Sociodemographic, lifestyle, and environmental determinants of vitamin D levels in pregnant women in Spain.

INTRODUCTION: Vitamin D deficiency (<20 ng/mL circulating levels) is a worldwide public health concern and pregnant women are especially vulnerable, affecting the health of the mother and the fetus. This study aims to evaluate the sociodemographic, lifestyle, and environmental determinants associated with circulating vitamin D levels in Spanish pregnant women. METHODS: We used data from the Spanish INMA ("Infancia y Medio Ambiente") prospective birth cohort study from the regions of Gipuzkoa, Sabadell, and Valencia. 25-hydroxyvitamin D3 (25(OH)D3) was measured in plasma collected in the first trimester of pregnancy. Information on 108 determinants was gathered: 13 sociodemographic, 48 lifestyle including diet, smoking and physical activity, and 47 environmental variables, representing the urban and the chemical exposome. Association of the determinants with maternal 25(OH)D3 levels was estimated in single- and multiple-exposure models. Machine learning techniques were used to predict 25(OH)D3 levels below sufficiency (30 ng/mL). RESULTS: The prevalence of < 30 ng/mL 25(OH)D3 levels was 51 %. In the single-exposure analysis, older age, higher socioeconomic status, taking vitamin D, B12 and other sup*plementation, and higher humidity, atmospheric pressure and UV rays were associated with higher levels of 25(OH)D3 (IQR increase of age: 1.2 [95 % CI: 0.6, 1.8] ng/mL 25(OH)D3). In the multiple-exposures model, most of these associations remained and others were revealed. Higher body mass index, PM2.5 and high deprivation area were associated with lower 25(OH)D3 levels (i.e., Quartile 4 of PM2.5 vs Q1: -3.6 [95 % CI: -5.6, -1.5] ng/mL of 25(OH)D3). History of allergy and asthma, being multiparous, intake of vegetable fat, vitamin B6, alcohol consumption and molybdenum were associated with higher levels. The machine learning classification model confirmed some of these associations. CONCLUSIONS: This comprehensive study shows that younger age, higher body mass index, higher deprived areas, higher air pollution and lower UV rays and humidity are associated with lower 25(OH)D3 levels.

State-of-the-art methods for exposure-health studies: Results from the exposome data challenge event.

The exposome recognizes that individuals are exposed simultaneously to a multitude of different environmental factors and takes a holistic approach to the discovery of etiological factors for disease. However, challenges arise when trying to quantify the health effects of complex exposure mixtures. Analytical challenges include dealing with high dimensionality, studying the combined effects of these exposures and their interactions, integrating causal pathways, and integrating high-throughput omics layers. To tackle these challenges, the Barcelona Institute for Global Health (ISGlobal) held a data challenge event open to researchers from all over the world and from all expertises. Analysts had a chance to compete and apply state-of-the-art methods on a common partially simulated exposome dataset (based on real case data from the HELIX project) with multiple correlated exposure variables (P > 100 exposure variables) arising from general and personal environments at different time points, biological molecular data (multi-omics: DNA methylation, gene expression, proteins, metabolomics) and multiple clinical phenotypes in 1301 mother-child pairs. Most of the methods presented included feature selection or feature reduction to deal with the high dimensionality of the exposome dataset. Several approaches explicitly searched for combined effects of exposures and/or their interactions using linear index models or response surface methods, including Bayesian methods. Other methods dealt with the multi-omics dataset in mediation analyses using multiple-step approaches. Here we discuss features of the statistical models used and provide the data and codes used, so that analysts have examples of implementation and can learn how to use these methods. Overall, the exposome data challenge presented a unique opportunity for researchers from different disciplines to create and share state-of-the-art analytical methods, setting a new standard for open science in the exposome and environmental health field.

The Use of Lower or Higher Than Recommended Doses of Folic Acid Supplements during Pregnancy Is Associated with Child Attentional Dysfunction at 4-5 Years of Age in the INMA Project.

