Publications by authors named "Vincent W V Jaddoe"

692 Publications

Associations of maternal angiogenic factors during pregnancy with childhood carotid intima-media thickness and blood pressure.

Atherosclerosis 2021 Nov 6;338:46-54. Epub 2021 Nov 6.

The Generation R Study Group, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Pediatrics, Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address:

Background And Aims: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.11.005DOI Listing
November 2021

Prenatal Exposure to Nonpersistent Chemical Mixtures and Fetal Growth: A Population-Based Study.

Environ Health Perspect 2021 Nov 24;129(11):117008. Epub 2021 Nov 24.

Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Durham, North Carolina, USA.

Background: Prenatal exposure to mixtures of nonpersistent chemicals is universal. Most studies examining these chemicals in association with fetal growth have been restricted to single exposure models, ignoring their potentially cumulative impact.

Objective: We aimed to assess the association between prenatal exposure to a mixture of phthalates, bisphenols, and organophosphate (OP) pesticides and fetal measures of head circumference, femur length, and weight.

Methods: Within the Generation R Study, a population-based cohort in Netherlands (), urinary concentrations of 11 phthalate metabolites, 3 bisphenols, and 5 dialkylphosphate (DAP) metabolites were measured at , 18-25, and of gestation and averaged. Ultrasound measures of head circumference, femur length, and estimated fetal weight (EFW) were taken at 18-25 and of gestation, and measurements of head circumference, length, and weight were performed at delivery. We estimated the difference in each fetal measurement per quartile increase in all exposures within the mixture with quantile g-computation.

Results: The average EFW at 18-25 wk and was 369 and , respectively, and the average birth weight was . Higher exposure was associated with smaller fetal and newborn growth parameters in a nonlinear fashion. At 18-25 wk, fetuses in the second, third, and fourth quartiles of exposure (Q2-Q4) had [, ], (, ), and (, 1) lower EFW compared with those in the first quartile (Q1). A similar dose-response pattern was observed at , but all effect sizes were smaller, and no association was observed comparing Q4 to Q1. At birth, we observed no differences in weight between Q1-Q2 or Q1-Q3. However, fetuses in Q4 had (, 76) lower birth weight in comparison with those in Q1. Results observed at 18-25 and were similar for femur length; however, no differences were observed at birth. No associations were observed for head circumference.

Discussion: Higher exposure to a mixture of phthalates, bisphenols, and OP pesticides was associated with lower EFW in the midpregnancy period. In late pregnancy, these differences were similar but less pronounced. At birth, the only associations observed appeared when comparing individuals from Q1 and Q4. This finding suggests that even low levels of exposure may be sufficient to influence growth in early pregnancy, whereas higher levels may be necessary to affect birth weight. Joint exposure to nonpersistent chemicals may adversely impact fetal growth, and because these exposures are widespread, this impact could be substantial. https://doi.org/10.1289/EHP9178.
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http://dx.doi.org/10.1289/EHP9178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8612241PMC
November 2021

Association between neighbourhood deprivation, fetal growth, small-for-gestational age and preterm birth: a population-based prospective cohort study.

BMJ Open 2021 Nov 16;11(11):e049075. Epub 2021 Nov 16.

Department of Obstetrics and Gynaecology, Division of Obstetrics and Prenatal Medicine, Erasmus MC, Rotterdam, The Netherlands.

Objective: To study the associations between neighbourhood deprivation and fetal growth, including growth in the first trimester, and adverse pregnancy outcomes.

Design: Prospective cohort study.

Setting: The Netherlands, Rotterdam.

Participants: 8617 live singleton births from the Generation R cohort study.

Exposition: Living in a deprived neighbourhood.

Main Outcome Measures: Fetal growth trajectories of head circumference, weight and length.

Secondary Outcomes Measures: Small-for-gestational age (SGA) and preterm birth (PTB).

Results: Neighbourhood deprivation was not associated with first trimester growth. However, a higher neighbourhood status score (less deprivation) was associated with increased fetal growth in the second and third trimesters (eg, estimated fetal weight; adjusted regression coefficient 0.04, 95% CI 0.02 to 0.06). Less deprivation was also associated with decreased odds of SGA (adjusted OR 0.91, 95% CI 0.86 to 0.97, p=0.01) and PTB (adjusted OR 0.89, 95% CI 0.82 to 0.96, p=0.01).

Conclusions: We found an association between neighbourhood deprivation and fetal growth in the second and third trimester pregnancy, but not with first trimester growth. Less neighbourhood deprivation is associated with lower odds of adverse pregnancy outcomes. The associations remained after adjustment for individual-level risk factors. This supports the hypothesis that living in a deprived neighbourhood acts as an independent risk factor for fetal growth and adverse pregnancy outcomes, above and beyond individual risk factors.
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http://dx.doi.org/10.1136/bmjopen-2021-049075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8596053PMC
November 2021

Epigenetic age acceleration and cardiovascular outcomes in school-age children: The Generation R Study.

Clin Epigenetics 2021 11 16;13(1):205. Epub 2021 Nov 16.

The Generation R Study Group (Na-2918), Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

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.
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http://dx.doi.org/10.1186/s13148-021-01193-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8597298PMC
November 2021

Cohort description: Measures of early-life behaviour and later psychopathology in the LifeCycle Project - EU Child Cohort Network.

J Epidemiol 2021 Nov 13. Epub 2021 Nov 13.

Section of Epidemiology, Department of Public Health, University of Copenhagen.

Background: The EU LifeCycle Project was launched in 2017 to combine, harmonise, and analyse data from more than 250,000 participants across Europe and Australia, involving cohorts participating in the EU-funded LifeCycle Project. The purpose of this cohort description is to provide a detailed overview over the major measures within mental health domains that are available in 17 European and Australian cohorts participating in the LifeCycle Project.

Methods: Data on cognitive, behavioural and psychological development has been collected on participants from birth until adulthood through questionnaire and medical data. We developed an inventory of the available data by mapping individual instruments, domain types, and age groups, providing the basis for statistical harmonization across mental health measures.

