Associations of Maternal Educational Level, Proximity to Greenspace During Pregnancy, and Gestational Diabetes With Body Mass Index From Infancy to Early Adulthood: A Proof-of-Concept Federated Analysis in 18 Birth Cohorts.

International sharing of cohort data for research is important and challenging. We explored the feasibility of multi-cohort federated analyses by examining associations between three pregnancy exposures (maternal education, exposure to green vegetation and gestational diabetes) with offspring BMI from infancy to 17 years. We used data from 18 cohorts (n=206,180 mother-child pairs) from the EU Child Cohort Network and derived BMI at ages 0-1, 2-3, 4-7, 8-13 and 14-17 years. Associations were estimated using linear regression via one-stage IPD meta-analysis using DataSHIELD. Associations between lower maternal education and higher child BMI emerged from age 4 and increased with age (difference in BMI z-score comparing low with high education age 2-3 years = 0.03 [95% CI 0.00, 0.05], 4-7 years = 0.16 [95% CI 0.14, 0.17], 8-13 years = 0.24 [95% CI 0.22, 0.26]). Gestational diabetes was positively associated with BMI from 8 years (BMI z-score difference = 0.18 [CI 0.12, 0.25]) but not at younger ages; however associations attenuated towards the null when restricted to cohorts which measured GDM via universal screening. Exposure to green vegetation was weakly associated with higher BMI up to age one but not at older ages. Opportunities of cross-cohort federated analyses are discussed.

Maternal Perfluoroalkyl Substances, Thyroid Hormones, and DIO Genes: A Spanish Cross-sectional Study.

Results of studies on perfluoroalkyl substances (PFASs) and thyroid hormones (THs) are heterogeneous, and the mechanisms underlying the action of PFASs to target THs have not been fully characterized. We examined the relation between first-trimester maternal PFAS and TH levels and the role played by polymorphisms in the iodothyronine deiodinase 1 (DIO1) and 2 (DIO2) genes in this association. Our sample comprised 919 pregnant Spanish women (recruitment = 2003-2008) with measurements of perfluorohexanesulfonic acid (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), thyroid-stimulating hormone (TSH), total triiodothyronine (TT3), and free thyroxine (FT4), and we genotyped for single-nucleotide polymorphisms in the DIO1 (rs2235544) and DIO2 (rs12885300) genes. We performed multivariate regression analyses between PFASs and THs and included the interaction term PFAS-genotypes in the models. PFHxS was associated with an increase in TSH (% change in outcome [95% CI] per 2-fold PFAS increase = 6.09 [-0.71, 13.4]), and PFOA and PFNA were associated with a decrease in TT3 (-7.17 [-13.5, -0.39] and -6.28 [-12.3, 0.12], respectively). We found stronger associations between PFOA, PFNA, and TT3 for DIO1-CC and DIO2-CT genotypes, although interaction p-values were not significant. In conclusion, this study found evidence of an inverse association between PFOA and TT3 levels. No clear effect modification by DIO enzyme genes was observed.

Urinary arsenic species and methylation efficiency during pregnancy: Concentrations and associated factors in Spanish pregnant women.

