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Summary: Background: Adaptations in maternal and foetal metabolic pathways may predispose to altered foetal growth and adverse birth outcomes. Objective: To assess the associations of maternal early‐pregnancy metabolite profiles and infant metabolite profiles at birth with foetal growth from first trimester onwards and the odds of adverse birth outcomes. Methods: In a prospective population‐based cohort among 976 Dutch pregnant women and their children, serum concentrations of amino acids, non‐esterified fatty acids (NEFA), phospholipids (PL) and carnitines in maternal early‐pregnancy blood and in cord blood were obtained by liquid‐chromatography tandem mass spectrometry. Information on foetal growth was available from first trimester onwards. Results: After false discovery rate correction for multiple testing, higher infant total and individual NEFA concentrations were associated with a lower weight, length, and head circumference at birth. Higher infant total and individual acyl‐lysophosphatidylcholine (lyso.PC.a) and alkyl‐lysophosphatidylcholine concentrations were associated with higher weight and head circumference (lyso.PC.a only) at birth, higher odds of LGA and lower odds of SGA. Few individual maternal metabolites were associated with foetal growth measures in third trimester and at birth, but not with the odds of adverse birth outcomes. Conclusions: Our results suggest that infant metabolite profiles, particularly total and individual lyso.PC.a and NEFA concentrations, were strongly related to growth measures at birth and the odds of adverse birth outcomes. Few individual maternal early‐pregnancy metabolites, but not total metabolite concentrations, are associated with foetal growth measures in third trimester and at birth. [ABSTRACT FROM AUTHOR]

Reduced maternal placental growth factor (PlGF) and higher soluble fms-like tyrosine kinase (sFlt-1) concentrations in pregnancy may have persistent effects on offspring vasculature. We hypothesized that suboptimal maternal angiogenic factors in pregnancy may adversely affect fetal vascular development, leading to an increased risk of adverse atheriosclerotic adaptations and higher blood pressure in offspring. In a population-based prospective cohort among 4565 women and their offspring, we examined the associations of maternal serum PlGF and sFlt-1 concentrations in the first half of pregnancy with offspring vascular development. We measured childhood blood pressure and obtained childhood carotid intima media thickness and carotid distensibility through ultrasonography at 9 years. After adjustment for maternal sociodemographic and lifestyle characteristics, no associations were present of maternal first and second trimester angiogenic factors with childhood blood pressure, carotid intima media thickness (IMT) or distensibility in the total population. In preterm born children only, higher maternal second trimester PlGF concentrations, but not sFlt-1 concentrations, were associated with a lower childhood diastolic blood pressure (difference: -0.16 SDS (95% CI -0.30, −0.03) per SDS increase in maternal second trimester PlGF concentration). No associations among children born small-for-gestational age were present. In a low-risk population, maternal angiogenic factors in the first half of pregnancy are not associated with childhood blood pressure, carotid IMT or carotid distensibility after considering maternal socio-demographic and lifestyle factors. Only in children born preterm, lower maternal second trimester PlGF concentrations are associated with higher childhood diastolic blood pressure, but not with other vascular outcomes. [Display omitted] • Maternal gestational angiogenic factors PIGF and sFlt-1 are not associated with childhood carotid intima media thickness. • Maternal gestational angiogenic factors PIGF and sFlt-1 are not associated with childhood carotid distensibility. • In preterm born children, lower maternal gestational PlGF is associated with a higher childhood blood pressure. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Low folic acid, folate and vitamin B12 might affect tooth formation and mineralization. The conversion of folic acid into folate is catalysed by the methylenetetrahydrofolate (MTHFR) enzyme which is encoded by the MTHFR gene. Among 3728 mothers and their 10‐year‐old children from the Generation R Study, we investigated associations of maternal folic acid supplementation and prenatal folate and vitamin B12 concentrations with child dental development. Secondly, we checked the modifying effect of MTHFR‐C677T polymorphism. Methods: Information on folic acid supplementation was obtained by questionnaires. Concentrations of folate and vitamin B12 were measured from venous samples taken in early pregnancy. Developmental stages of teeth were defined by the Demirjian method at the age‐10 assessment. In addition, dental age of the children was calculated using the Dutch standard. GLM and multivariate linear regression models were built to study the associations. Results: Folic acid supplementation started when pregnancy was known (β = −0.09; 95% CI: −0.17, −0.01) and folic acid supplementation started prior to known pregnancy (β = −0.12; 95% CI: −0.20, −0.04) were both associated with decelerated dental development by 1‐2 months lower dental age of 10‐year‐old children. Folate (β = −0.02, 95% CI: −0.05, 0.02) and vitamin B12 (β = 0.03, 95% CI: −0.00, 0.06) were not associated with dental age. MTHFR‐C677T did not modify the associations. Conclusions: Maternal folic acid supplementation delays dental development of children by 1‐2 months dental age, whereas maternal folate and vitamin B12 concentrations in early pregnancy do not affect the timing of child dental development. [ABSTRACT FROM AUTHOR]

Objective: Maternal obesity and metabolic health affect pregnancy outcomes. We examined whether maternal metabolic profiles are associated with placental and fetal hemodynamics.Study Design: In a population-based prospective cohort study among 1175 women we examined the associations of an adverse maternal metabolic profile in early pregnancy with placental, fetal cerebral and cardiac hemodynamic development. We obtained maternal pre-pregnancy BMI by questionnaire and measured blood pressure, cholesterol, triglycerides and glucose concentrations at a median gestational age of 12.6 (95 % range 9.6-17.1) weeks. An adverse maternal metabolic profile was defined as ≥4 risk factors. Placental and fetal hemodynamics were measured by pulsed-wave-Doppler at a median gestational age of 30.3 (95 % range 28.8-32.3) weeks.Results: An adverse maternal metabolic profile was associated with a 0.29 Z-score higher (95 %CI 0.08-0.50) fetal cerebral middle artery pulsatility index (PI), but not with placental or fetal cardiac hemodynamic patterns. When the individual components of an adverse maternal metabolic profile were assessed, we observed that higher maternal total cholesterol and triglyceride concentrations were associated with a higher cerebral middle artery PI (Z-score, 0.09 (95 %CI 0.02-0.15), 0.09 (95 %CI 0.03-0.15) per Z-score increase). Higher total and HDL maternal cholesterol concentrations were also associated with a higher aorta ascendens peak systolic velocity (PSV) Z-score, 0.08 (95 %CI 0.01-0.14)), and a larger left cardiac output (Z-score, 0.08 (95 %CI 0.00-0.15), respectively).Conclusion: An adverse maternal metabolic profile, especially higher cholesterol and triglycerides concentrations, are associated with increased fetal cerebral vascular resistance and larger fetal aorta ascendens diameter, PSV and left cardiac output, but not with placental vascular resistance indices. Further studies are needed to identify long-term consequences of the observed associations. [ABSTRACT FROM AUTHOR]

Stress inducement by physical exercise requires major cardiovascular adaptations in both adults and children to maintain an adequate perfusion of the body. As physical exercise causes a stress situation for the cardiovascular system, cardiovascular exercise stress tests are widely used in clinical practice to reveal subtle cardiovascular pathology in adult and childhood populations with cardiac and cardiovascular diseases. Recently, evidence from small studies suggests that the cardiovascular stress response can also be used within research settings to provide novel insights on subtle differences in cardiovascular health in non-diseased adults and children, as even among healthy populations an abnormal response to physical exercise is associated with an increased risk of cardiovascular diseases. This narrative review is specifically focused on the possibilities of using the cardiovascular stress response to exercise combined with advanced imaging techniques in pediatric population-based studies focused on the early origins of cardiovascular diseases. We discuss the physiology of the cardiovascular stress response to exercise, the type of physical exercise used to induce the cardiovascular stress response in combination with advanced imaging techniques, the obtained measurements with advanced imaging techniques during the cardiovascular exercise stress test and their associations with cardiovascular health outcomes. Finally, we discuss the potential for cardiovascular exercise stress tests to use in pediatric population-based studies focused on the early origins of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Background: Airway bacterial carriage might play a role in respiratory disease. We hypothesize that nasal carriage with Staphylococcus aureus or nasopharyngeal carriage with Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae predisposes individuals to adverse respiratory health. Objective: To examine the association of early‐life airway bacterial carriage with respiratory tract infections and vice versa, and of early‐life airway bacterial carriage with wheezing, lung function, and asthma in later childhood. Methods: We collected upper airway swabs for bacterial culturing for S aureus, H influenzae, M catarrhalis, and H influenzae at six timepoints between the ages of 6 weeks and 6 years among 945 children participating in a population‐based prospective cohort study. Information on respiratory tract infections and wheezing until age 6 years, and asthma at age 10 years was obtained by questionnaires. Lung function at age 10 years was measured by spirometry. We tested possible bidirectional associations between airway bacterial carriage and respiratory tract infections by cross‐lagged models, and associations of repeatedly measured airway bacterial carriage with wheezing, lung function, and asthma by generalized estimating equations models and regression models. Results: Cross‐lagged modeling showed that early‐life airway bacterial carriage was not consistently associated with upper and lower respiratory tract infections or vice versa. Nasopharyngeal carriage with any bacteria in infancy was associated with an increased risk of wheezing (OR [95% CI]: 1.66 [1.31, 2.10]). Airway bacterial carriage was not consistently associated with school‐age lung function or asthma. Conclusion: Nasopharyngeal carriage with any bacteria is associated with wheezing, but not respiratory tract infections, asthma, or lung function. [ABSTRACT FROM AUTHOR]