Results: The mental health data in LifeCycle contain longitudinal and cross-sectional data for ages 0-18+ years, covering domains across a wide range of behavioural and psychopathology indicators and outcomes (including executive function, depression, ADHD and cognition). These data span a unique combination of qualitative data collected through behavioural/cognitive/mental health questionnaires and examination, as well as data from biological samples and indices in the form of brain imaging (MRI, foetal ultrasound) and DNA methylation data. Harmonized variables on a subset of mental health domains have been developed, providing statistical equivalence of measures required for longitudinal meta-analyses across instruments and cohorts.

Conclusion: Mental health data harmonized through the LifeCycle project can be used to study life course trajectories and exposure-outcome models that examine early life risk factors for mental illness and develop predictive markers for later-life disease.
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http://dx.doi.org/10.2188/jea.JE20210241DOI Listing
November 2021

Influence of maternal vomiting during early pregnancy on school-age respiratory health.

Pediatr Pulmonol 2021 Nov 5. Epub 2021 Nov 5.

Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: Hyperemesis gravidarum, a clinical entity characterized by severe nausea and excess vomiting, might lead to a suboptimal maternal nutritional status during pregnancy and subsequently to adverse respiratory health in the offspring. The role of common vomiting symptoms on offspring's respiratory health is unclear. We examined the associations of maternal daily vomiting during early pregnancy with childhood respiratory outcomes, and potential explaining factors.

Methods: This study was embedded in a population-based prospective cohort study from early pregnancy onwards among 4232 mothers and their children. Maternal vomiting during early pregnancy was assessed by a questionnaire. At age 10 years, information on current wheezing and ever asthma was obtained by a questionnaire, and lung function was measured by spirometry at our research center. We used multiple regression analyses to assess the associations of maternal daily vomiting during early pregnancy with childhood respiratory outcomes.

Results: Compared to children from mothers without daily vomiting during early pregnancy, children from mothers with daily vomiting during early pregnancy had a higher forced expiratory flow when 75% of the forced vital capacity (FVC) is exhaled (Z-score difference [95% confidence interval, CI]: 0.13 [0.03, 0.23]), and an increased risk of current wheezing and ever asthma ([odds ratio, OR] [95% CI]: 1.75 [1.10, 2.79] and 1.61 [1.13, 2.31], respectively). These associations were fully explained by sociodemographic factors, but not sex or lifestyle-, infectious-, or growth-related factors. Maternal daily vomiting during early pregnancy was not associated with forced expiratory volume in 1 s (FEV ), FVC, and FEV /FVC.

Conclusion: Only sociodemographic factors explain the associations of maternal daily vomiting during early pregnancy with childhood respiratory outcomes.
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http://dx.doi.org/10.1002/ppul.25747DOI Listing
November 2021

Foetal tobacco and cannabis exposure, body fat and cardio-metabolic health in childhood.

Pediatr Obes 2021 Oct 21:e12863. Epub 2021 Oct 21.

The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: Foetal tobacco and cannabis exposure may have persistent cardio-metabolic consequences in the offspring.

Objective: We examined the associations of maternal and paternal tobacco and cannabis use during pregnancy with offspring body fat and cardio-metabolic outcomes.

Methods: In a population-based prospective cohort study among 4792 mothers, fathers, and children, we assessed parental substance use by questionnaires. Childhood outcomes included body mass index (BMI), body fat, blood pressure, and lipid, glucose and insulin concentrations at 10 years.

Results: Children exposed to maternal tobacco use during pregnancy had a higher android/gynoid fat mass ratio (difference 0.22 SDS, 95% confidence interval [CI]: 0.13, 0.30), fat mass index (difference 0.20 SDS, 95% CI: 0.12, 0.28), triglyceride concentrations (difference 0.15 SDS, 95% CI: 0.04, 0.26), and a higher risk of overweight (odds ratio [OR] 1.35, 95% CI: 1.07, 1.71), compared to non-exposed. Children exposed to maternal cannabis during pregnancy had a higher BMI (difference 0.26 SDS, 95% CI: 0.08, 0.44), android/gynoid fat mass ratio (difference 0.21 SDS, 95% CI: 0.04, 0.39), and fat-free mass index (difference 0.24 SDS, 95% CI: 0.06, 0.41), compared to non-exposed. The associations for paternal substance use with child cardio-metabolic health outcomes were similar as those for maternal use.

Conclusions: Similar associations for maternal and paternal substance use during pregnancy suggest that these findings may be explained by shared family-based social and lifestyle factors, rather than by direct foetal programming.
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http://dx.doi.org/10.1111/ijpo.12863DOI Listing
October 2021

Associations of maternal bisphenol urine concentrations during pregnancy with neonatal metabolomic profiles.

Metabolomics 2021 09 13;17(9):84. Epub 2021 Sep 13.

The Generation R Study Group (Na-29), Erasmus MC, University Medical Center, PO Box 2040, 3000 CA, Rotterdam, the Netherlands.

Background: Fetal exposure to bisphenols is associated with altered fetal growth, adverse birth outcomes and childhood cardio-metabolic risk factors. Metabolomics may serve as a tool to identify the mechanisms underlying these associations. We examined the associations of maternal bisphenol urinary concentrations in pregnancy with neonatal metabolite profiles from cord blood.

Methods: In a population-based prospective cohort study among 225 mother-child pairs, maternal urinary bisphenol A, S and F concentrations in first, second and third trimester were measured. LC-MS/MS was used to determine neonatal concentrations of amino acids, non-esterified fatty acids (NEFA), phospholipids (PL), and carnitines in cord blood.

Results: No associations of maternal total bisphenol concentrations with neonatal metabolite profiles were present. Higher maternal average BPA concentrations were associated with higher neonatal mono-unsaturated alkyl-lysophosphatidylcholine concentrations, whereas higher maternal average BPS was associated with lower neonatal overall and saturated alkyl-lysophosphatidylcholine (p-values < 0.05).Trimester-specific analyses showed that higher maternal BPA, BPS and BPF were associated with alterations in neonatal NEFA, diacyl-phosphatidylcholines, acyl-alkyl-phosphatidylcholines, alkyl-lysophosphatidylcholine, sphingomyelines and acyl-carnitines, with the strongest effects for third trimester maternal bisphenol and neonatal diacyl-phosphatidylcholine, sphingomyeline and acyl-carnitine metabolites (p-values < 0.05). Associations were not explained by maternal socio-demographic and lifestyle characteristics or birth characteristics.