BACKGROUND: Arsenic (As) is considered to be toxic for humans, the main routes of exposure being through drinking water and the diet. Once ingested, inorganic arsenic can be methylated sequentially to monomethyl and dimethyl arsenicals. Several factors can affect both As exposure and methylation efficiency. OBJECTIVES: To describe the urinary concentrations of the different As species and evaluate the methylation efficiency during pregnancy, as well as their associated factors in a birth cohort of pregnant Spanish women. METHODS: Participants in this cross-sectional study were 1017 pregnant women from two areas of Spain who had taken part in the INMA (Environment and Childhood) project (2003-2008). Total As (organic and inorganic compounds) and its main metabolites (monomethylarsonic acid, [MMA], dimethylarsinic acid, [DMA], inorganic As [iAs]) and arsenobetaine [AB]) were measured in urine samples collected during the first trimester. Sociodemographic and dietary information was collected through questionnaires. Multivariate linear regression models were used to explore the association between As species concentrations and covariates. Arsenic methylation efficiency was determined through the percentages of the metabolites and using As methylation phenotypes, obtained from principal component analysis. RESULTS: Median urine concentrations were 33.0, 21.6, 6.5, 0.35 and 0.33 µg/g creatinine for total As, AB, DMA, MMA and iAs, respectively. Daily consumption of rice and seafood during the first trimester of pregnancy were positively associated with the concentration of As species (i.e., ß [CI95%] = 0.36 [0.09, 0.64] for rice and iAs, and 1.06 [0.68, 1.44] for seafood and AB). TAs, AB and iAs concentrations, and DMA and MMA concentrations were associated with legume and vegetable consumption, respectively. The medians of the percentage of As metabolites were 89.7 for %DMA, 5.1 for %MMA and 4.7 for %iAs. Non-smoker women and those with higher body mass index presented a higher methylation efficiency (denoted by a higher %DMA and lower %MMA). DISCUSSION: Certain dietary, lifestyle, and environmental factors were observed to have an influence on both As species concentrations and methylation efficiency in our population. Further birth cohort studies in low exposure areas are necessary to improve knowledge about arsenic exposure, especially to inorganic forms, and its potential health impact during childhood.

Prenatal Se concentrations and anthropometry at birth in the INMA study (Spain).

We assessed whether prenatal selenium (Se) exposure is associated with anthropometry at birth, placental weight and gestational age. Study subjects were 1249 mother-child pairs from the Valencia and Gipuzkoa cohorts of the Spanish Childhood and Environment Project (INMA, 2003-2008). Se was determined in serum samples taken at the first trimester of pregnancy. Socio-demographic and dietary characteristics were also collected by questionnaires. Mean (SD) serum Se concentration was 79.57 (9.64) µg/L. Se showed weak associations with both head circumference and gestational age. The association between serum Se concentration and birth weight and length was negative, and direct for placental weight and probability of preterm birth, although the coefficients did not reach statistical significance. Individuals with total mercury (THg) levels >15 µg/L reversed the serum Se concentration effect on head circumference. Significant interactions were found between sex and both gestational age and prematurity. Spontaneous birth gestational ages were estimated to be lower for males and their probability of prematurity was higher. In conclusion, prenatal Se exposure may be associated with lower head circumference and lower gestational ages at spontaneous birth. Interactions with THg exposure and gender should be considered when assessing these relationships.

Urine Metabolic Signatures of Multiple Environmental Pollutants in Pregnant Women: An Exposome Approach.

Exposure to environmental pollutants, particularly during pregnancy, can have adverse consequences on child development but little is known about the effects of pollutant mixtures on endogenous metabolism in pregnant women. We aimed to identify urinary metabolic signatures associated with low level exposure to multiple environmental pollutants in pregnant women from the INMA (INfancia y Medio Ambiente) birth cohort (Spain, N = 750). 35 chemical exposures were quantified in first trimester blood samples (organochlorine pesticides, PCBs, PFAS), in cord blood (mercury), and twice in urine at 12 and 32 weeks of pregnancy (metals, phthalates, bisphenol A). 1H nuclear magnetic resonance (NMR) metabolic profiles of urine were acquired in the same samples as pollutants. We explored associations between exposures and metabolism through an exposome-metabolome wide association scan and multivariate O2PLS modeling. Novel and reproducible associations were found across two periods of pregnancy for three nonpersistent pollutants and across two subcohorts for four of the persistent pollutants. We found novel metabolic signatures associated with arsenic exposure: TMAO and dimethylamine possibly related to gut microbial methylamine metabolism and homarine related to fish intake. Tobacco smoke exposure was related to coffee metabolism and PCBs with 3-hydroxyvaleric acid, usually released under ketoacidosis. These findings will have implications for further understanding of maternal-fetal health, and health across the life-course.