We assessed the association between the use of lower- and higher-than-recommended doses of folic acid supplements (FAs) during pregnancy and attentional function in boys and girls at age of 4-5. We analyzed data from 1329 mother-child pairs from the mother-child cohort INfancia y Medio Ambiente Project (INMA) study. Information on FAs use during pregnancy was collected in personal interviews at weeks 12 and 30, and categorized in <400, 400-999 (recommended dose), and ≥1000 µg/day. Child attentional function was assessed by Conners' Kiddie Continuous Performance Test. Multivariable regression analyses were used to estimate incidence rate ratios (IRR) and beta coefficients with 95% confidence intervals (CI). Compared to recommended FAs doses, the periconceptional use of <400 and ≥1000 µg/day was associated with higher risk of omission errors-IRR = 1.14 (95% CI: 1.01; 1.29) and IRR = 1.16 (95% CI: 1.02; 1.33), respectively. The use of FAs < 400 µg/day and ≥1000 µg/day was significantly associated with deficits of attentional function only in boys. FAs use < 400 µg/day was associated with higher omission errors with IRR = 1.22 and increased hit reaction time (HRT) ß = 34.36, and FAs use ≥ 1000 µg/day was associated with increased HRT ß = 33.18 and HRT standard error ß = 3.31. The periconceptional use of FAs below or above the recommended doses is associated with deficits of attentional function in children at age of 4-5, particularly in boys.

Applying the exposome concept in birth cohort research: a review of statistical approaches.

The exposome represents the totality of life course environmental exposures (including lifestyle and other non-genetic factors), from the prenatal period onwards. This holistic concept of exposure provides a new framework to advance the understanding of complex and multifactorial diseases. Prospective pregnancy and birth cohort studies provide a unique opportunity for exposome research as they are able to capture, from prenatal life onwards, both the external (including lifestyle, chemical, social and wider community-level exposures) and the internal (including inflammation, metabolism, epigenetics, and gut microbiota) domains of the exposome. In this paper, we describe the steps required for applying an exposome approach, describe the main strengths and limitations of different statistical approaches and discuss their challenges, with the aim to provide guidance for methodological choices in the analysis of exposome data in birth cohort studies. An exposome approach implies selecting, pre-processing, describing and analyzing a large set of exposures. Several statistical methods are currently available to assess exposome-health associations, which differ in terms of research question that can be answered, of balance between sensitivity and false discovery proportion, and between computational complexity and simplicity (parsimony). Assessing the association between many exposures and health still raises many exposure assessment issues and statistical challenges. The exposome favors a holistic approach of environmental influences on health, which is likely to allow a more complete understanding of disease etiology.

Early-Life Environmental Exposures and Blood Pressure in Children.

BACKGROUND: Growing evidence exists about the fetal and environmental origins of hypertension, but mainly limited to single-exposure studies. The exposome has been proposed as a more holistic approach by studying many exposures simultaneously. OBJECTIVES: This study aims to evaluate the association between a wide range of prenatal and postnatal exposures and blood pressure (BP) in children. METHODS: Systolic and diastolic BP were measured among 1,277 children from the European HELIX (Human Early-Life Exposome) cohort aged 6 to 11 years. Prenatal (n = 89) and postnatal (n = 128) exposures include air pollution, built environment, meteorology, natural spaces, traffic, noise, chemicals, and lifestyles. Two methods adjusted for confounders were applied: an exposome-wide association study considering the exposures independently, and the deletion-substitution-addition algorithm considering all the exposures simultaneously. RESULTS: Decreases in systolic BP were observed with facility density (ß change for an interquartile-range increase in exposure: -1.7 mm Hg [95% confidence interval (CI): -2.5 to -0.8 mm Hg]), maternal concentrations of polychlorinated biphenyl 118 (-1.4 mm Hg [95% CI: -2.6 to -0.2 mm Hg]) and child concentrations of dichlorodiphenyldichloroethylene (DDE: -1.6 mm Hg [95% CI: -2.4 to -0.7 mm Hg]), hexachlorobenzene (-1.5 mm Hg [95% CI: -2.4 to -0.6 mm Hg]), and mono-benzyl phthalate (-0.7 mm Hg [95% CI: -1.3 to -0.1 mm Hg]), whereas increases in systolic BP were observed with outdoor temperature during pregnancy (1.6 mm Hg [95% CI: 0.2 to 2.9 mm Hg]), high fish intake during pregnancy (2.0 mm Hg [95% CI: 0.4 to 3.5 mm Hg]), maternal cotinine concentrations (1.2 mm Hg [95% CI: -0.3 to 2.8 mm Hg]), and child perfluorooctanoate concentrations (0.9 mm Hg [95% CI: 0.1 to 1.6 mm Hg]). Decreases in diastolic BP were observed with outdoor temperature at examination (-1.4 mm Hg [95% CI: -2.3 to -0.5 mm Hg]) and child DDE concentrations (-1.1 mm Hg [95% CI: -1.9 to -0.3 mm Hg]), whereas increases in diastolic BP were observed with maternal bisphenol-A concentrations (0.7 mm Hg [95% CI: 0.1 to 1.4 mm Hg]), high fish intake during pregnancy (1.2 mm Hg [95% CI: -0.2 to 2.7 mm Hg]), and child copper concentrations (0.9 mm Hg [95% CI: 0.3 to 1.6 mm Hg]). CONCLUSIONS: This study suggests that early-life exposure to several chemicals, as well as built environment and meteorological factors, may affect BP in children.