Discussion: Higher maternal bisphenol A, F and S concentrations in pregnancy are associated with alterations in neonatal metabolite profile, mainly in NEFA, PL and carnitines concentrations. These findings provide novel insight into potential mechanisms underlying associations of maternal bisphenol exposure during pregnancy with adverse offspring outcomes but need to be replicated among larger, diverse populations.
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http://dx.doi.org/10.1007/s11306-021-01836-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437833PMC
September 2021

Maternal diet in pregnancy and child's respiratory outcomes: an individual participant data meta-analysis of 18 000 children.

Eur Respir J 2021 Sep 9. Epub 2021 Sep 9.

The Generation R Study Group, Erasmus MC, University Medical Center, Rotterdam, the Netherlands

Rationale: Severe fetal malnutrition has been related to an increased risk of respiratory diseases later in life, but evidence for the association of a suboptimal diet during pregnancy with respiratory outcomes in childhood is conflicting. We aimed to examine whether a pro-inflammatory or low-quality maternal diet during pregnancy was associated with child's respiratory health.

Methods: We performed an individual participant meta-analysis among 18 326 mother-child pairs from seven European birth cohorts. Maternal pro-inflammatory and low-quality diet were estimated by energy-adjusted Dietary Inflammatory Index (E-DII) and Dietary Approaches to Stop Hypertension (DASH) scores. Preschool wheezing and school-age asthma were measured by questionnaires and lung function by spirometry.

Results: After adjustment for lifestyle and sociodemographic factors, we observed that a higher maternal E-DII score (a more pro-inflammatory diet) during pregnancy was associated only with a lower FVC in children (Z-score difference (95% confidence interval (CI)): -0.05 (-0.08, -0.02), per IQR increase). No linear associations of the maternal E-DII or DASH score with child's wheezing or asthma were observed. When exploratively examining the extremes, a very low DASH score (<10th percentile) (a very low dietary quality) was associated with an increased risk of preschool wheezing and a low FEV/FVC (z-score <-1.64) (OR (95% CI) 1.20 (1.06, 1.36), 1.40 (1.06, 1.85), compared to ≥10th percentile), with corresponding population attributable risk fractions of 1.7% and 3.3%.

Conclusion: Main results from this individual participant data meta-analysis do not support the hypothesis that maternal pro-inflammatory or low-quality diet in pregnancy are related to respiratory diseases in childhood.
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http://dx.doi.org/10.1183/13993003.01315-2021DOI Listing
September 2021

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.

Nat Genet 2021 09 6;53(9):1311-1321. Epub 2021 Sep 6.

Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
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http://dx.doi.org/10.1038/s41588-021-00923-xDOI Listing
September 2021

Vitamin B12, folate and homocysteine concentrations during pregnancy and early signs of atherosclerosis at school-age.

Clin Nutr 2021 09 9;40(9):5133-5140. Epub 2021 Aug 9.

The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000, CA, Rotterdam, the Netherlands; Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000, CA, Rotterdam, the Netherlands. Electronic address:

Background & Aims: Suboptimal circulating vitamin B12, folate and homocysteine concentrations during fetal life seem to be associated with cardiometabolic health at school-age. We examined whether fetal exposure to lower circulating vitamin B12 and folate concentrations and higher circulating homocysteine concentrations is also associated with early signs of atherosclerosis at school-age.

Methods: This study among 3826 school-age children and their mothers was embedded in the Generation R Study, a population-based prospective cohort study from early pregnancy onwards. We examined the associations of early-pregnancy and cord blood serum total and active B12 and plasma folate and homocysteine concentrations with common carotid artery intima-media thickness and distensibility in the children aged ten years.

Results: As compared to normal early-pregnancy serum total B12 concentrations (≥145 pmol/L), low serum total B12 concentrations (<145 pmol/L) were associated with higher carotid intima-media thickness in the children at school-age (difference 0.09 standard deviations score (SDS); 95% confidence interval (CI): 0.01, 0.16). As compared to normal early-pregnancy plasma folate concentrations (≥8 nmol/L), low plasma folate concentrations (<8 nmol/L) were associated with lower carotid distensibility in the children at school-age (difference -0.16 SDS; 95% CI: -0.28, -0.04). Early-pregnancy circulating total and active B12, folate and homocysteine concentrations measured continuously were not associated with carotid intima-media thickness or carotid distensibility in the children at school-age. One SDS higher plasma homocysteine concentrations measured in cord blood at birth was associated with a -0.05 SDS (95% CI: -0.09, -0.02) lower carotid distensibility at school-age. Cord blood total and active B12 and folate concentrations were not associated with carotid intima-media thickness or carotid distensibility at school-age.

Conclusions: Circulating total B12, folate and homocysteine concentrations during fetal life seem to be associated with markers of subclinical atherosclerosis at school-age. Further studies need to examine the causality and mechanisms underlying these associations.
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http://dx.doi.org/10.1016/j.clnu.2021.08.001DOI Listing
September 2021

Maternal body mass index, early-pregnancy metabolite profile and birthweight.

J Clin Endocrinol Metab 2021 Aug 14. Epub 2021 Aug 14.

The Generation R Study Group, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.

Context: Maternal prepregnancy BMI has a strong influence on gestational metabolism, but detailed metabolic alterations are unknown.

Objective: First, to examine the associations of maternal prepregnancy BMI with maternal early-pregnancy metabolite alterations. Second, to identify an early-pregnancy metabolite profile associated with birthweight in women with a higher prepregnancy BMI that improved prediction of birthweight compared to glucose and lipid concentrations.

Design, Setting And Participants: Prepregnancy BMI was obtained in a subgroup of 682 Dutch pregnant women from the Generation R prospective cohort study.

Main Outcome Measures: Maternal non-fasting targeted amino acid, non-esterified fatty acid, phospholipid and carnitine concentrations measured in blood serum at mean gestational age of 12.8 weeks. Birthweight, obtained from medical records.

Results: A higher prepregnancy BMI was associated with 72 altered amino acid, non-esterified fatty acid, phospholipid and carnitine concentrations and 6 metabolite ratios reflecting Krebs cycle, inflammatory, oxidative stress and lipid metabolic processes (p-values<0.05). Using penalized regression models, a metabolite profile was selected including 15 metabolites and 4 metabolite ratios, based on its association with birthweight in addition to prepregnancy BMI. The adjusted R 2 of birthweight was 6.1% for prepregnancy BMI alone, 6.2% after addition of glucose and lipid concentrations and 12.9% after addition of the metabolite profile.