Introduction: Fetal changes in DNA methylation may underlie associations of maternal smoking during pregnancy with adverse outcomes in children. We examined critical periods and doses of maternal smoking during pregnancy in relation to newborn DNA methylation, and associations of paternal smoking with newborn DNA methylation.Aims and Methods: This study was embedded in the Generation R Study, a population-based prospective cohort study from early pregnancy onwards. We assessed parental smoking during pregnancy using questionnaires. We analyzed associations of prenatal smoke exposure with newborn DNA methylation at 5915 known maternal smoking-related cytosine-phosphate-guanine sites (CpGs) in 1261 newborns using linear regression. Associations with false discovery rate-corrected p-values < .05 were taken forward.Results: Sustained maternal smoking was associated with newborn DNA methylation at 1391 CpGs, compared with never smoking. Neither quitting smoking early in pregnancy nor former smoking was associated with DNA methylation, compared with never smoking. Among sustained smokers, smoking ≥5, compared with <5, cigarettes/d was associated with DNA methylation at seven CpGs. Paternal smoking was not associated with DNA methylation, independent of maternal smoking status.Conclusions: Our results suggest that CpGs associated with sustained maternal smoking are not associated with maternal smoking earlier in pregnancy or with paternal smoking. Some of these CpGs show dose-response relationships with sustained maternal smoking. The third trimester may comprise a critical period for associations of smoking with newborn DNA methylation, or sustained smoking may reflect higher cumulative doses. Alternatively, maternal smoking limited to early pregnancy and paternal smoking may be associated with DNA methylation at specific other CpGs not studied here.Implications: Our results suggest that quitting maternal smoking before the third trimester of pregnancy, and possibly lowering smoking dose, may prevent differential DNA methylation in the newborns at CpGs associated with sustained smoking. If the relevance of DNA methylation for clinical outcomes is established, these results may help in counseling parents-to-be about quitting smoking. [ABSTRACT FROM AUTHOR]

Objective: Gestational diabetes mellitus has been associated with offspring cardiac congenital malformations, ventricular hypertrophy, and diastolic dysfunction in large observational cohort studies and experimental animal models. We assessed the associations of maternal random glucose concentrations across the full range with childhood cardiac ventricular structure and function.Research Design and Methods: In a population-based prospective cohort among 1,959 women and their offspring, maternal random glucose concentrations were measured at a median 13.1 weeks' gestation (95% range 10.5-16.8 weeks). We obtained offspring cardiac outcomes, relative to body size, through cardiac MRI at 10 years.Results: The mean maternal random glucose concentration was 4.4 mmol/L (SD 0.8). The highest quintile of maternal glucose concentrations, compared with the lowest quintile, was associated with a lower childhood left ventricular mass (-0.19 SD score [SDS]; 95% CI -0.31, -0.07) and left ventricular end-diastolic volume (-0.17 SDS; 95% -0.28, -0.05). Also, higher maternal glucose concentrations across the full range per 1 mmol/L increase were associated with a lower childhood left ventricular mass and left ventricular end-diastolic volume (P values ≤0.05). Adjustment for maternal prepregnancy BMI, gestational age, and weight at birth or childhood BMI and blood pressure did not influence the effect estimates. Maternal glucose concentrations were not significantly associated with childhood right ventricular end-diastolic volume or left and right ventricular ejection fraction.Conclusions: Higher maternal random glucose concentrations in the first half of pregnancy are associated with a lower childhood left ventricular mass and left ventricular end-diastolic volume, with the strongest associations for childhood left ventricular mass. These associations were not explained by maternal, birth, or childhood characteristics. Further studies are needed to replicate these findings using repeated maternal glucose measurements throughout pregnancy and offspring cardiac outcomes throughout childhood and adulthood. [ABSTRACT FROM AUTHOR]

Objective: To examine the associations of maternal age at the start of pregnancy across the full range with second and third trimester uterine and umbilical artery flow indices, and placental weight.Study Design: In a population-based prospective cohort study among 8271 pregnant women, we measured second and third trimester uterine artery resistance and umbilical artery pulsatility indices and the presence of third trimester uterine artery notching using Doppler ultrasound.Results: Compared to women aged 25-29.9 years, higher maternal age was associated with a higher third trimester uterine artery resistance index (difference for women 30-34.9 years was 0.10 SD (95% Confidence Interval (CI) 0.02 to 0.17), and for women aged ≥40 years 0.33 SD (95% CI 0.08 to 0.57), overall linear trend 0.02 SD (95% CI 0.01 to 0.03) per year). Compared to women aged 25-29.9 years, women younger than 20 years had an increased risk of third trimester uterine artery notching (Odds Ratio (OR) 1.97 (95% CI 1.30-3.00)). A linear trend was present with a decrease in risk of third trimester uterine artery notching per year increase in maternal age (OR 0.96 (95% CI 0.94 to 0.98)). Maternal age was not consistently associated with umbilical artery pulsatility indices or placental weight.Conclusions: Young maternal age is associated with higher risk of third trimester uterine artery notching, whereas advanced maternal age is associated with a higher third trimester uterine artery resistance index, which may predispose to an increased risk of pregnancy complications. [ABSTRACT FROM AUTHOR]

Summary Background: Maternal caffeine intake during pregnancy is associated with an increased risk of childhood obesity. Studies in adults suggest that caffeine intake might also directly affect visceral and liver fat deposition, which are strong risk factors for cardio‐metabolic disease. Objective: To assess the associations of maternal caffeine intake during pregnancy with childhood general, abdominal, and liver fat mass at 10 years of age. Methods: In a population‐based cohort from early pregnancy onwards among 4770 mothers and children, we assessed maternal caffeine intake during pregnancy and childhood fat mass at age 10 years. Results: Compared with children whose mothers consumed <2 units of caffeine per day during pregnancy, those whose mothers consumed 4‐5.9 and ≥6 units of caffeine per day had a higher body mass index, total body fat mass index, android/gynoid fat mass ratio, and abdominal subcutaneous and visceral fat mass indices. Children whose mothers consumed 4‐5.9 units of caffeine per day had a higher liver fat fraction. The associations with abdominal visceral fat and liver fat persisted after taking childhood total body fat mass into account. Conclusions: High maternal caffeine intake during pregnancy was associated with higher childhood body mass index, total body fat, abdominal visceral fat, and liver fat. The associations with childhood abdominal visceral fat and liver fat fraction were independent of childhood total body fat. This suggests differential fat accumulation in these depots, which may increase susceptibility to cardio‐metabolic disease in later life. [ABSTRACT FROM AUTHOR]

Introduction: Adverse exposures in early life may predispose children to cardio-metabolic disease in later life. Metabolomics may serve as a valuable tool to disentangle the metabolic adaptations and mechanisms that potentially underlie these associations. Objectives: To describe the acquisition, processing and structure of the metabolomics data available in a population-based prospective cohort from early pregnancy onwards and to examine the relationships between metabolite profiles of pregnant women and their children at birth and in childhood. Methods: In a subset of 994 mothers-child pairs from a prospective population-based cohort study among pregnant women and their children from Rotterdam, the Netherlands, we used LC–MS/MS to determine concentrations of amino acids, non-esterified fatty acids, phospholipids and carnitines in blood serum collected in early pregnancy, at birth (cord blood), and at child's age 10 years. Results: Concentrations of diacyl-phosphatidylcholines, acyl-alkyl-phosphatidylcholines, alkyl-lysophosphatidylcholines and sphingomyelines were the highest in early pregnancy, concentrations of amino acids and non-esterified fatty acids were the highest at birth and concentrations of alkyl-lysophosphatidylcholines, free carnitine and acyl-carnitines were the highest at age 10 years. Correlations of individual metabolites between pregnant women and their children at birth and at the age of 10 years were low (range between r = − 0.10 and r = 0.35). Conclusion: Our results suggest that unique metabolic profiles are present among pregnant women, newborns and school aged children, with limited intergenerational correlations between metabolite profiles. These data will form a valuable resource to address the early metabolic origins of cardio-metabolic disease. [ABSTRACT FROM AUTHOR]