Influence of the Urban Exposome on Birth Weight.

BACKGROUND: The exposome is defined as the totality of environmental exposures from conception onwards. It calls for providing a holistic view of environmental exposures and their effects on human health by evaluating multiple environmental exposures simultaneously during critical periods of life. OBJECTIVE: We evaluated the association of the urban exposome with birth weight. METHODS: We estimated exposure to the urban exposome, including the built environment, air pollution, road traffic noise, meteorology, natural space, and road traffic (corresponding to 24 environmental indicators and 60 exposures) for nearly 32,000 pregnant women from six European birth cohorts. To evaluate associations with either continuous birth weight or term low birth weight (TLBW) risk, we primarily relied on the Deletion-Substitution-Addition (DSA) algorithm, which is an extension of the stepwise variable selection method. Second, we used an exposure-by-exposure exposome-wide association studies (ExWAS) method accounting for multiple hypotheses testing to report associations not adjusted for coexposures. RESULTS: The most consistent statistically significant associations were observed between increasing green space exposure estimated as Normalized Difference Vegetation Index (NDVI) and increased birth weight and decreased TLBW risk. Furthermore, we observed statistically significant associations among presence of public bus line, land use Shannon's Evenness Index, and traffic density and birth weight in our DSA analysis. CONCLUSION: This investigation is the first large urban exposome study of birth weight that tests many environmental urban exposures. It confirmed previously reported associations for NDVI and generated new hypotheses for a number of built-environment exposures. https://doi.org/10.1289/EHP3971.

High doses of folic acid in the periconceptional period and risk of low weight for gestational age at birth in a population based cohort study.

PURPOSE: We investigated the association between maternal use of folic acid (FA) during pregnancy and child anthropometric measures at birth. METHODS: We included 2302 mother-child pairs from a population-based birth cohort in Spain (INMA Project). FA dosages at first and third trimester of pregnancy were assessed using a specific battery questionnaire and were categorized in non-user, < 1000, 1000-4999, and ≥ 5000 µg/day. Anthropometric measures at birth (weight in grams, length and head circumference in centimetres) were obtained from medical records. Small for gestational age according to weight (SGA-w), length (SGA-l) and head circumference (SGA-hc) were defined using the 10th percentile based on Spanish standardized growth reference charts. Multiple linear and logistic regression analyses were used to explore the association between FA dosages in different stages of pregnancy and child anthropometric measures at birth. RESULTS: In the multiple linear regression analysis, we found a tendency for a negative association between the use of high dosages of FA (≥ 5000 µg/day) in the periconceptional period of pregnancy and weight at birth compared to mothers who were non-users of FA (ß = - 73.83; 95% CI - 151.71, 4.06). In the multiple logistic regression, a greater risk of SGA-w was also evident among children whose mothers took FA dosages of 1000-4999 (OR = 2.21; 95% CI 1.17, 4.19) and of ≥ 5000 µg/day (OR = 2.32; 95% CI 1.06, 5.08) compared to mothers non-users of FA in the periconceptional period of pregnancy. CONCLUSION: Our findings suggest that a high dosage of FA (≥ 1000 µg/day) may be associated with an increased risk of SGA-w at birth.