Conclusions: A higher maternal prepregnancy BMI was associated with altered maternal early-pregnancy amino acids, non-esterified fatty acids, phospholipids and carnitines. Using these metabolites, we identified a maternal metabolite profile which improved prediction of birthweight in women with a higher prepregnancy BMI compared to glucose and lipid concentrations.
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http://dx.doi.org/10.1210/clinem/dgab596DOI Listing
August 2021

Associations of maternal and infant metabolite profiles with foetal growth and the odds of adverse birth outcomes.

Pediatr Obes 2021 Aug 12:e12844. Epub 2021 Aug 12.

The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

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.
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http://dx.doi.org/10.1111/ijpo.12844DOI Listing
August 2021

Body fat, cardiovascular risk factors and brain structure in school-age children.

Int J Obes (Lond) 2021 11 15;45(11):2425-2431. Epub 2021 Jul 15.

Department of Pediatrics, Erasmus MC-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: In adults, cardiovascular risk factors are known to be associated with brain health. We hypothesized that these associations are already present at school-age. We examined the associations of adverse body fat measures and cardiovascular risk factors with brain structure, including volumetric measures and white matter microstructure, in 10-year-old children.

Methods: We performed a cross-sectional analysis in a population-based prospective cohort study in Rotterdam, the Netherlands. Analyses were based on 3098 children aged 10 years with neuroimaging data and at least one measurement of body fat and cardiovascular risk factors. Body fat measures included body mass index (BMI), fat mass index and android fat mass percentage obtained by Dual-energy X-ray absorptiometry. Cardiovascular risk factors included blood pressure, and serum glucose, insulin and lipids blood concentrations. Structural neuroimaging, including global and regional brain volumes, was quantified by magnetic resonance imaging. DTI was used to assess white matter microstructure, including global fractional anisotropy (FA) and mean diffusivity (MD).

Results: As compared to children with a normal weight, those with underweight had a smaller total brain and white matter volumes (differences -18.10 (95% Confidence Interval (CI) -30.97,-5.22) cm, -10.64 (95% CI -16.82,-4.47) cm, respectively). In contrast, one SDS (Standard Deviation Score) increase in fat mass index was associated with a smaller gray matter volume (differences -3.48 (95% CI -16.82, -4.47) cm). Also, one SDS increase in android fat mass percentage was associated with lower white matter diffusivity (difference -0.06 (95% CI -0.10, -0.02) SDS). None of the other cardiovascular risk factors were associated with any of the brain outcomes.

Conclusions: Body fat measures, but not other cardiovascular risk factors, were associated with structural neuroimaging outcomes in school-aged children. Prospective studies are needed to assess causality, direction and long-term consequences of the associations.
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http://dx.doi.org/10.1038/s41366-021-00913-3DOI Listing
November 2021

Maternal Iron Status in Pregnancy and Child Health Outcomes after Birth: A Systematic Review and Meta-Analysis.

Nutrients 2021 Jun 28;13(7). Epub 2021 Jun 28.

Department of Pediatrics, Division of Neonatology, Erasmus MC-Sophia, University Medical Center, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands.

In pregnancy, iron deficiency and iron overload increase the risk for adverse pregnancy outcomes, but the effects of maternal iron status on long-term child health are poorly understood. The aim of the study was to systematically review and analyze the literature on maternal iron status in pregnancy and long-term outcomes in the offspring after birth. We report a systematic review on maternal iron status during pregnancy in relation to child health outcomes after birth, from database inception until 21 January 2021, with methodological quality rating (Newcastle-Ottawa tool) and random-effect meta-analysis. (PROSPERO, CRD42020162202). The search identified 8139 studies, of which 44 were included, describing 12,7849 mother-child pairs. Heterogeneity amongst the studies was strong. Methodological quality was predominantly moderate to high. Iron status was measured usually late in pregnancy. The majority of studies compared categories based on maternal ferritin, however, definitions of iron deficiency differed across studies. The follow-up period was predominantly limited to infancy. Fifteen studies reported outcomes on child iron status or hemoglobin, 20 on neurodevelopmental outcomes, and the remainder on a variety of other outcomes. In half of the studies, low maternal iron status or iron deficiency was associated with adverse outcomes in children. Meta-analyses showed an association of maternal ferritin with child soluble transferrin receptor concentrations, though child ferritin, transferrin saturation, or hemoglobin values showed no consistent association. Studies on maternal iron status above normal, or iron excess, suggest deleterious effects on infant growth, cognition, and childhood Type 1 diabetes. Maternal iron status in pregnancy was not consistently associated with child iron status after birth. The very heterogeneous set of studies suggests detrimental effects of iron deficiency, and possibly also of overload, on other outcomes including child neurodevelopment. Studies are needed to determine clinically meaningful definitions of iron deficiency and overload in pregnancy.
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http://dx.doi.org/10.3390/nu13072221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308244PMC
June 2021

Fetal Growth Trajectories Among Small for Gestational Age Babies and Child Neurodevelopment.

Epidemiology 2021 09;32(5):664-671

The Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands.

Background: Being born small for gestational age (SGA, <10th percentile) is a risk factor for worse neurodevelopmental outcomes. However, this group is a heterogeneous mix of healthy and growth-restricted babies, and not all will experience poor outcomes. We sought to determine whether fetal growth trajectories can distinguish who will have the worst neurodevelopmental outcomes in childhood among babies born SGA.

Methods: The present analysis was conducted in Generation R, a population-based cohort in Rotterdam, the Netherlands (N = 5,487). Using group-based trajectory modeling, we identified fetal growth trajectories for weight among babies born SGA. These were based on standard deviation scores of ultrasound measures from mid-pregnancy and late pregnancy in combination with birth weight. We compared child nonverbal intelligence quotient (IQ) and attention deficit hyperactivity disorder (ADHD) symptoms at age 6 between SGA babies within each growth trajectory to babies born non-SGA.