Influence of genetic polymorphisms on arsenic methylation efficiency during pregnancy: Evidence from a Spanish birth cohort.

BACKGROUND: Inorganic arsenic (iAs) is a widespread toxic metalloid. It is well-known that iAs metabolism and its toxicity are mediated by polymorphisms in AS3MT and other genes. However, studies during pregnancy are scarce. We aimed to examine the role of genetic polymorphisms in AS3MT, GSTO2, N6AMT1, MTHFR, MTR, FTCD, CBS, and FOLH1 in iAs methylation efficiency during pregnancy. METHODS: The study included 541 pregnant participants from the INMA (Environment and Childhood) Spanish cohort. Using high-performance liquid chromatography coupled to inductively coupled plasma-tandem mass, we measured arsenic (iAs and the metabolites monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)) in urine samples collected during the first trimester. iAs methylation efficiency was determined based on relative concentrations of the As metabolites in urine (%MMA, %DMA, and %iAs). Thirty-two single nucleotide polymorphisms (SNPs) in nine genes were determined in maternal DNA; AS3MT haplotypes were inferred. We assessed the association between genotypes/haplotypes and maternal As methylation efficiency using multivariate linear regression models. RESULTS: The median %MMA and %DMA were 5.3 %, and 89 %, respectively. Ancestral alleles of AS3MT SNPs (rs3740393, rs3740390, rs11191453, and rs11191454) were significantly associated with higher %MMA, %iAs, and lower %DMA. Pregnant participants with zero copies of the GGCTTCAC AS3MT haplotype presented a higher %MMA. Statistically significant associations were also found for the FOLH1 SNP rs202676 (ß 0.89 95%CI: 0.24, 1.55 for carriers of the G allele vs. the A allele). CONCLUSIONS: Our study shows that ancestral alleles in AS3MT polymorphisms were associated with lower As methylation efficiency in early pregnancy and suggests that FOLH1 also plays a role in As methylation efficiency. These results support the hypothesis that As metabolism is multigenic, being a key element for identifying susceptible populations.

Pre and postnatal exposure to mercury and respiratory health in preschool children from the Spanish INMA Birth Cohort Study.

Effects of mercury on maturing immune system have been reported, however the association with respiratory and allergy problems during infancy remains unclear. The aim of this study is to evaluate the association between pre and postnatal mercury exposure and respiratory and allergy problems among preschool children and to examine the role of potential modifying factors. Study subjects were children participant in Spanish Childhood and Environment Project (INMA, 2003-2008). We measured total mercury levels in cord blood (n = 1868) and hair at 4 years of age (n = 1347). Respiratory outcomes (wheezing, severe wheezing, chestiness, persistent cough, eczema and otitis) were obtained by questionnaires administered to parents. Associations were investigated by logistic regression adjusted for socio-demographic and lifestyle-related variables in each cohort and subsequent meta-analysis. We tested effect modification by factors related to individual susceptibility, diet and co-exposure with other pollutants. The geometric mean of cord blood and hair total mercury was 8.20 µg/L and 0.97 µg/g, respectively. No statistically significant association between pre or postnatal mercury exposure and respiratory and allergy outcomes was found. Notwithstanding, lower maternal intake of fruits and vegetables increased the risk of some respiratory outcomes due to the prenatal exposure to mercury (pint < 0.05). Moreover, an inverse association between prenatal mercury exposure and some respiratory outcomes was observed among children with higher maternal exposure to organocholorine compounds or smoking (pint < 0.05). Also, sex and postnatal smoking exposure modulated mercury postnatal effects on persistent cough (pint < 0.05). In conclusion, no association between pre and postnatal mercury exposure and respiratory and allergy problems among the whole population at study was found. However, diet and other toxicants could modulate this relation, especially during prenatal period. More research on this topic is warranted due to the limited evidence.

Explaining social acceptance of a municipal waste incineration plant through sociodemographic and psycho-environmental variables.