Background: Epstein‐Barr virus (EBV) and cytomegalovirus (CMV) infection are common in early childhood. CMV infection favours a T‐helper‐1 and EBV infection a T‐helper‐2 cell response, possibly leading to disbalanced T‐helper cell response, and subsequent risk of asthma or atopy. Objective: To study the associations of EBV and CMV with lung function, asthma and inhalant allergic sensitization at school age. Methods: This study among 3546 children was embedded in a population‐based prospective cohort. At age 6 years, serum IgG levels against EBV and CMV were measured by ELISA. At age 10 years, lung function was measured by spirometry, asthma by questionnaire and inhalant allergic sensitization by skin prick test. Results: Unadjusted models showed that seropositivity for EBV was associated with a higher FEV1 and FEF75 (Z‐score difference (95% CI): 0.09 (0.02, 0.16) and 0.09 (0.02, 0.15)), while seropositivity for CMV was not. Specific combinations of viruses showed that seropositivity for EBV was only associated with FEV1 and FEF75 in the presence of seropositivity for CMV (0.12 (0.04, 0.20)) and 0.08 (0.01, 0.15)). Seropositivity for CMV in the absence of seropositivity for EBV was associated with an increased risk of inhalant allergic sensitization (OR (95% CI): 1.31 (1.02, 1.68)). All effect estimates attenuated into non‐significant mainly after adjustment for child's ethnicity. Seropositivity for EBV or CMV was not associated with asthma. Conclusions and Clinical Relevance: Associations of EBV and CMV infections in early childhood with school‐age lung function and inhalant allergic sensitization are explained by ethnicity, or sociodemographic and lifestyle‐related factors. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic fatty liver disease is the most common chronic liver disease in children in western countries. Adverse early-life exposures are associated with higher liver fat percentages in children. Differential DNA methylation may underlie these associations. We aimed to identify differential DNA methylation in newborns and children associated with liver fat accumulation in childhood. We also examined whether DNA methylation at 22 cytosine-phosphate-guanine sites (CpGs) associated with adult non-alcoholic fatty liver disease is associated with liver fat in children. Within a population-based prospective cohort study, we analyzed epigenome-wide DNA methylation data of 785 newborns and 344 10-year-old children in relation to liver fat fraction at 10 years. DNA methylation was measured using the Infinium HumanMethylation450 BeadChip (Illumina). We measured liver fat fraction by Magnetic Resonance Imaging. Associations of single CpG DNA methylation at the two-time points with liver fat accumulation were analyzed using robust linear regression models. We also analyzed differentially methylation regions using the dmrff package. We looked-up associations of 22 known adult CpGs at both ages with liver fat at 10 years. Results: The median liver fat fraction was 2.0% (95% range 1.3, 5.1). No single CpGs and no differentially methylated regions were associated with liver fat accumulation. None of the 22 known adult CpGs were associated with liver fat in children. Conclusions: DNA methylation at birth and in childhood was not associated with liver fat accumulation in 10-year-old children in this study. This may be due to modest sample sizes or DNA methylation changes being a consequence rather than a determinant of liver fat. [ABSTRACT FROM AUTHOR]

Background: Obesity, specifically abdominal adiposity, is associated with increased risks of lung function impairment and asthma in children, but potential adverse effects among adolescents are unknown. We hypothesized that elevated amounts of specific abdominal fat depots during childhood and adolescence may lead to adverse respiratory outcomes in adolescents. Methods: In a population‐based prospective cohort study among 2877 children at 13 years, we measured specific abdominal fat depots including subcutaneous fat mass and visceral fat mass by magnetic resonance imaging. Lung function was measured by spirometry, and current asthma by a questionnaire. Conditional regression analyses were used to examine the associations of abdominal fat depots with respiratory outcomes in adolescence. Results: After adjustment for confounders and child's body mass index, higher subcutaneous and visceral fat mass index at age 13 years, independent of these measures at earlier age, were associated with lower FEV1, FEV1/FVC, and FEF75 (range Z‐score difference (95% CI): −0.10 (−0.15, −0.06) to −0.06 (−0.11, −0.01)). Also, an increase in subcutaneous and visceral fat between ages 10 and 13 years was associated with a decrease in FEV1, FEV1/FVC, and FEF75 during the same period. No associations of abdominal fat depots with asthma were observed. Conclusion: Adolescents with higher amounts of subcutaneous and visceral fat, independent of that at an earlier age and body mass index, have an increased risk of lung function impairment. [ABSTRACT FROM AUTHOR]

Objectives The existing body of evidence reports an inconsistent association between subjective and objective orthodontic treatment need. The concept of oral health-related quality of life ( OHRQoL) might help to explain the differences in subjective and objective orthodontic treatment need. Our aim was to investigate the association of subjective orthodontic treatment with OHRQoL in children. Methods This cross-sectional study was embedded in the Generation R Study, a population-based prospective cohort study. OHRQoL and subjective orthodontic treatment need were assessed by parental questionnaires. Questionnaire items were individually compared among children with no, borderline and definite subjective orthodontic need. The association between subjective orthodontic treatment need and OHRQoL was investigated in multivariate regression analysis with weighted least squares. Differences by sex and levels of objective orthodontic treatment need were evaluated. Results In total, 3774 children were included in the analysis. Children with borderline subjective orthodontic treatment need and those with definite subjective orthodontic treatment need had significantly poorer OHRQoL based on the fully adjusted model (adjusted regression coefficient (aβ)=−0.49, 95% CI: −0.75, −0.30; (aβ)=−1.58, 95% CI: −1.81, −1.58, respectively). The association between subjective orthodontic treatment need and OHRQoL was stronger in girls than in boys and stronger in children with objective orthodontic treatment need than in those with none. Conclusions Oral health-related quality of life is poorer in children with subjective orthodontic treatment need. This has not been investigated before in such a large-population-based study and clearly offers an explanation for the lack of concurrence between objective and subjective orthodontic treatment need. [ABSTRACT FROM AUTHOR]

Pregnant women are exposed to various chemicals, including endocrine-disrupting chemicals (EDCs) such as phthalates and bisphenols. Increasing evidence suggests that early life exposures to phthalates and bisphenols may contribute to cardiometabolic risks. The aim of this narrative review was to summarize current knowledge of the effects of fetal and childhood exposure to phthalates and bisphenols on child growth and child cardiometabolic outcomes and the effects on maternal outcomes. In total, 54 studies were identified and included. The majority of studies found effects of phthalates and bisphenols on maternal, child growth, and cardiometabolic outcomes. Currently results suggest that early life exposure to phthalates and bisphenols may have a substantial influence on perinatal and postnatal cardiometabolic programming. In a large part of the investigated outcomes studies show contradictory results. However, the majority of the existing evidence is based on non-cohort studies with single samples neglecting time-variant effects and complicating conclusions regarding causal inference. More studies are needed investigating the mechanisms and its potential interactions. [ABSTRACT FROM AUTHOR]

Background: Limited information is available about the prevalence, ethnic disparities, and risk factors of hypertension within developing countries. We used data from a nationwide study on non-communicable disease (NCD) risk factors to estimate, explore, and compare the prevalence of hypertension overall and in subgroups of risk factors among different ethnic groups in Suriname. Method: The Suriname Health Study used the World Health Organization Steps design to select respondents with a stratified multistage cluster sample of households. The overall and ethnic specific prevalences of hypertension were calculated in general and in subgroups of sex, age, marital status, educational level, income status, employment, smoking status, residence, physical activity, body mass index (BMI), and waist circumference (WC). Differences in the prevalence between ethnic subgroups were assessed using the Chi-square test. We used several adjustment models to explore whether the observed ethnic differences were explained by biological, demographic, lifestyle, or anthropometric risk factors. Results: The prevalence of hypertension was 26.2 % (95 % confidence interval 25.1 %-27.4 %). Men had higher mean values for systolic and diastolic blood pressure compared to women. Blood pressure increased with age. The prevalence was highest for Creole, Hindustani, and Javanese and lowest for Amerindians, Mixed, and Maroons. Differences between ethnic groups were measured in the prevalence of hypertension in subcategories of sex, marital status, education, income, smoking, physical activity, and BMI. The major difference in association of ethnic groups with hypertension was between Hindustani and Amerindians. Conclusion: The prevalence of hypertension in Suriname was in the range of developing countries. The highest prevalence was found in Creoles, Hindustani, and Javanese. Differences in the prevalence of hypertension were observed between ethnic subgroups with biological, demographic, lifestyle, and anthropometric risk factors. These findings emphasize the need for ethnic-specific research and prevention and intervention programs. [ABSTRACT FROM AUTHOR]