Risk of Lung Cancer Mortality in Nuclear Workers from Internal Exposure to Alpha Particle-emitting Radionuclides.

BACKGROUND: Carcinogenic risks of internal exposures to alpha-emitters (except radon) are poorly understood. Since exposure to alpha particles-particularly through inhalation-occurs in a range of settings, understanding consequent risks is a public health priority. We aimed to quantify dose-response relationships between lung dose from alpha-emitters and lung cancer in nuclear workers. METHODS: We conducted a case-control study, nested within Belgian, French, and UK cohorts of uranium and plutonium workers. Cases were workers who died from lung cancer; one to three controls were matched to each. Lung doses from alpha-emitters were assessed using bioassay data. We estimated excess odds ratio (OR) of lung cancer per gray (Gy) of lung dose. RESULTS: The study comprised 553 cases and 1,333 controls. Median positive total alpha lung dose was 2.42 mGy (mean: 8.13 mGy; maximum: 316 mGy); for plutonium the median was 1.27 mGy and for uranium 2.17 mGy. Excess OR/Gy (90% confidence interval)-adjusted for external radiation, socioeconomic status, and smoking-was 11 (2.6, 24) for total alpha dose, 50 (17, 106) for plutonium, and 5.3 (-1.9, 18) for uranium. CONCLUSIONS: We found strong evidence for associations between low doses from alpha-emitters and lung cancer risk. The excess OR/Gy was greater for plutonium than uranium, though confidence intervals overlap. Risk estimates were similar to those estimated previously in plutonium workers, and in uranium miners exposed to radon and its progeny. Expressed as risk/equivalent dose in sieverts (Sv), our estimates are somewhat larger than but consistent with those for atomic bomb survivors.See video abstract at, http://links.lww.com/EDE/B232.

Fish and seafood consumption during pregnancy and the risk of asthma and allergic rhinitis in childhood: a pooled analysis of 18 European and US birth cohorts.

Background: It has been suggested that prenatal exposure to n-3 long-chain fatty acids protects against asthma and other allergy-related diseases later in childhood. The extent to which fish intake in pregnancy protects against child asthma and rhinitis symptoms remains unclear. We aimed to assess whether fish and seafood consumption in pregnancy is associated with childhood wheeze, asthma and allergic rhinitis. Methods: We pooled individual data from 60 774 mother-child pairs participating in 18 European and US birth cohort studies. Information on wheeze, asthma and allergic rhinitis prevalence was collected using validated questionnaires. The time periods of interest were: infancy (0-2 years), preschool age (3-4 years), and school age (5-8 years). We used multivariable generalized models to assess associations of fish and seafood (other than fish) consumption during pregnancy with child respiratory outcomes in cohort-specific analyses, with subsequent random-effects meta-analyses. Results: The median fish consumption during pregnancy ranged from 0.44 times/week in The Netherlands to 4.46 times/week in Spain. Maternal fish intake during pregnancy was not associated with offspring wheeze symptoms in any age group nor with the risk of child asthma [adjusted meta-analysis relative risk (RR) per 1-time/week = 1.01, 95% confidence interval 0.97-1.05)] and allergic rhinitis at school age (RR = 1.01, 0.99-1.03). These results were consistently found in further analyses by type of fish and seafood consumption and in sensitivity analyses. Conclusion: We found no evidence supporting a protective association of fish and seafood consumption during pregnancy with offspring symptoms of wheeze, asthma and allergic rhinitis from infancy to mid childhood.

The INMA-INfancia y Medio Ambiente-(Environment and Childhood) project: More than 10 years contributing to environmental and neuropsychological research.