Municipal waste incineration plants (MWIPs) are a source of emission of diverse pollutants that have been associated with environmental and health effects, mainly in relation to premises that are old and not well equipped or maintained. As a result, the public usually holds a negative view of such plants and tends to react adversely to construction of new plants. Understanding a population's perceptions is key to ensuring the correct development of such infrastructure and adequately managing population health concerns and behaviours. In this study, we surveyed 173 residents living close (≤ 10 km) to an MWIP being built in San Sebastian (Gipuzkoa, Spain) and 164 living further away (>10 km). The questionnaire included sociodemographic and psycho-environmental measures. Answers to the questionnaire revealed a fairly low acceptance rate and the perception of a high risk for human health and the environment (average scores of 0.57, 3.07 and 2.89 respectively in a 0 to 4 scale), with no statistically significant differences between people living nearby and further afield. A hierarchical regression model built to explore the public's acceptance of the MWIP explained 59% of the variance. Dominance and relative weight analyses revealed that the most important predictors of acceptance were trust in the information provided by the local government and perceived risk for human health, which accounted for 33.7% and 27.4% of the variance explained by the model respectively. Preference for landfilling and MWIP acceptance in a farther location made a less relevant contribution.

Prenatal manganese exposure and neuropsychological development in early childhood in the INMA cohort.

INTRODUCTION: Manganese (Mn) is an essential element, diet being its main source. Some epidemiological studies have found that a prenatal excess of Mn could negatively affect neuropsychological development during infancy, but the evidence is inconclusive. The aim of this study was to explore the relationship between maternal serum Mn concentrations and child neuropsychological development assessed at 1 year of age. METHODS: study subjects were 1179 mother-child pairs from two Spanish cohorts (Valencia and Gipuzkoa) of the INMA (Environment and Childhood) Project. Mn was measured in serum samples collected during the first trimester of pregnancy. Child neuropsychological development was assessed using the Bayley Scales of Infant Development, composed of both mental and psychomotor scales. Sociodemographic, lifestyle and dietary information was collected through questionnaires during pregnancy and during the child's first year of life. Serum Mn was log-2 transformed. Multivariable linear regression models were built. Generalized additive models were used to assess the shape of the relation between prenatal exposure to Mn and the neuropsychological test scores. RESULTS: geometric mean and 95% confidence interval (95% CI) of maternal serum Mn was 1.50 (1.48-1.53) µg/L. Levels of Mn were higher among non-working mothers and in those with a higher consumption of nuts. The association between maternal Mn levels and child neuropsychological development was negative in the multivariable models for the mental (ß [95% CI] = -0.39 [-2.73, 1.95]) and psychomotor scales (ß [95% CI] = -0.92 [-3.48, 1.65]), although the coefficients were not statistically significant. The best shape describing the relationship between Mn and the Bayley scales was linear in both cases. CONCLUSION: This study shows a null association between maternal prenatal levels of Mn and neuropsychological development at one year after birth in two cohorts within the INMA study.

Prenatal exposure to persistent organic pollutants and rapid weight gain and overweight in infancy.

OBJECTIVE: To examine the effects of prenatal exposure to persistent organic pollutants (POPs) on rapid growth in the first 6 months of life and overweight at 14 months of age. DESIGN AND METHODS: In a Spanish birth cohort study, the POPs dichlorodiphenyldichloroethylene (DDE), hexachlorobenzene (HCB), and polychlorinated biphenyls (PCBs-congeners 153, 138, 180) were measured in maternal serum collected in the first trimester of pregnancy during 2003-2008. Rapid growth was defined as a z-score weight gain >0.67 SD between 6 months of age and birth. Overweight at 14 months was defined as a BMI z-score ≥85th percentile. Generalized linear models examined the association between POPs and rapid growth (N = 1285) and overweight (N = 1198). RESULTS: The analysis population included 24% rapid growers and 30% overweight infants. DDE and HCB were positively associated with rapid growth and with overweight. There was some indication that infant sex and exclusive breastfeeding duration may modify the effects of DDE, and that maternal prepregnancy BMI status may influence the effects of HCB. PCBs were not related to postnatal growth. CONCLUSION: Prenatal exposure to DDE and HCB may be associated with early postnatal growth. Further research is needed to evaluate the persistence of these associations at older ages.