Background: Fetal exposure to maternal smoking is associated with an adverse cardiovascular risk profile in later life. Early microvasculature adaptations might be part of the underlying mechanisms for these associations.Aims: The aim of this study was to examine the influence of maternal smoking during pregnancy on retinal vessel calibers in children.Study Design: We performed a population-based prospective cohort study among 3564 school-age children. Maternal smoking patterns during pregnancy were assessed by questionnaires.Outcome Measures: At the median age of 6.0 years (95% range 5.8, 8.0 years), we measured childhood retinal vessel calibers from retinal photographs.Results: No differences were observed in childhood retinal arteriolar and venular calibers among offspring from mothers who smoked in the first trimester and mothers who continued smoking throughout pregnancy, as compared to mothers who did not smoke during pregnancy. Also, no dose-dependent associations of the number of cigarettes smoked during pregnancy with childhood retinal vessel calibers were present.Conclusion: Maternal smoking during pregnancy did not influence childhood retinal arteriolar and venular calibers. The mechanisms linking fetal smoke exposure with cardiovascular risk factors in later life may include other mechanisms than structural microvasculature adaptations. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVE: Alterations in retinal microvasculature are associated with increased risk of cardiovascular disease. We examined the associations of retinal vessel caliber with cardiovascular markers in school-age children. METHODS: Among 4007 school-age children (median age of 6.0 years), we measured cardiovascular markers and retinal vessel calibers from digitized retinal photographs. RESULTS: Narrower retinal arteriolar caliber was associated with higher systolic and diastolic blood pressure (20.20 SD score [SDS] [95% confidence interval (CI) -0.24 to -0.18] and -0.14 SDS [-0.17 to -0.11], respectively, per SDS increase in retinal arteriolar caliber), mean arterial pressure, and pulse pressure, but not with carotid-femoral pulse wave velocity, heart rate, cardiac output, or left ventricular mass. A wider retinal venular caliber was associated with lower systolic blood pressure, mean arterial pressure, and pulse pressure and higher carotid-femoral pulse wave velocity (carotid-femoral pulse wave velocity difference = 0.04 SDS [95% CI 0.01 to 0.07] per SDS increase in retinal venular caliber). Both narrower retinal arteriolar and venular calibers were associated with higher risk of hypertension at the age of 6 years, with the strongest association for retinal arteriolar caliber (odds ratio 1.35 [95% CI 1.21 to 1.45] per SDS decrease in arteriolar caliber). Adjustment for parental and infant sociodemographic factors did not influence the observed associations. CONCLUSIONS: Both retinal arteriolar and venular calibers are associated with blood pressure in school-age children, whereas retinal venular caliber is associated with carotid-femoral pulse wave velocity. Microvascular adaptations in childhood might influence cardiovascular health and disease from childhood onward. [ABSTRACT FROM AUTHOR]

Customized fetal growth charts take account of the individual variation in the fetal growth potential based on non-pathological maternal and fetal characteristics. Application of these customized weight charts might improve the distinction between pathological growth-restricted fetuses and fetuses that are small but have reached their growth potential. Current models for customized growth standards have been based on birth weight and fetal growth data. Variables used for customization are gestational age, maternal age, parity, ethnicity, height, weight and fetal sex. Thus far, it remains controversial whether these maternal and fetal characteristics used for customization are strong enough predictors for fetal growth on an individual level and are truly physiological characteristics. The currently available customized growth charts might be of benefit for use in epidemiological studies and clinical practice. Further studies are needed to validate these customized growth models and to examine whether and to what extend they improve identification of children that are at risk for morbidity in the perinatal period and later in life. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

OBJECTIVE We evaluated the associations of both maternal and paternal smoking during pregnancy with the risk of type 2 diabetes in daughters and explored whether any association was explained by weight at birth or BMI throughout life. RESEARCH DESIGN AND METHODS We used data from 34, 453 participants of the Nurses' Health Study II. We used Cox proportional hazards models to examine the associations of maternal and paternal smoking during pregnancy with incidence of type 2 diabetes in daughters between 1989 and 2009. RESULTS Maternal smoking during the first trimester only was associated with the risk of type 2 diabetes in the offspring, independent of confounders, birth weight, and later-life BMI (fully adjusted hazard ratio 1.34 [95% CI 1.01, 1.76]). In the age adjusted models, both continued maternal smoking during pregnancy and paternal smoking tended to be associated with an increased risk of type 2 diabetes in daughters. Perinatal and adult life variables did not explain these associations, but additional adjustment for current BMI fully attenuated the effect estimates. CONCLUSIONS The associations of maternal and paternal smoking during pregnancy with the risk of type 2 diabetes in daughters were largely explained by BMI throughout the life course. Further studies are needed to explore the role of first-trimester-only maternal smoking on insulin resistance in the offspring. Also, similar effect estimates for maternal and paternal smoking suggest that the associations reflect shared family-based or lifestyle-related factors. [ABSTRACT FROM AUTHOR]

The objective of this study was to examine the validity of the diagnosis of "febrile seizure" as reported by parents. The study was embedded in a population-based prospective cohort study. Information on paroxysmal events was obtained by screening questions at ages 1, 2, and 3 years. One of these questions was the following: "Did your child have a febrile seizure?" If a screen-positive result was found, an additional questionnaire was sent and the medical record was consulted. Based on this information, paroxysmal events were classified by a pediatric neurologist as febrile seizure or other event. The validity of a positive reply to the screening question on febrile seizures was assessed, taking this classification as reference standard. Analyses were based on participants who reported at least one paroxysmal event (n = 610). The sensitivity of the positive reply to the question, "Did your child have a febrile seizure?", for the diagnosis of febrile seizures was 92%, the specificity 72%, the positive predictive value 41%, and the negative predictive value 98%. In conclusion, the sensitivity of the question, "Did your child have a febrile seizure?", is high. The positive predictive value is only 41%. Although this question may be appropriate as a screening instrument for febrile seizures, a second stage of evaluation is necessary to identify true cases. [ABSTRACT FROM AUTHOR]

Background Inflammatory processes during pregnancy might affect fetal lung development and immune responses. We examined the associations of maternal and cord blood C-reactive protein levels with respiratory symptoms and eczema in preschool children. Methods This study was embedded in a population-based prospective cohort study of 4984 children. Generalized estimating equations were used to assess the effect of C-reactive protein levels on respiratory symptoms or eczema. C-reactive protein levels were measured during early pregnancy and at birth. Wheezing, lower respiratory tract infections, and eczema until the age of 4 yr were annually obtained by questionnaires. Results Maternal C-reactive protein was not associated with the risks of wheezing and lower respiratory tract infections. Compared to children with maternal C-reactive protein in the lowest quarter, children in the highest quarter had increased risks of eczema OR 1.20 (1.03, 1.40). Compared to children with cord blood C-reactive protein lower than 0.20 mg/l, those with levels higher than 0.20 mg/l had increased risks of wheezing, OR 1.21 (1.07, 1.36), and lower respiratory tract infections, OR 1.21 (1.05, 1.39), but not of eczema. Conclusions Our results suggest that elevated maternal C-reactive protein in pregnancy is associated with a higher risk of eczema, and C-reactive protein in cord blood with a higher risk of wheezing and lower respiratory tract infections in the first 4 yrs. [ABSTRACT FROM AUTHOR]

Aim General developmental outcome is known to be good in school-aged children who experienced febrile seizures. We examined cognitive and behavioural outcomes in preschool children with febrile seizures, including language and executive functioning outcomes. Method This work was performed in the Generation R Study, a population-based cohort study in Rotterdam from early fetal life onwards. Information about the occurrence of febrile seizures was collected by questionnaires at the ages of 1, 2, and 3 years. At the age of 3 years, behaviour and emotion were assessed using the Child Behavior Checklist. Information on expressive language development was obtained by the Language Development Survey at the age of 2 years 6 months. To assess executive functioning, parents completed the Behaviour Rating Inventory of Executive Function - Preschool Version when their children were 4 years old. Final analyses were based on 3157 children. Results No associations were found between febrile seizures and the risk of behavioural problems or executive functioning. In contrast to single febrile seizures, recurrent febrile seizures were significantly associated with an increased risk of delayed vocabulary development (odds ratio 3.22, [95% confidence interval 1.30-7.94]). Interpretation Febrile seizures are not associated with problem behaviour or executive functioning in preschool children, but the results suggest that children with recurrent febrile seizures might be at risk for delayed language development. [ABSTRACT FROM AUTHOR]

The article details a study which analyzed the link between parental smoking during pregnancy and wheezing in preschool children. The study also examined if such link can be explained by postnatal smoke exposure or small for gestational age at birth. It concluded that fetal exposure to continued maternal smoking increases risks of wheezing in preschool children.