Results: Among SGA individuals (n = 656), we identified three distinct fetal growth trajectories for weight. Children who were consistently small from mid-pregnancy (n = 64) had the lowest IQ (7 points lower compared to non-SGA babies, 95% confidence interval [CI] = -11.0, -3.5) and slightly more ADHD symptoms. Children from the trajectory that started larger but were smaller at birth showed no differences in outcomes compared to children born non-SGA.

Conclusions: Among SGA children, those who were smaller beginning in mid-pregnancy exhibited the worst neurodevelopmental outcomes at age 6. Fetal growth trajectories may help identify SGA babies who go on to have poor neurodevelopmental outcomes.
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http://dx.doi.org/10.1097/EDE.0000000000001387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338787PMC
September 2021

Parental cannabis and tobacco use during pregnancy and childhood hair cortisol concentrations.

Drug Alcohol Depend 2021 08 21;225:108751. Epub 2021 May 21.

Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2040, 3000CA, Rotterdam, the Netherlands; Department of Child and Adolescent Psychiatry, Erasmus MC, University Medical Center Rotterdam, 3000CB, Rotterdam, the Netherlands; Department of Psychology, Education and Child Studies, Erasmus School of Social and Behavioral Sciences, Erasmus University Rotterdam, 3062PA, Rotterdam, the Netherlands.

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.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.108751DOI Listing
August 2021

Associations of Hair Cortisol Concentrations With Cardiometabolic Risk Factors in Childhood.

J Clin Endocrinol Metab 2021 08;106(9):e3400-e3413

The Generation R Study Group, Erasmus MC, University Medical Center, CA Rotterdam, the Netherlands.

Context: Biological stress is related to cardiovascular disease in adults. The associations of stress with cardiovascular and metabolic diseases may originate in childhood.

Objective: This work aims to examine the associations of hair cortisol concentrations at age 6 years with cardiometabolic risk factors at ages 6 and 10 years.

Methods: Cortisol concentrations were measured in hair of 6-year-old children (n = 2598) participating in the Generation R Study, a population-based prospective cohort study in Rotterdam, the Netherlands. Main outcome measures included blood pressure, heart rate, concentrations of insulin, glucose, lipids, and C-reactive protein in blood at ages 6 and 10 years.

Results: Higher hair cortisol concentrations at age 6 years were associated with higher systolic blood pressure at age 10 years (difference 0.17 SD score; 95% CI, 0.03-0.31). The association attenuated into nonsignificance after adjustment for childhood body mass index (BMI) at age 6 years. Higher hair cortisol concentrations at age 6 years were associated with an increase in total and low-density lipoprotein cholesterol between ages 6 and 10 years but not with those measurements at age 6 or 10 years. Hair cortisol concentrations were not associated with other cardiometabolic risk factors at age 6 or 10 years.

Conclusion: Hair cortisol concentrations were not independent of BMI associated with cardiometabolic risk factors at 6 or 10 years. The associations of biological stress with cardiometabolic risk factors may develop at later ages.
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http://dx.doi.org/10.1210/clinem/dgab379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372666PMC
August 2021

Maternal Early-Pregnancy Glucose Concentrations and Liver Fat Among School-Age Children.

Hepatology 2021 Oct 15;74(4):1902-1913. Epub 2021 Aug 15.

The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background And Aims: Gestational diabetes seems to be associated with offspring NAFLD. We hypothesized that maternal glucose concentrations across the full range may have persistent effects on offspring liver fat accumulation.

Approach And Results: In a multiethnic, population-based, prospective cohort study among 2,168 women and their offspring, maternal early-pregnancy glucose concentrations were measured at a median of 13.1 weeks' gestation (95% CI, 9.6-17.2). Liver fat fraction was measured at 10 years by MRI. NAFLD was defined as liver fat fraction ≥5.0%. We performed analyses among all mothers with different ethnic backgrounds and those of European ancestry only. The multiethnic group had a median maternal early-pregnancy glucose concentration of 4.3 mmol/L (interquartile range, 3.9-4.9) and a 2.8% (n = 60) prevalence of NAFLD. The models adjusted for child age and sex only showed that in the multiethnic group, higher maternal early-pregnancy glucose concentrations were associated with higher liver fat accumulation and higher odds of NAFLD, but these associations attenuated into nonsignificance after adjustment for potential confounders. Among mothers of European ancestry only, maternal early-pregnancy glucose concentrations were associated with increased odds of NAFLD (OR, 1.95; 95% CI, 1.32; 2.88, after adjustment for confounders) per 1-mmol/L increase in maternal early-pregnancy glucose concentration. These associations were not explained by maternal prepregnancy and childhood body mass index, visceral fat, and metabolic markers.

Conclusions: In this study, maternal early-pregnancy glucose concentrations were only among mothers of European ancestry associated with offspring NAFLD. The associations of higher maternal early-pregnancy glucose concentrations with offspring NAFLD may differ between ethnic groups.
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http://dx.doi.org/10.1002/hep.31910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8519071PMC
October 2021

Maternal bisphenol urine concentrations, fetal growth and adverse birth outcomes: A population-based prospective cohort.

Environ Health 2021 05 15;20(1):60. Epub 2021 May 15.

The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, Rotterdam, 3000 CA, the Netherlands.

Background: Exposure to bisphenols may affect fetal growth and development. The trimester-specific effects of bisphenols on repeated measures of fetal growth remain unknown. Our objective was to assess the associations of maternal bisphenol urine concentrations with fetal growth measures and birth outcomes and identify potential critical exposure periods.

Methods: In a population-based prospective cohort study among 1379 pregnant women, we measured maternal bisphenol A, S and F urine concentrations in the first, second and third trimester. Fetal head circumference, length and weight were measured in the second and third trimester by ultrasound and at birth.

Results: An interquartile range increase in maternal pregnancy-averaged bisphenol S concentrations was associated with larger fetal head circumference (difference 0.18 (95% confidence interval (CI) 0.01 to 0.34) standard deviation scores (SDS), p-value< 0.05) across pregnancy. When focusing on specific critical exposure periods, any detection of first trimester bisphenol S was associated with larger second and third trimester fetal head circumference (difference 0.15 (95% CI 0.05 to 0.26) and 0.12 (95% CI 0.02 to 0.23) SDS, respectively) and fetal weight (difference 0.12 (95% CI 0.02 to 0.22) and 0.16 (95% CI 0.06 to 0.26) SDS, respectively). The other bisphenols were not consistently associated with fetal growth outcomes. Any detection of bisphenol S and bisphenol F in first trimester was also associated with a lower risk of being born small size for gestational age (Odds Ratio 0.56 (95% CI 0.38 to 0.74) and 0.55 (95% CI 0.36 to 0.85), respectively). Bisphenols were not associated with risk of preterm birth.