BACKGROUND: In 2003 the INMA-INfancia y Medio Ambiente (Environment and Childhood) project, a Spanish national network of birth cohorts including more than 3500 participants, was set up with the aim to assess the health impacts of pre- and postnatal environmental exposures on children. The project has published more than 60 papers on maternal and environmental factors related to neuropsychological development in children, one of the main research interests within the project. With the present review, we evaluate the evidence provided by the INMA project on this topic and discuss how the data can contribute to cover the challenges that children's environmental health research will face in the coming years. RESULTS: The INMA project has contributed to provide increasing evidence of the association between prenatal exposure to persistent organic pollutants (POPs) and child neuropsychological development, but it has also shown, using innovative methodologies, that postnatal exposure to these compounds does not play a role in this association. The project has also contributed to show the detrimental influence of certain air pollutants on child neuropsychological development, as well as how a balanced maternal fish intake can protect from the potential adverse effects of prenatal exposure to mercury. Also, the project has contributed to the understanding of impacts of nutritional factors including supplement intake and vitamin D levels during pregnancy and the role of breastfeeding on the neuropsychological benefits. CONCLUSIONS: INMA findings underscore the importance of continued research on the delineation of the sensitive windows of exposure both during pregnancy and postnatally and on the combined effects of environmental exposures, denoted the exposome. In terms of health policy, INMA findings have important implications for the development of public health policies to advance the health and development of children.

The Pregnancy Exposome.

The exposome concept takes a holistic approach facilitated by new and emerging technologies to describe 'the totality of human environmental (i.e. non-genetic) exposures from conception onwards, complementing the genome'. It provides a framework to advance the environmental epidemiology field that has until now focused almost exclusively on single-exposure health effects. The exposome includes an external domain, measured by methods including geo-spatial modelling, questionnaire and biomonitoring of external exposures while the internal domain is commonly assessed through molecular omics platforms. The internal domain, in part, reflects the biological response to the external domain. New statistical frameworks are required to integrate and assess exposome-health effects. The pregnancy period is a key starting point to describe the dynamic exposome, due to its heightened sensitivity and potential lifetime impact. A handful of studies have started to move towards an exposome approach in assessing the effects of the multiple exposures during pregnancy on child development. New research projects are underway to test the exposome approach on a large scale.

The Pregnancy Exposome: Multiple Environmental Exposures in the INMA-Sabadell Birth Cohort.

The "exposome" is defined as "the totality of human environmental exposures from conception onward, complementing the genome" and its holistic approach may advance understanding of disease etiology. We aimed to describe the correlation structure of the exposome during pregnancy to better understand the relationships between and within families of exposure and to develop analytical tools appropriate to exposome data. Estimates on 81 environmental exposures of current health concern were obtained for 728 women enrolled in The INMA (INfancia y Medio Ambiente) birth cohort, in Sabadell, Spain, using biomonitoring, geospatial modeling, remote sensors, and questionnaires. Pair-wise Pearson's and polychoric correlations were calculated and principal components were derived. The median absolute correlation across all exposures was 0.06 (5th-95th centiles, 0.01-0.54). There were strong levels of correlation within families of exposure (median = 0.45, 5th-95th centiles, 0.07-0.85). Nine exposures (11%) had a correlation higher than 0.5 with at least one exposure outside their exposure family. Effectively all the variance in the data set (99.5%) was explained by 40 principal components. Future exposome studies should interpret exposure effects in light of their correlations to other exposures. The weak to moderate correlation observed between exposure families will permit adjustment for confounding in future exposome studies.

The exposome: a new paradigm to study the impact of environment on health.

Environmental factors, here taken to include pollutants, lifestyle factors and behaviours, can play an important role in serious, chronic pathologies with large societal and economic costs, including respiratory disease. However, measurement of the environmental component in epidemiological studies has traditionally relied on much more uncertain and incomplete assessments than measurement of the genome. The 'exposome' has therefore been proposed as a new paradigm to encompass the totality of human environmental (meaning all non-genetic) exposures from conception onwards, complementing the genome. Evidently, there are large challenges in developing the exposome concept into a workable approach for epidemiological research. These include: (1) the accurate and reliable measurement of many exposures in the external environment, (2) the measurement of a wide range of biological responses in the internal environment, and (3) addressing the dynamic, life course nature of the exposome. New tools and technologies that can be applied to address these challenges include exposure biomarker technologies, geographical mapping and remote sensing technologies, smartphone applications and personal exposure sensors, and high-throughput molecular 'omics' techniques. Prospective, population-based cohort studies have recently started to implement these methods using the exposome framework. The exposome thus offers a new and exciting paradigm for improvement and integration of currently scattered and uncertain data on the environmental component in disease aetiology. This should lead to a better understanding of the role of environmental risk factors in respiratory disease and other chronic pathologies, and ultimately to better primary prevention strategies.