OBJECTIVE-To examine whether exposure to the Chinese famine during fetal life and early childhood is associated with the risks of metabolic syndrome and whether this association is modified by later life environment. RESEARCH DESIGN AND METHODS-We used data of 7,874 adults born between 1954 and 1964 from the 2002 China National Nutrition and Health Survey. Famine exposure groups were defined as nonexposed; fetal exposed; and early childhood, midchildhood, or late childhood exposed. Excess death rate was used to determine the severity of the famine. The ATP III criteria were used for the definition of metabolic syndrome (three or more of the following variables: elevated fasting triglyceride levels, lower HDL cholesterol levels, elevated fasting glucose levels, higher waist circumference, high blood pressure). RESULTS--In severely affected famine areas, adults who were exposed to the famine during fetal life had a higher risk of metabolic syndrome, as compared with nonexposed subjects (odds ratio 3.13 [95% CI 1.24-7.89, P = 0.016]). Similar associations were observed among adults who were exposed to the famine during early childhood, but not for adults exposed to the famine during mid- or late childhood. Participants who were born in severely affected famine areas and had Western dietary habits in adulthood or were overweight in adulthood had a particularly high risk of metabolic syndrome in later life. CONCLUSIONS--Exposure to the Chinese famine during fetal life or infancy is associated with an increased risk of metabolic syndrome in adulthood. These associations are stronger among subjects with a Western dietary pattern or who were overweight in adulthood. [ABSTRACT FROM AUTHOR]

To examine whether parental, foetal and postnatal characteristics and growth patterns in foetal life and infancy are associated with bone mass at 6 months, as bone acquisition seems to be associated with genetic and environmental factors. This study was embedded in the Generation R Study, a prospective cohort from early foetal life onwards. Bone mineral density (BMD) and bone mineral content (BMC) total body (TB) and BMD lumbar spine (LS) were measured by dual-energy X-ray absorptiometry in 252 infants at 6 months. Parental, foetal and postnatal data were collected by physical and foetal ultrasound examinations and questionnaires. Maternal, foetal and postnatal anthropometrics were positively associated with BMD and BMC at 6 months, but only postnatal anthropometrics were associated with BMD. A gain in weight-SD-score during foetal life and prenatal catch-up in weight were positively associated with BMD. After birth, a gain in weight-SD-score was positively associated with BMD and bone mineral apparent density (BMAD). The effect was strongest between 6 weeks and 6 months. Catch-up in weight was associated with a lower probability of low (lowest quartile of) BMD and BMD. Children remaining in the first tertile of weight from birth to 6 months had a much higher risk of low BMD at 6 months [OR (95% CI): 15 (2, 88)]. Our findings suggest that growth patterns in foetal and postnatal life are associated with bone mass in infancy and may have consequences for bone mass in later life. Follow-up studies are needed to assess whether and to what extent maternal anthropometrics, foetal and postnatal growth patterns have an effect on bone status in adulthood. [ABSTRACT FROM AUTHOR]

Aim To examine the incidence of paroxysmal epileptic and non-epileptic disorders and the associated prenatal and perinatal factors that might predict them in the first year of life in a population-based cohort. Method This study was embedded in the Generation R Study, a population-based prospective cohort study from early fetal life onwards. Information about the occurrence of paroxysmal events, defined as suddenly occurring episodes with an altered consciousness, altered behaviour, involuntary movements, altered muscle tone, and/or a changed breathing pattern, was collected by questionnaires at the ages of 2, 6, and 12 months. Information on possible prenatal and perinatal determinants was obtained by measurements and questionnaires during pregnancy and after birth. Results Information about paroxysmal events in the first year of life was available in 2860 participants (1410 males, 1450 females). We found an incidence of paroxysmal disorders of 8.9% ( n=255) in the first year of life. Of these participants, 17 were diagnosed with febrile seizures and two with epilepsy. Non-epileptic events included physiological events, apnoeic spells, loss of consciousness by causes other than epileptic seizures or apnoeic spells, parasomnias, and other events. Preterm birth ( p<0.001) and low Apgar score at 1 minute ( p<0.05) were significantly associated with paroxysmal disorders in the first year of life. Continued maternal smoking during pregnancy and preterm birth were significantly associated with febrile seizures in the first year of life ( p<0.05). Interpretation Paroxysmal disorders are frequent in infancy. They are associated with preterm birth and a low Apgar score. Epileptic seizures only form a minority of the paroxysmal events in infancy. In this study, children whose mothers continued smoking during pregnancy had a higher reported incidence of febrile seizures in the first year of life. These findings may generate various hypotheses for further investigations. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Recommendations on folic acid use to prevent neural tube defects have been launched in several countries. Adequate folic acid use seems to be low. This study assesses the prevalence of folic acid use and identifies its determinants. Methods: The study was embedded in the Generation R Study Rotterdam, the Netherlands, a population-based prospective cohort study between 2002 and 2006. Complete information of 6940 women was available. Information on folic acid use and potential determinants was obtained by questionnaires and physical examination. Results: Of all women 37% adequately used folic acid during the preconception period. Most important risk factors for inadequate use were unplanned pregnancy (OR 9.5, CI 7.2–12.4, p <0.001), low educational level (OR 2.5, CI 1.8–3.6, p <0.001) and non-western ethnicity, (OR 3.5, CI 2.9–4.3, p <0.001). After stratification for ethnicity, unplanned pregnancy remained the most important risk factor for inadequate use. Other risk factors for inadequate use were younger age, single marital status, smoking, multiparity (all p <0.001) and alcohol use (p <0.05). In contrast, previous spontaneous abortion decreased the risk of inadequate folic acid use (p <0.001). Conclusion: Adequate preconception folic acid supplementation is still too low. Implementation of preconception programs and other public health strategies are strongly needed. [Copyright &y& Elsevier]

The objective of this study was to examine the associations between active and passive smoking in different periods of pregnancy and changing smoking habits during pregnancy, with low birthweight and preterm birth. The study was embedded in the Generation R Study, a population-based prospective cohort study from early fetal life onwards in Rotterdam, The Netherlands. Active and passive smoking were assessed by questionnaires in early, mid- and late pregnancy. Analyses were based on 7098 pregnant women and their children. Active smoking until pregnancy was ascertained and was not associated with low birthweight and preterm birth. Continued active smoking after pregnancy was also recorded and was associated with low birthweight (adjusted odds ratio 1.75 [95% CI 1.20, 2.56]) and preterm birth (adjusted odds ratio 1.36 [95% CI 1.04, 1.78]). The strongest associations were found for active maternal smoking in late pregnancy. Passive maternal smoking in late pregnancy was associated with continuously measured birthweight ( P for trend <0.001). For all active smoking categories in early pregnancy, quitting smoking was associated with a higher birthweight than continuing to smoke. Tendencies towards smaller non-significant beneficial effects on mean birthweight were found for reducing the number of cigarettes without quitting completely. This study shows that active and passive smoking in late pregnancy are associated with adverse effects on weight and gestational age at birth. Smoking in early pregnancy only, seems not to affect fetal growth adversely. Health care strategies for pregnant women should be aimed at quitting smoking completely rather than reducing the number of cigarettes. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To examine the associations of maternal smoking in pregnancy with development of cholesterol levels from childhood to adulthood. Methods: Total cholesterol, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol were measured annually from 1975 to 1993 and in 2002 in 350 subjects aged 5–19 years at baseline who participate in a prospective cohort study. Pregnancy and birth data were obtained through questionnaires sent to the parents. Results: Children of mothers who smoked in pregnancy showed a higher annual change in total cholesterol of 0.12mmol/l per 10 years (95% confidence interval (CI): 0, 0.23) compared to children whose mothers did not smoke in pregnancy. Larger effect estimates were found in children with moderate overweight (0.39mmol/l per 10 years (95% CI: 0.14, 0.63). HDL-cholesterol and LDL-cholesterol showed tendencies towards a decrease and increase, respectively, in children of mothers who smoked in pregnancy compared to children whose mothers did not smoke in pregnancy. Adjustment for potential confounders did not materially change the effect estimates. Conclusion: This study suggests for the first time that maternal smoking in pregnancy is associated with an increased rise in total cholesterol levels and a tendency towards an adverse lipoprotein profile in the offspring. [Copyright &y& Elsevier]

Purpose: To examine the associations of alcohol consumption in different periods of pregnancy with the risks of low birth weight and preterm birth. Methods: This study was based on 7141 subjects participating in a population-based prospective cohort study from early pregnancy. Alcohol consumption was assessed in early, mid, and late pregnancy. Birth outcomes were birth weight in grams, low birth weight (<2500 g), small size for gestational age at birth (< −2 standard deviation scores) and preterm birth (gestational age <37 weeks). Results: Overall, alcohol consumption during pregnancy was not associated with adverse birth outcomes. However, dose-response analyses showed tendencies toward adverse effects of average consumption of 1 or more alcoholic drinks per day in early pregnancy on birth weight (difference −129 g [95% confidence interval (CI): −271, 12]), low birth weight (adjusted odds ratio [aOR] 4.81 [95% CI: 1.10, 21.08]), small size for gestational age at birth (aOR 1.45 [95% CI: 0.33, 6.44]) and preterm birth (aOR 2.51 [95% CI: 0.92, 6.81]). Similar effects were found in late pregnancy. Conclusion: Average consumption of one or more but not less than one alcoholic drink per day in early or late pregnancy seems to be associated with adverse birth outcomes in the offspring. [Copyright &y& Elsevier]