Conclusions: Higher maternal bisphenol S urine concentrations, especially in the first trimester, seem to be related with larger fetal head circumference, higher weight and a lower risk of being small size for gestational age at birth.
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http://dx.doi.org/10.1186/s12940-021-00747-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126069PMC
May 2021

Associations of circulating folate, vitamin B12 and homocysteine concentrations in early pregnancy and cord blood with epigenetic gestational age: the Generation R Study.

Clin Epigenetics 2021 04 29;13(1):95. Epub 2021 Apr 29.

The Generation R Study Group (Na-2918), Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

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.
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http://dx.doi.org/10.1186/s13148-021-01065-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082638PMC
April 2021

The EU Child Cohort Network's core data: establishing a set of findable, accessible, interoperable and re-usable (FAIR) variables.

Eur J Epidemiol 2021 May 21;36(5):565-580. Epub 2021 Apr 21.

Department of Social Medicine, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece.

The Horizon2020 LifeCycle Project is a cross-cohort collaboration which brings together data from multiple birth cohorts from across Europe and Australia to facilitate studies on the influence of early-life exposures on later health outcomes. A major product of this collaboration has been the establishment of a FAIR (findable, accessible, interoperable and reusable) data resource known as the EU Child Cohort Network. Here we focus on the EU Child Cohort Network's core variables. These are a set of basic variables, derivable by the majority of participating cohorts and frequently used as covariates or exposures in lifecourse research. First, we describe the process by which the list of core variables was established. Second, we explain the protocol according to which these variables were harmonised in order to make them interoperable. Third, we describe the catalogue developed to ensure that the network's data are findable and reusable. Finally, we describe the core data, including the proportion of variables harmonised by each cohort and the number of children for whom harmonised core data are available. EU Child Cohort Network data will be analysed using a federated analysis platform, removing the need to physically transfer data and thus making the data more accessible to researchers. The network will add value to participating cohorts by increasing statistical power and exposure heterogeneity, as well as facilitating cross-cohort comparisons, cross-validation and replication. Our aim is to motivate other cohorts to join the network and encourage the use of the EU Child Cohort Network by the wider research community.
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http://dx.doi.org/10.1007/s10654-021-00733-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159791PMC
May 2021

First trimester fetal proportion volumetric measurements using a Virtual Reality approach.

Prenat Diagn 2021 Jun 3;41(7):868-876. Epub 2021 May 3.

The Generation R Study Group, Erasmus University Medical Center, Rotterdam, The Netherlands.

Objective: To establish feasibility and reproducibility of fetal proportion volumetric measurements, using three-dimensional (3D) ultrasound and a Virtual Reality (VR) system.

Methods: Within a population-based prospective birth cohort, 3D ultrasound datasets of 50 fetuses in the late first trimester were collected by three ultrasonographers in a single research center. V-scope software was used for volumetric measurements of total fetus, extremities, head-trunk, head, trunk, thorax, and abdomen. All measurements were performed independently by two researchers. Intraobserver and interobserver reproducibility were analyzed using Bland and Altman methods.

Results: Intraobserver and interobserver analyses of volumetric measurements of total fetus, head-trunk, head, trunk, thorax and abdomen showed intraclass correlation coefficients above 0.979, coefficients of variation below 7.51% and mean difference below 3.44%. The interobserver limits of agreement were within the ±10% range for volumetric measurements of total fetus, head-trunk, head and trunk. The interobserver limits of agreement for extremities, thorax and abdomen were -26.09% to 4.77%, -14.14% to 10.00% and -14.47% to 8.83%, respectively.

Conclusion: First trimester fetal proportion volumetric measurements using 3D ultrasound and VR are feasible and reproducible, except volumetric measurements of the fetal extremities. These novel volumetric measurements may be used in future research to enable detailed studies on first trimester fetal development and growth.
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http://dx.doi.org/10.1002/pd.5947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251560PMC
June 2021

Cardio-metabolic risk factors during childhood in relation to lung function and asthma.

Pediatr Allergy Immunol 2021 07 4;32(5):945-952. Epub 2021 May 4.

Division of Respiratory Medicine and Allergology, Department of Pediatrics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Background: Cardio-metabolic risk factors might have an adverse effect on respiratory outcomes, but associations in children are unknown. We aimed to study the longitudinal associations of cardio-metabolic risk factors with lung function and asthma at school age. We also examined whether any association was explained by child's body mass index (BMI).

Methods: In a population-based cohort study among 4988 children, cardio-metabolic risk factors were measured at 6 and 10 years and included blood pressure, cholesterol, triglycerides, insulin, and C-reactive protein (CRP) concentrations. At age 10 years, lung function was measured by spirometry and current physician-diagnosed asthma was assessed by questionnaire.

Results: After adjustment for confounders, child's BMI, and multiple testing, we observed that a higher diastolic blood pressure at the age of 6 years was associated with a higher forced vital capacity (FVC) at the age of 10 years (Z-score difference (95% CI): 0.05 (0.01, 0.08), per SDS increase in diastolic blood pressure). Also, child's CRP concentrations above the 75th percentile at both ages 6 and 10 years were related to a lower FVC as compared to CRP concentrations below the 75th percentile at both ages (Z-score difference (95% CI) -0.21 (-0.36, -0.06)). No consistent associations of other cardio-metabolic risk factors with respiratory outcomes were observed.

Conclusion: Blood pressure and CRP, but not lipids and insulin, were associated with lower lung function but not with asthma. The underlying mechanisms and long-term effects of these associations require further investigation.
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http://dx.doi.org/10.1111/pai.13509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360082PMC
July 2021

Maternal First-Trimester Cow-Milk Intake Is Positively Associated with Childhood General and Abdominal Visceral Fat Mass and Lean Mass but Not with Other Cardiometabolic Risk Factors at the Age of 10 Years.