Breastfeeding, long-chain polyunsaturated fatty acids in colostrum, and infant mental development.

BACKGROUND: Breastfeeding has been associated with improved neurodevelopment in children. However, it remains unknown to what extent nutritional advantages of breast milk may explain this relationship. OBJECTIVE: We assessed the role of parental psychosocial factors and colostrum long-chain polyunsaturated fatty acid (LC-PUFA) levels in the relationship between breastfeeding and children's neurodevelopment. METHODS: A population-based birth cohort was established in the city of Sabadell (Catalonia, Spain) as part of the INMA-INfancia y Medio Ambiente Project. A total of 657 women were recruited during the first trimester of pregnancy. Information about parental characteristics and breastfeeding was obtained by using a questionnaire, and trained psychologists assessed mental and psychomotor development by using the Bayley Scales of Infant Development in 504 children at 14 months of age. RESULTS: A high percentage of breastfeeds among all milk feeds accumulated during the first 14 months was positively related with child mental development (0.37 points per month of full breastfeeding [95% confidence interval: 0.06-0.67]). Maternal education, social class, and intelligence quotient only partly explained this association. Children with a longer duration of breastfeeding also exposed to higher ratios between n-3 and n-6 PUFAs in colostrum had significantly higher mental scores than children with low breastfeeding duration exposed to low levels. CONCLUSIONS: Greater levels of accumulated breastfeeding during the first year of life were related to higher mental development at 14 months, largely independently from a wide range of parental psychosocial factors. LC-PUFA levels seem to play a beneficial role in children's mental development when breastfeeding levels are high.

Genetic variants of the FADS gene cluster and ELOVL gene family, colostrums LC-PUFA levels, breastfeeding, and child cognition.

INTRODUCTION: Breastfeeding effects on cognition are attributed to long-chain polyunsaturated fatty acids (LC-PUFAs), but controversy persists. Genetic variation in fatty acid desaturase (FADS) and elongase (ELOVL) enzymes has been overlooked when studying the effects of LC-PUFAs supply on cognition. We aimed to: 1) to determine whether maternal genetic variants in the FADS cluster and ELOVL genes contribute to differences in LC-PUFA levels in colostrum; 2) to analyze whether these maternal variants are related to child cognition; and 3) to assess whether children's variants modify breastfeeding effects on cognition. METHODS: Data come from two population-based birth cohorts (n = 400 mother-child pairs from INMA-Sabadell; and n = 340 children from INMA-Menorca). LC-PUFAs were measured in 270 colostrum samples from INMA-Sabadell. Tag SNPs were genotyped both in mothers and children (13 in the FADS cluster, 6 in ELOVL2, and 7 in ELOVL5). Child cognition was assessed at 14 mo and 4 y using the Bayley Scales of Infant Development and the McCarthy Scales of Children's Abilities, respectively. RESULTS: Children of mothers carrying genetic variants associated with lower FADS1 activity (regulating AA and EPA synthesis), higher FADS2 activity (regulating DHA synthesis), and with higher EPA/AA and DHA/AA ratios in colostrum showed a significant advantage in cognition at 14 mo (3.5 to 5.3 points). Not being breastfed conferred an 8- to 9-point disadvantage in cognition among children GG homozygote for rs174468 (low FADS1 activity) but not among those with the A allele. Moreover, not being breastfed resulted in a disadvantage in cognition (5 to 8 points) among children CC homozygote for rs2397142 (low ELOVL5 activity), but not among those carrying the G allele. CONCLUSION: Genetically determined maternal supplies of LC-PUFAs during pregnancy and lactation appear to be crucial for child cognition. Breastfeeding effects on cognition are modified by child genetic variation in fatty acid desaturase and elongase enzymes.