In this paper the Generation R Study is presented. This study examines growth, development and health in urban children from fetal life until young adulthood. With an integrated approach of epidemiological, clinical and basic research, it focuses on four primary areas of research: (1) growth and physical development; (2) behavioural and cognitive development; (3) diseases in childhood; and (4) health and health care for pregnant women and children. The general aims of the study are: 1. to describe normal and abnormal growth, development and health from fetal life until young adulthood in a multiethnic population-based cohort; 2. to identify biological, social and environmental determinants of normal and abnormal growth, development and health from fetal life until adulthood; 3. to examine the utilisation and effectiveness of current strategies for prevention and early identification of groups at risk. Eventually, this study will contribute to the development of strategies for optimising health and health care for pregnant women and children. The Generation R Study is a prospective population-based cohort study in Rotterdam, the Netherlands. In this urban setting, 10 000 children will be examined from early fetal life until young adulthood. Data are collected by physical examinations, questionnaires, interviews, ultrasound and biological samples. The study entered its pilot phase to test the logistics in December 2001. Full participant recruitment and complete data collection started in 2002. [ABSTRACT FROM AUTHOR]

In this paper the Generation R Study is presented. This study examines growth, development and health in urban children from fetal life until young adulthood. With an integrated approach of epidemiological, clinical and basic research, it focuses on four primary areas of research: (1) growth and physical development; (2) behavioural and cognitive development; (3) diseases in childhood; and (4) health and health care for pregnant women and children. The general aims of the study are: 1. to describe normal and abnormal growth, development and health from fetal life until young adulthood in a multiethnic population-based cohort; 2. to identify biological, social and environmental determinants of normal and abnormal growth, development and health from fetal life until adulthood; 3. to examine the utilisation and effectiveness of current strategies for prevention and early identification of groups at risk. Eventually, this study will contribute to the development of strategies for optimising health and health care for pregnant women and children. The Generation R Study is a prospective population-based cohort study in Rotterdam, the Netherlands. In this urban setting, 10 000 children will be examined from early fetal life until young adulthood. Data are collected by physical examinations, questionnaires, interviews, ultrasound and biological samples. The study entered its pilot phase to test the logistics in December 2001. Full participant recruitment and complete data collection started in 2002. [ABSTRACT FROM AUTHOR]

Background: The dietary glycemic index (GI) and load (GL) reflect carbohydrate quality and quantity, potentially impacting fertility through modulation of insulin sensitivity and generation of oxidative stress. While fertility is influenced by both women and men, reproductive research often emphasizes maternal factors. We first examined periconception dietary intake in both women and male partners, and subsequent associations of dietary GI and GL with fecundability and subfertility. Methods: Among 830 women and 651 male partners, participating in a population-based prospective cohort study from preconception onwards, we assessed periconception dietary intake and calculated GI and GL, using a food frequency questionnaire (FFQ) at median 12.4 weeks gestation (95% range 10.9, 18.4). Information on time to pregnancy was obtained through questionnaires, with subfertility defined as a time to pregnancy ≥ 12 months or use of assisted reproductive technology. Results: In the periconception period, mean energy intake in women was 1870 kcal (SD: 500; 46% carbohydrates, 16% protein, 33% fat; dietary GI 56.2 (SD: 3.5) and GL 141.4 (SD: 67.4)). Mean energy intake in men was 2350 kcal (SD: 591; 43% carbohydrates, 16% protein, 33% fat; dietary GI 56.8 (SD: 3.2) and GL 156.7 (SD: 75.4)). Median time to pregnancy was 4.8 months (IQR: 1.2, 16.4), with 30.6% of 830 women experiencing subfertility. Dietary GI and GL were not associated with fertility outcomes in women. In men, higher dietary GI and GL across the full range were associated with decreased fecundability, after adjusting for socio-demographic and lifestyle factors, as well as dietary GI or GL of female partners [FR: 0.91, 95% CI 0.83, 0.99; FR: 0.90, 95% CI 0.81, 0.99, per SDS increase in dietary GI and GL, respectively]. When assessing the combined influence of dietary GI clinical categories in women and men, both partners adhering to a low GI diet tended to be associated with increased fecundability, but not with subfertility risk. Conclusions: Suboptimal periconception carbohydrate intake may be negatively associated with male fertility, but not with fertility outcomes in women. Further studies are needed to assess whether a lower GI and GL diet is a feasible lifestyle intervention to improve couples fertility. [ABSTRACT FROM AUTHOR]

Background: Social inequalities in child mental health are an important public health concern. Whilst previous studies have examined inequalities at a single time point, very few have used repeated measures outcome data to describe how these inequalities emerge. Our aims were to describe social inequalities in child internalising and externalising problems across multiple countries and to explore how these inequalities change as children age. Methods: We used longitudinal data from eight birth cohorts containing participants from twelve countries (Australia, Belgium, Denmark, France, Germany, Greece, Italy, Netherlands, Poland, Norway, Spain and the United Kingdom). The number of included children in each cohort ranged from N = 584 (Greece) to N = 73,042 (Norway), with a total sample of N = 149,604. Child socio‐economic circumstances (SEC) were measured using self‐reported maternal education at birth. Child mental health outcomes were internalising and externalising problems measured using either the Strengths and Difficulties Questionnaire or the Child Behavior Checklist. The number of data collection waves in each cohort ranged from two to seven, with the mean child age ranging from two to eighteen years old. We modelled the slope index of inequality (SII) using sex‐stratified multi‐level models. Results: For almost all cohorts, at the earliest age of measurement children born into more deprived SECs had higher internalising and externalising scores than children born to less deprived SECs. For example, in Norway at age 2 years, boys born to mothers of lower education had an estimated 0.3 (95% CI 0.3, 0.4) standard deviation higher levels of internalising problems (SII) compared to children born to mothers with high education. The exceptions were for boys in Australia (age 2) and both sexes in Greece (age 6), where we observed minimal social inequalities. In UK, Denmark and Netherlands inequalities decreased as children aged, however for other countries (France, Norway, Australia and Crete) inequalities were heterogeneous depending on child sex and outcome. For all countries except France inequalities remained at the oldest point of measurement. Conclusions: Social inequalities in internalising and externalising problems were evident across a range of EU countries, with inequalities emerging early and generally persisting throughout childhood. [ABSTRACT FROM AUTHOR]

Background: Fetal exposure to cannabis and tobacco during pregnancy leads to adverse fetal and childhood outcomes. We hypothesized that fetal exposure to cannabis and tobacco have persistent programming effects on hypothalamic pituitary adrenal (HPA) axis functioning in childhood. Therefore, we examined the associations of parental cannabis and tobacco use during pregnancy with childhood hair cortisol and cortisone concentrations at 6 years, as biomarkers of long-term HPA-axis functioning.Method: In a population-based prospective birth cohort among 2577 mothers and their children, information of parental cannabis and tobacco use was collected by questionnaires, and maternal urine samples were additionally analyzed to detect cannabis metabolite concentrations. Cortisol and cortisone were measured in hair samples at 6 years. Linear regression analysis with adjustment for several confounders was used to test our hypothesis.Results: As compared to non-exposed children, offspring exposed to cannabis during pregnancy (in combination with tobacco) had higher childhood cortisol concentrations (log-10 transformed difference 0.16, 95 % Confidence Interval 0.04 to 0.28). This association was not mediated by birth weight. No differences in cortisone concentrations among cannabis-exposed children were observed. Maternal tobacco use during pregnancy was not associated with childhood cortisol or cortisone concentrations. Further, paternal cannabis or tobacco use was not associated with childhood cortisol or cortisone concentrations.Conclusions: Our findings suggest that maternal cannabis use, combined with tobacco, during pregnancy is associated with alterations in offspring HPA-axis functioning. Further studies need to replicate these findings, and assess the causality and long-term consequences of these associations. [ABSTRACT FROM AUTHOR]

Studies involving large observational datasets commonly face the challenge of dealing with multiple missing values. The most popular approach to overcome this challenge, multiple imputation using chained equations, however, has been shown to be sub-optimal in complex settings, specifically in settings with longitudinal outcomes, which cannot be easily and adequately included in the imputation models. Bayesian methods avoid this difficulty by specification of a joint distribution and thus offer an alternative. A popular choice for that joint distribution is the multivariate normal distribution. In more complicated settings, as in our two motivating examples that involve time-varying covariates, additional issues require consideration: the endo- or exogeneity of the covariate and its functional relation with the outcome. In such situations, the implied assumptions of standard methods may be violated, resulting in bias. In this work, we extend and study a more flexible, Bayesian alternative to the multivariate normal approach, to better handle complex incomplete longitudinal data. We discuss and compare assumptions of the two Bayesian approaches about the endo- or exogeneity of the covariates and the functional form of the association with the outcome, and illustrate and evaluate consequences of violations of those assumptions using simulation studies and two real data examples. [ABSTRACT FROM AUTHOR]

The authors respond to comments on the LifeCycle Project-Maternal Obesity and Childhood Outcomes Study Group's optimal pregnancy weight gain ranges. Topics covered are the use of a composite outcome based on equally weighted results in evaluating the linked between gestational weight gain, subjectivity of ranking the outcomes' severity or importance and the relevance of highly prevalent outcomes in the optimal gestational weight gain ranges.