J Nutr 2021 Jul;151(7):1965-1975

The Generation R Study Group, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Background: Higher maternal cow-milk intake during pregnancy is associated with higher fetal growth measures and higher birth weight.

Objective: The aim of this study was to assess the associations of maternal milk intake during pregnancy with body fat measures and cardiometabolic risk factors at the age of 10 y.

Methods: In a population-based cohort of Dutch mothers and their children (n = 2466) followed from early pregnancy onwards, we assessed maternal first-trimester milk intake (milk and milk drinks) by food-frequency questionnaire. Maternal milk intake was categorized into 0-0.9, 1-1.9, 2-2.9, 3-3.9, 4-4.9, and ≥5 glasses/d, with 1 glass equivalent to 150 mL milk. For children at the age of 10 y, we calculated BMI and obtained detailed measures of body and organ fat by DXA and MRI. We also measured blood pressure and lipid, insulin, and glucose concentrations. Data were analyzed using linear and logistic regression models.

Results: Compared with children whose mothers consumed 0-0.9 glass of milk/d during their pregnancy, those whose mothers consumed ≥5 glasses of milk/d had a 0.29 SD (95% CI: 0.10, 0.48) higher BMI, 0.27 SD (95% CI: 0.08, 0.47) higher fat mass, 0.26 SD (95% CI: 0.07, 0.46) higher lean mass, 0.30 SD (95% CI: 0.09, 0.50) higher android-to-gynoid fat mass ratio and 0.38 SD (95% CI: 0.09, 0.67) higher abdominal visceral fat mass. After correction for multiple comparisons, groups of maternal milk intake were not associated with pericardial fat mass index, liver fat fraction, blood pressure, or lipid, insulin, or glucose concentrations (P values >0.0125).

Conclusions: Our results suggest that maternal first-trimester milk intake is positively associated with childhood general and abdominal visceral fat mass and lean mass, but not with other cardiometabolic risk factors.
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http://dx.doi.org/10.1093/jn/nxab047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245880PMC
July 2021

Associations of Early Pregnancy and Neonatal Circulating Folate, Vitamin B-12, and Homocysteine Concentrations with Cardiometabolic Risk Factors in Children at 10 y of Age.

J Nutr 2021 06;151(6):1628-1636

The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: Higher circulating folate and vitamin B-12 concentrations and lower circulating homocysteine concentrations during pregnancy seem to be associated with fetal development. These micronutrients may also be associated with cardiometabolic health.

Objective: We examined the associations of circulating folate, vitamin B-12, and homocysteine concentrations during pregnancy and in neonates with childhood cardiometabolic outcomes.

Methods: This study was embedded in the Generation R Study, a population-based prospective cohort study from early pregnancy onward. We sampled blood in early pregnancy and cord blood. We measured cardiometabolic outcomes in the children at school age. Among 4449 children aged 10 y (median: 9.7; 95% range: 9.3, 10.7), we examined associations of plasma folate, serum vitamin B-12, and plasma homocysteine concentrations in early pregnancy and at birth with BMI, body fat distribution, heart rate, blood pressure, and insulin, glucose, and lipid concentrations, using linear regression models. Using logistic models, we examined the associations of these micronutrients with risks of overweight/obesity and clustering of cardiovascular risk factors.

Results: One standard deviation score (SDS) higher maternal plasma folate concentration was associated with lower BMI (-0.04 SDS; 95% CI: -0.08, -0.01), android-to-gynoid fat ratio (-0.04 SDS; 95% CI: -0.07, -0.01), systolic blood pressure (-0.06 SDS; 95% CI: -0.10, -0.03), risk of overweight (OR: 0.87; 95% CI: 0.78, 0.96), and clustering of cardiovascular risk factors (OR: 0.79; 95% CI: 0.68, 0.91). One SDS higher maternal serum total B-12 concentration was associated with lower glucose (-0.06 SDS; 95% CI: -0.10, -0.02) and higher HDL cholesterol concentrations (0.04 SDS; 95% CI: 0.00, 0.08). Cord blood folate, vitamin B-12, and homocysteine concentrations were not consistently associated with cardiometabolic outcomes.

Conclusions: Subtle differences in circulating folate and vitamin B-12 concentrations in early pregnancy may be associated with child cardiometabolic health at age 10 y. The causality and mechanisms underlying these associations need further study.
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http://dx.doi.org/10.1093/jn/nxab039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243896PMC
June 2021

Associations of maternal early-pregnancy dietary glycemic index with childhood general, abdominal and ectopic fat accumulation.

Clin Nutr 2021 04 6;40(4):1628-1636. Epub 2021 Mar 6.

The Generation R Study Group, Erasmus MC, University Medical Center, Rotterdam, The Netherlands; Department of Pediatrics, Sophia's Children's Hospital, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Electronic address:

Background & Aims: Maternal hyperglycemia during pregnancy is an important risk factor for childhood adiposity. Maternal dietary glycemic index during pregnancy directly influences maternal and fetal glucose concentrations. We examined the associations of maternal early-pregnancy dietary glycemic index with offspring general, abdominal and ectopic fat accumulation among normal weight and overweight or obese pregnant women and their offspring.

Methods: In a population-based cohort study among 2488 Dutch pregnant women and their children, we assessed maternal dietary glycemic index by food frequency questionnaire at median 13.4 (95% range 10.7; 21.1) weeks gestation. Dietary glycemic index was used continuously and categorized into low (≤55), normal (56-69) and high (≥70) glycemic index diet. We measured offspring BMI, total fat mass and android/gynoid fat mass ratio by DXA, and visceral fat mass and liver fat fraction by MRI at 10 years.

Results: No associations of maternal early-pregnancy dietary glycemic index with offspring adiposity were present among normal weight women and their children. Among overweight and obese women and their children, 1-Standard Deviation Score (SDS) increase in maternal early-pregnancy dietary glycemic index was associated with higher childhood BMI (0.10 SDS, 95% Confidence Interval (CI) 0.01; 0.19), total fat mass index (0.13 SDS, 95% CI 0.05; 0.22), visceral fat mass index (0.19 SDS, 95% CI 0.07; 0.32) and tended to be associated with a higher android/gynoid fat mass ratio (0.09 SDS, 95% CI -0.01; 0.19) and higher risk of childhood overweight (Odds Ratio (OR) 1.20, 95% CI 0.97; 1.48). Overweight and obese women consuming an early-pregnancy low-glycemic index diet, as compared to an early-pregnancy normal-glycemic index diet, had children with lower BMI, total fat mass index, visceral fat mass index and android/gynoid fat mass ratio at 10 years (p-values<0.05). No women consumed a high-glycemic index diet. No associations were explained by maternal socio-economic, lifestyle and dietary characteristics, birth or childhood characteristics. No associations with liver fat fraction were present.

