02591, PI11/02038, PI1.3/1944-, PI13/2032, P114/00891, PI14/01687, and PI16/1288; Miguel Servet-FEDER CP11/00178, CP15/00025, and CPII16/00051), and Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, and UGP-15-249).r INMA-Gipuzkoar This study was funded by grants from the Institute. de Salad Carlos III (Red INMA G03/176).; r KOALAr Data collection for the KOALA study from pregnancy up to age 1 year was financially supported by grants from Royal Friesland Foods (Leeuwarden); Trio dos Foundation (Zeist); Phoenix Foundation; Raphael Foundation; Iona Foundation, Foundation for the Advancement of Heilpedagogie (all in the Netherlands).r Krakow Cohortr The study received funding from a NIEHS R01 grants entitled: Vulnerability of the Fetus/Infant to PAH, PM2.5 and FTS and Developmental effects of early-life exposure to airborne PAC (R01ES010165 and R01ES015282) and from The Lundin Foundation, The John and Wendy Neu Family Foundation, The Gladys and Roland Harriman Foundation and an Anonymous Foundation.r LISAplusr The LISAplus study was mainly supported by grants from the Federal Ministry for Education Science, Research and Technology and in addition from Helmholtz Zentrum Munich (former GSF), Helmholtz Centre for Environmental Research-UFZ, Leipzig, Research Institute at Marien-Hospital Wesel, Pediatric Practice, Bad Honnef for the first 2 years. The 4-year, 6-year, 10-year, and 15-year follow-up examinations of the LISA-plus Study were covered from the respective budgets of the involved partners (Helmholtz Zentrum Munich (former GSF), Helmholtz Centre for Enironmental Research-UFZ, Leipzig, Research Institute at Marien-Hospital Wesel Pediatric Practice, Bad Honnef, IUr-Leibniz-Research Institute for Environmental Medicine at the University of Dusseldorf) and in addition by a grant from the Federal Ministry for Environment (IUF-Dussedorf, FKZ 204622961. Further, the 15-year follow-up examination of the LISAplus study was supported by the Commission of the FaMpean Communities and the 7th Framework Program: McDALL project.r LUKAS The grants from the Academy of Finland (grants 139021;287675); the Juho Vainio Foundation; the Foundation for Pediatric Research; EVE/VTR-funding; Paivikki and Saran Sohlberg Foundation; The Finnish Cultural Foundation; European Union QLK4-CT-2001-00250; and by the National Institute for Health and Welfare, Finland.r MoBar The Norwegian Mother and Child Cohort Study is supported by the Norwegian [Ministry of Health and Care. Services and the Ministry of Education and Research, NIH/NIEHS (contract no. N01-ES-75558), NIH/NINDS (grant. no. 1 UO1 NS 047537-01 and grant no. 2 UO1 NS 047537-06A1).r NINFEAr The NINFEA cohort was partially funded by the Compagnia San Paolo Fundation and by the Piedmont Region.r PELAGIEr The Pelagic cohort was supported by the French National Research Agency (ANR-2010-PRSP-007) and the French Research Institute for Public Health (AMC11004NSA-DGS).r PIAMAr The PIAMA study was supported by the Netherlands Organization for Health Research and Development; The Netherlands Organization for Scientific Research; The Netherlands Asthma Fund; The Netherlands Ministry of Spatial Planning, Housing, and the Environment; and The Netherlands Ministry of Health, Welfare, and Sport.r Piccolipiur The Piccolipiu project was financially supported by the Italian National Center for Disease Prevention and Control (CCM grants years 2010 and 2014) and by the Italian Ministry of Health (art 12 and 12 bis D.Igs 502/92).r PRIDE Studyr The PRIDE Study is supported by grants from the Netherlands Organization for Health Research and Development, the Radboud Institute for Health Sciences, and the Lung Foundation Netherlands.r Project Vivar National Institutes of Health (R01 HD034568, UGOD023286).; r RAINE Studyr The Western Australian Pregnancy Cohort (Raine Study) has been funded by program and project grants from the Australian National Health and Medical Research Council, the Commonwealth Scientific and Industrial Research Organization, Healthway, and the Lions Eye Institute in Western Australia. The University of Western Australia (UWA), Curtin University, the Raine Medical Research Foundation, the Telethon Kids Institute, the Women's and Infant's Research Foundation (KEMH), Murdoch University, The University of Notre Dame Australia, and Edith Cowan University provide funding for the Core Management of the Raine Study.r REPRO_PLr National Science Centre, Poland, under the grant DEC-2014/15/3/NZ7/00998, FP7 HEALS Grant No. 603946 and the Ministry of Science and Higher Education, under grant agreement no. 3068/7.PR./2014/2.r RHEAr The Rhea project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP&.STREP Hiwate, EU FP7 ENV.2007.1222 Project No. 211250 Escape, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009-single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No. 226285 ENIIIECO, EU-FP/-HEALTH-2012 Proposal No 308333 HELIX) and the Greer: Ministry of Health (Program of Prevention of obesity and ileuMdevelopmental disorders in preschool children, in Heraklion District, Crete, Greece: 2011-2014; Rhea Plus: Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health 2012-15).r Slovak PCB studyr Support was provided by US National Institutes of Health grants R01 CA096525, R03 TW007152, P30 E5001247, and K12 ES019852.r STEPSr This study was supported by the University of Turku, Abo Akademi University, the Turku University Hospital, and the City of Turku, as well as by the Academy of Finland (grants 121569 and 123571), the Juno Vainio Foundation, the Yrjo Jahnsson Foundation, the TorKu.r SWSr The SWS is supported by grants from the Medical Research Council, National Institute for Health Research Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton National Health Service Foundation Trust, and the European Union's Seventh Framework Programme. (P7/2007-2013), project EarlyNutrifion (grant 289346). Study participants were drawn from a cohort study funded by the Medical Research council and the Dunhill Medical Trust.

BACKGROUND: Physical activity (PA) is important in combating childhood obesity. Parents, and thus parental PA, could influence PA in young children. We examined whether the time spent at different intensities of PA and the type of parental PA are associated with the PA of children aged 4-7 years, and whether the associations between child-parent pairs were sex-specific.METHODS: All the participants were recruited from the Groningen Expert Center for Kids with Obesity (GECKO) birth cohort (babies born between 1 April 2006 and 1 April 2007 in Drenthe province, the Netherlands) and were aged 4-7 years during measurement. PA in children was measured using the ActiGraph GT3X (worn at least 3 days, ≥10 h per day). PA in parents was assessed using the validated SQUASH questionnaire.RESULTS: Of the N = 1146 children with valid ActiGraph data and 838 mothers and 814 fathers with valid questionnaire data, 623 child-parent pairs with complete data were analysed. More leisure time PA in mothers was associated with more time spent in moderate-to-vigorous PA (MVPA) in children (Spearman r = 0.079, P CONCLUSIONS: Higher PA in mothers, for instance in leisure activities, is related to higher PA in daughters, and more active fathers are related to more active sons. To support PA in young children, interventions could focus on the PA of the parent of the same sex as the child. Special attention may be needed for families where the parents have sedentary jobs, as children from these families seem to adopt more sedentary behaviour.