• Bisphenol A and phthalates were associated with increased weight gain postpartum. • Among women without subsequent pregnancies, only phthalates remained significant. • Pre-pregnancy BMI was identified as an effect modifier of this association. • A significant association is observed among overweight and obese women. • To conclude, higher phthalate exposure in pregnancy may lead to weight gain. Experimental evidence suggests that exposures to phthalates and bisphenols may interfere with processes related to glucose and lipid metabolism, insulin sensitivity, and body weight. Few studies have considered the possible influence of chemical exposures during pregnancy on maternal weight gain or metabolic health outcomes postpartum. To examine the associations of early and mid-pregnancy bisphenol and phthalate urine concentrations with maternal weight gain 6 years postpartum. We analyzed urine samples for bisphenol, phthalate and creatinine concentrations from early and mid-pregnancy in 1192 women in a large, population-based birth cohort in Rotterdam, the Netherlands, and examined postpartum weight gain using maternal anthropometrics before pregnancy and 6 years postpartum. We have used covariate-adjusted linear regressions to evaluate associations of early and mid-pregnancy bisphenols and phthalate metabolites with weight change. Mediator and interaction models have been used to assess the role of gestational weight gain and breastfeeding, respectively. Sensitivity analysis is performed among women without subsequent pregnancies. Among all 1192 mothers included in the analysis, each log unit increase in the average bisphenol A and all assessed phthalate groupings were associated with increased maternal weight gain. As a proxy for phthalate exposure, each log unit increase in averaged phthalic acid was associated with 734 g weight gain (95% CI 273–1196 g) between pre-pregnancy and 6 years postpartum. Mediation by gestational weight gain was not present. Breastfeeding and ethnicity did not modify the effects. Stratification revealed these associations to be strongest among overweight and obese women. Among women without subsequent pregnancies (n = 373) associations of bisphenols, HMW phthalate metabolites and di-2-ethylhexylphthalate metabolites attenuated. For phthalic acid, LMW phthalate metabolites and di-n-octylphthalate metabolites associations increased. Similarly to the whole group, stratification yielded significant results among overweight and obese women. In a large population-based birth cohort, early and mid-pregnancy phthalate exposures are associated with weight gain 6 years postpartum, particularly among overweight and obese women. These data support ongoing action to replace phthalates with safer alternatives. [ABSTRACT FROM AUTHOR]

Background: Intrauterine exposure to a disturbed maternal glucose metabolism is associated with adverse offspring outcomes. DNA methylation is a potential mechanism underlying these associations. We examined whether maternal early-pregnancy glucose and insulin concentrations are associated with newborn DNA methylation. In a population-based prospective cohort study among 935 pregnant women, maternal plasma concentrations of non-fasting glucose and insulin were measured at a median of 13.1 weeks of gestation (95% range 9.4–17.4). DNA methylation was measured using the Infinium HumanMethylation450 BeadChip (Ilumina). We analyzed associations of maternal early-pregnancy glucose and insulin concentrations with single-CpG DNA methylation using robust linear regression models. Differentially methylated regions were analyzed using the dmrff package in R. We stratified the analyses on normal weight versus overweight or obese women. We also performed a look-up of CpGs and differently methylated regions from previous studies to be associated with maternal gestational diabetes, hyperglycemia or hyperinsulinemia, or with type 2 diabetes in adults. Results: Maternal early-pregnancy glucose and insulin concentrations were not associated with DNA methylation at single CpGs nor with differentially methylated regions in the total group. In analyses stratified on maternal BMI, maternal early-pregnancy glucose concentrations were associated with DNA methylation at one CpG (cg03617420, XKR6) among normal weight women and at another (cg12081946, IL17D) among overweight or obese women. No stratum-specific associations were found for maternal early-pregnancy insulin concentrations. The two CpGs were not associated with birth weight or childhood glycemic measures (p values > 0.1). Maternal early-pregnancy insulin concentrations were associated with one CpG known to be related to adult type 2 diabetes. Enrichment among nominally significant findings in our maternal early-pregnancy glucose concentrations was found for CpGs identified in a previous study on adult type 2 diabetes. Conclusions: Maternal early-pregnancy glucose concentrations, but not insulin concentrations, were associated with DNA methylation at one CpG each in the subgroups of normal weight and of overweight or obese women. No associations were present in the full group. The role of these CpGs in mechanisms underlying offspring health outcomes needs further study. Future studies should replicate our results in larger samples with early-pregnancy information on maternal fasting glucose metabolism. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine the associations between hypertensive disorders of pregnancy and early childhood cardiometabolic risk factors in the offspring. Therefore, 7794 women from the Generation Rotterdam Study were included, an ongoing population-based prospective birth cohort. Women with a hypertensive disorder of pregnancy were classified as such when they were affected by pregnancy induced hypertension, pre-eclampsia or the haemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome during pregnancy. Early childhood cardiometabolic risk factors were defined as the body mass index at the age of 2, 6, 12, 36 months and 6 years. Additionally, it included systolic blood pressure, diastolic blood pressure, total fat mass, cholesterol, triglycerides, insulin and clustering of cardiometabolic risk factors at 6 years of age. Sex-specific differences in the associations between hypertensive disorders and early childhood cardiometabolic risk factors were investigated. Maternal hypertensive disorders of pregnancy were inversely associated with childhood body mass index at 12 months (confounder model: -0.15 SD, 95% CI -0.27; -0.03) and childhood triglyceride at 6 years of age (confounder model: -0.28 SD, 95% CI -0.45; -0.10). For the association with triglycerides, this was only present in girls. Maternal hypertensive disorders of pregnancy were not associated with childhood body mass index at 2, 6 and 36 months. No associations were observed between maternal hypertensive disorders of pregnancy and systolic blood pressure, diastolic blood pressure, body mass index, fat mass index and cholesterol levels at 6 years of age. Our findings do not support an independent and consistent association between maternal hypertensive disorders of pregnancy and early childhood cardiometabolic risk factors in their offspring. However, this does not rule out possible longer term effects of maternal hypertensive disorders of pregnancy on offspring cardiometabolic health. [ABSTRACT FROM AUTHOR]

Background: Customized birth weight charts take into account physiological maternal characteristics that are known to influence fetal growth to differentiate between physiological and pathological abnormal size at birth. It is unknown whether customized birth weight charts better identify newborns at risk of long-term adverse outcomes than population birth weight charts. We aimed to examine whether birth weight classification according to customized charts is superior to population charts at identification of newborns at risk of adverse cardio-metabolic and respiratory health outcomes.Methods: In a population-based prospective cohort study among 6052 pregnant women and their children, we measured infant catch-up growth, overweight, high blood pressure, hyperlipidemia, liver steatosis, clustering of cardio-metabolic risk factors, and asthma at age 10. Small size and large size for gestational age at birth was defined as birth weight in the lowest or highest decile, respectively, of population or customized charts. Association with birth weight classification was assessed using logistic regression models.Results: Of the total of 605 newborns classified as small size for gestational age by population charts, 150 (24.8%) were reclassified as appropriate size for gestational age by customized charts, whereas of the total of 605 newborns classified as large size for gestational age by population charts, 129 (21.3%) cases were reclassified as appropriate size for gestational age by customized charts. Compared to newborns born appropriate size for gestational age, newborns born small size for gestational age according to customized charts had increased risks of infant catch-up growth (odds ratio (OR) 5.15 (95% confidence interval (CI) 4.22 to 6.29)), high blood pressure (OR 2.05 (95% CI 1.55 to 2.72)), and clustering of cardio-metabolic risk factors at 10 years (OR 1.66 (95% CI 1.18 to 2.34)). No associations were observed for overweight, hyperlipidemia, liver steatosis, or asthma. Newborns born large-size for gestational age according to customized charts had higher risk of catch-down-growth only (OR 3.84 (95% CI 3.22 to 4.59)). The direction and strength of the observed associations were largely similar when we used classification according to population charts.Conclusions: Small-size-for-gestational-age newborns seem to be at risk of long-term adverse cardio-metabolic health outcomes, irrespective of the use of customized or population birth weight charts. [ABSTRACT FROM AUTHOR]