Conclusions: In overweight or obese women and their children, a higher maternal early-pregnancy dietary glycemic index is associated with childhood general, abdominal and visceral fat accumulation, but not with liver fat. Intervention studies among overweight and obese pregnant women may need to target the dietary glycemic index to prevent childhood adiposity.
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http://dx.doi.org/10.1016/j.clnu.2021.02.046DOI Listing
April 2021

Changes in Family Poverty Status and Child Health.

Pediatrics 2021 04 8;147(4). Epub 2021 Mar 8.

Public Health, and

Objectives: In this study, we aim to assess the associations over time between poverty and child weight status, asthma, and health-related quality of life (HRQoL).

Methods: We analyzed data for 3968 children from the Generation R Study, a population-based cohort study in the Netherlands. Net household income and the number of adults and children living from this income were measured at 4 time-points (during pregnancy and at ages 2, 3, and 6). Poverty was defined on the basis of the equivalized household income being <60% of the median national income. Child health outcomes were measured at age 6 years. The association was explored by using logistic and linear regression models.

Results: In this cohort, 9.8% of children were born into poverty and 6.0% had experienced 3 to 4 episodes of poverty. Independent of current poverty status, children born into poverty had an odds ratio (OR) of 1.68 for having overweight/obesity and a lower physical HRQoL (OR = -1.32) than those not born into poverty. Children having experienced 3 to 4 episodes of poverty had an OR of 1.94 for having asthma and a lower physical HRQoL (OR = -3.32) compared with children from never-poor families. Transition out of poverty before age 2 was associated with lower risk of asthma and a higher physical HRQoL compared with children who remained in poverty.

Conclusions: Being born into poverty or experiencing multiple episodes of poverty is associated with negative child health outcomes, such as having overweight, asthma, or a lower HRQoL. Support for children and families with a low household income is warranted.
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http://dx.doi.org/10.1542/peds.2020-016717DOI Listing
April 2021

Maternal iron status during early pregnancy and school-age, lung function, asthma, and allergy: The Generation R Study.

Pediatr Pulmonol 2021 06 3;56(6):1771-1778. Epub 2021 Mar 3.

Division of Neonatology, Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: Iron deficiency during early life could affect the developing lung and immune system, and influence child's respiratory or allergy outcomes in later life.

Objective: To examine the associations of maternal iron status during early pregnancy with child's lung function, asthma, inhalant allergic sensitization, and physician-diagnosed inhalant allergy at school-age.

Methods: In a population-based cohort study, among 3825 mother-child pairs, ferritin, transferrin concentrations, and transferrin saturation were measured from maternal venous blood samples during early pregnancy. In children at the age of 10 years, spirometry was used to determine child's lung function, current asthma and physician-diagnosed inhalant allergy were assessed by questionnaires, and inhalant allergic sensitization was measured by skin prick tests. We used multivariable regression models to examine the associations.

Results: After adjustment for gestational age at maternal iron status measurement and sociodemographic or lifestyle-related confounders, a higher maternal transferrin concentration was associated with a higher risk of physician-diagnosed inhalant allergy (odds ratio [95% confidence interval]: 1.13 [1.01 to1.26]), but not with lung function, asthma, or inhalant allergic sensitization. This association did not attenuate after further adjustment for maternal hemoglobin levels or early growth factors. We observed no consistent association of maternal ferritin concentrations or transferrin saturation with child's respiratory or allergy outcomes.

Conclusion: Higher maternal transferrin concentrations during pregnancy, reflecting lower serum iron levels, were associated with an increased risk of child's physician-diagnosed inhalant allergy but not lung outcomes. Underlying mechanisms and clinical implications need to be explored.
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http://dx.doi.org/10.1002/ppul.25324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251584PMC
June 2021

Mental Health in Early Childhood and Changes in Cardiometabolic Dysregulation by Preadolescence.

Psychosom Med 2021 04;83(3):256-264

From the Department of Social and Behavioral Sciences (Qureshi, Tiemeier, Kubzansky), Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Psychology, Education and Child Studies (Derks), Erasmus University Rotterdam, Rotterdam, the Netherlands; Department of Child and Adolescent Psychiatry/Psychology (Derks) and; The Generation R Study Group, Department of Pediatrics (Jaddoe), Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands; and Department of Epidemiology (Williams, Koenen), Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Objective: Poor mental health in childhood is associated with a greater risk of cardiometabolic disease in adulthood, but less is known about when these associations begin to emerge. This study tests whether poor mental health (indexed by emotional and behavioral problems) in early childhood predicts increases in cardiometabolic dysregulation over 4 years of follow-up.

Methods: Data are from 4327 participants in the Generation R Study. Problem behaviors were reported by mothers using the Child Behavior Checklist at age 6 years. Repeated measurements of six cardiometabolic parameters were collected at ages 6 and 10 years: high-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, systolic and diastolic blood pressures, C-reactive protein, and body mass index. Standardized measures were used to create continuous cardiometabolic dysregulation scores at ages 6 and 10 years. Change in dysregulation was defined as the difference in dysregulation scores over time. Cross-sectional and prospective associations were tested using linear regression, sequentially adjusting for relevant confounders. Additional analyses examined whether prospective relationships were robust to adjustment for baseline levels of dysregulation.

Results: There was no association between child problem behaviors and cardiometabolic dysregulation at age 6 years. However, higher levels of problem behaviors predicted increases in cardiometabolic dysregulation (β = 0.12, 95% confidence interval = 0.00-0.23) from ages 6 to 10 years.

Conclusions: Worse child mental health may be associated with increases in cardiometabolic dysregulation by preadolescence. To our knowledge, this is the first study to demonstrate that adverse physiologic effects of psychological distress identified in adult populations may be observed as early as childhood.
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http://dx.doi.org/10.1097/PSY.0000000000000927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016708PMC
April 2021
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