Maternal vitamin D deficiency during pregnancy may have persistent adverse effects on childhood growth and development. We examined whether 25‐hydroxyvitamin D (25(OH)D) concentrations during pregnancy and at cord blood were associated with childhood body composition and cardiovascular outcomes. This study was embedded in a population‐based prospective cohort in Rotterdam, The Netherlands, among 4,903 mothers and their offspring. We measured 25(OH)D concentrations at a median gestational age of 20.4 weeks (95% range 18.5–23.4 weeks) and at birth (40.1 weeks [95% range 35.8–42.3 weeks]). 25(OH)D concentrations were categorized into severely deficient (<25.0 nmol/L); deficient (25.0 to 49.9 nmol/L); sufficient (50.0 to 74.9 nmol/L) and optimal (≥75.0 nmol/L). At 6 years, we measured childhood body mass index; fat and lean mass by Dual‐energy X‐ray Absorptiometry; blood pressure; and serum cholesterol, triglycerides, and insulin concentrations. Compared with children from mothers with optimal 25(OH)D concentrations (≥75.0 nmol/L), those of severely deficient vitamin D (<25.0 nmol/L) mothers had a 0.12 standard deviation score (SDS); (95% Confidence Interval (CI) [0.03, 0.21]) higher fat mass percentage and a 0.13 SDS (95% CI [−0.22, −0.04]) lower lean mass percentage. These associations remained after adjustment for current child vitamin D status. Maternal and cord blood 25(OH)D concentrations were not associated with cardiovascular risk factors in childhood. In conclusion, severe maternal 25(OH)D deficiency (<25.0 nmol/L) during pregnancy is associated with an adverse childhood body composition profile, but we did not observe evidence for an association with childhood cardiovascular risk factors. Further studies are needed to replicate our findings, to examine the underlying mechanisms, the causality of the associations, and the potential for public health interventions. [ABSTRACT FROM AUTHOR]

Objectives: To identify possibly distinct acute otitis media (AOM) trajectories in childhood and identify determinants associated with specific AOM trajectories. To explore which child will become prone to recurrent AOM episodes and which will not. Design: Population‐based prospective cohort study among 7863 children from birth until 10 years and their mothers. Methods: This study was embedded in the Generation R Study: a population‐based prospective cohort study. Data on AOM and determinants were collected by repeated parental questionnaires. Distinct AOM trajectories within the population were identified with latent‐class analyses. Next, using multivariate analysis we checked whether specific determinants were associated with specific trajectories. Results: Three distinct trajectories were identified; that is, non–otitis prone, early AOM—that is children who suffered AOM episodes until 3 years of age but not beyond, and persistent AOM—that is children who remained otitis‐prone. Male gender (OR: 1.26, CI: 1.11‐1.43) and day‐care attendance (OR: 1.31, CI: 1.06‐1.60) were associated with increased odds of early AOM. Breastfeeding was beneficial for children in both the early‐AOM and persistent‐AOM trajectories (OR: 0.78 and 0.77, respectively). Birth in the summer or autumn as compared with birth in the spring decreased odds of AOM only in the persistent‐AOM trajectory. Half of all AOM‐prone children recovered after the age of 3 years. Conclusion: Specific determinants are associated with different AOM trajectories. Future research is needed to better predict which child will remain otitis‐prone and which recovers after the age of 3 years to better tailor treatment towards the needs of the individual child. [ABSTRACT FROM AUTHOR]

• We examined early life stress and stool microbiome in the general population. • We found no significant association between overall ELS and children's microbiome. • One stress domain – contextual risk – was associated with a less diverse microbiome. • Enriched pathways for this stressor included bacterial tryptophan biosynthesis. • Associations were partly mediated by diet factors and BMI. Early-life stress (ELS) has been robustly associated with a range of poor mental and physical health outcomes. Recent studies implicate the gut microbiome in stress-related mental, cardio-metabolic and immune health problems, but research on humans is scarce and thus far often based on small, selected samples, often using retrospective reports of ELS. We examined associations between ELS and the human gut microbiome in a large, population-based study of children. ELS was measured prospectively from birth to 10 years of age in 2,004 children from the Generation R Study. We studied overall ELS, as well as unique effects of five different ELS domains, including life events, contextual risk, parental risk, interpersonal risk, and direct victimization. Stool microbiome was assessed using 16S rRNA sequencing at age 10 years and data were analyzed at multiple levels (i.e. α- and β-diversity indices, individual genera and predicted functional pathways). In addition, we explored potential mediators of ELS-microbiome associations, including diet at age 8 and body mass index at 10 years. While no associations were observed between overall ELS (composite score of five domains) and the microbiome after multiple testing correction, contextual risk – a specific ELS domain related to socio-economic stress, including risk factors such as financial difficulties and low maternal education – was significantly associated with microbiome variability. This ELS domain was associated with lower α-diversity, with β-diversity, and with predicted functional pathways involved, amongst others, in tryptophan biosynthesis. These associations were in part mediated by overall diet quality, a pro-inflammatory diet, fiber intake, and body mass index (BMI). These results suggest that stress related to socio-economic adversity – but not overall early life stress – is associated with a less diverse microbiome in the general population, and that this association may in part be explained by poorer diet and higher BMI. Future research is needed to test causality and to establish whether modifiable factors such as diet could be used to mitigate the negative effects of socio-economic adversity on the microbiome and related health consequences. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Depression and obesity are 2 highly prevalent and often comorbid conditions. Exposure to early-life stress (ELS) has been associated with both depression and obesity in adulthood, as well as their preclinical manifestations during development. However, it remains unclear whether (1) associations differ depending on the timing of stress exposure (prenatal vs postnatal), and whether (2) ELS is a shared risk factor underlying the comorbidity between the 2 conditions. Leveraging data from 2 large population-based birth cohorts (ALSPAC: n = 8,428 [52% male participants]; Generation R: n = 4,268 [48% male participants]), we constructed comprehensive cumulative measures of prenatal (in utero) and postnatal (from birth to 10 years) ELS. At age 13.5 years, we assessed the following: internalizing symptoms (using maternal reports); fat mass percentage (using dual-energy X-ray absorptiometry); and their comorbidity, defined as the co-occurrence of high internalizing and high adiposity. Both prenatal (total effect [95% CI] = 0.20 [0.16; 0.22]) and postnatal stress (β [95%CI] = 0.22 [0.17; 0.25]) were associated with higher internalizing symptoms, with evidence of a more prominent role of postnatal stress. A weaker association (driven primarily by prenatal stress) was observed between stress and adiposity (prenatal: 0.07 [0.05; 0.09]; postnatal: 0.04 [0.01; 0.07]). Both prenatal (odds ratio [95%CI] = 1.70 [1.47; 1.97]) and postnatal (1.87 [1.61; 2.17]) stress were associated with an increased risk of developing comorbidity. We found evidence of timing and shared causal effects of ELS on psycho-cardiometabolic health in adolescence; however, future research is warranted to clarify how these associations may unfold over time. We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. [ABSTRACT FROM AUTHOR]

Exposure to specific stressors has been found to associate with higher adiposity in adulthood. However, the potential overlapping effects of stress domains have been overlooked, as well as the role of parenting‐related stressors that mothers are widely exposed to in mid‐adulthood. Therefore, we assessed the association of overlapping effects of stress domains, including parenting‐related stress, with subsequent adiposity in mothers. In 3957 mothers from the population‐based Generation R Study, life stress was assessed during the first 10 years of child‐rearing and measured as a reflective latent variable of stress domains. Structural equation modelling was used to assess the association of life stress and its individual domains with body mass index (BMI) and waist circumference after 14 years of follow‐up. Greater life stress over the course of 10 years was associated with a higher BMI (standardized adjusted difference: 0.57 kg/m2 [95% CI: 0.41–0.72]) and a larger waist circumference (1.15 cm [0.72–1.57]). When examining individual stress domains, we found that life events was independently associated with a higher BMI (0.16 kg/m2) and contextual stress was independently associated with a higher BMI (0.43 kg/m2) and larger waist circumference (1.04 cm). Parenting stress and interpersonal stress were not independently associated with adiposity at follow‐up. The overlap of multiple domains of stress in mothers is associated with a higher risk of adiposity. This effect was stronger than for individual life stress domains, reiterating the need to consider overlapping effects of different life stress domains. [ABSTRACT FROM AUTHOR]