Associations between blood persistent organic pollutants and 25-hydroxyvitamin D3 in pregnancy.

Persistent organic pollutants (POPs) are suggested to contribute to lower vitamin D levels; however, studies in humans are scarce and have never focused on pregnancy, a susceptibility period for vitamin D deficiency. We investigated whether serum levels of POPs were associated with circulating 25-hydroxyvitamin D3 [25(OH)D3] concentration in pregnancy. Cross-sectional associations of serum concentrations of eight POPs with plasma 25(OH)D3 concentration were analyzed in 2031 pregnant women participating in the Spanish population-based cohort INfancia y Medio Ambiente (INMA) Project. Serum concentrations of POPs were measured by gas chromatography and plasma 25(OH)D3 concentration was measured by high-performance liquid chromatography in pregnancy (mean 13.3±1.5weeks of gestation). Multivariable regression models were performed to assess the relationship between blood concentrations of POPs and 25(OH)D3. An inverse linear relationship was found between serum concentration of PCB180 and circulating 25(OH)D3. Multivariate linear regression models showed higher PCB180 levels to be associated with lower 25(OH)D3 concentration: quartile Q4 vs. quartile Q1, coefficient=-1.59, 95% CI -3.27, 0.08, p trend=0.060. A non-monotonic inverse relationship was found between the sum of predominant PCB congeners (PCB 180, 153 and 138) and 25(OH)D3 concentration: coefficient (95% CI) for quartile Q2 vs. Q1 [-0.50 (-1.94, 0.94)], quartile Q3 vs. Q1 [-1.56 (-3.11, -0.02)] and quartile Q4 vs. Q1 [-1.21 (-2.80, 0.38)], p trend=0.081. No significant associations were found between circulating 25(OH)D3 and serum levels of p,p'-DDE, p,p'-DDT, HCB, and ß-HCH. Our results suggest that the background exposure to PCBs may result in lower 25(OH)D3 concentration in pregnant women.

Levels of polychlorinated dibenzo-p-dioxins, dibenzofurans and dioxin-like polychlorinated biphenyls in placentas from the Spanish INMA birth cohort study.

Because fetuses are considered significantly more sensitive to various environment toxicants, there is a need for continuous biomonitoring of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls PCBs (DL-PCBs) to assess their impact on this susceptible population. The aim of this study was to assess the concentration of PCDD/Fs and DL-PCBs in placenta samples from women participating in the Spanish Environment and Childhood (INMA) birth cohort study and to evaluate whether maternal and child characteristics predict placenta concentrations of these pollutants. The presence of PCDD/Fs and DL-PCBs was investigated in 50 placenta samples selected at random in the recruitment period 2000-2008. Multivariable regression models were constructed. Mothers had a mean age at delivery of 30.7 years (18.0-38.0 years), pre-pregnancy BMI of 23.3 kg/m² (18.0-40.2 kg/m²), and 31% were smokers. Median total concentrations of PCDD/Fs and DL-PCBs were 6.9 pg WHO-TEQ/g lipid and 2.1 pg WHO-TEQ/g lipid, respectively. In comparison to the few previous studies in placenta, total TEQ levels were among the lowest recorded in comparable general populations. The congener distribution pattern and the frequencies and concentrations of PCDD/F and DL-PCB congeners were similar to previous reports in placenta. PCDD/F and DL-PCB exposure was related to the age of the mother and the year of the delivery. Although placental concentrations cannot be considered wholly appropriate predictors for evaluating fetal exposure to these contaminants, they can provide a good indication of both maternal and infant prenatal and postnatal exposure and can be used as a proxy for fetal exposure.

Socioeconomic status and exposure to multiple environmental pollutants during pregnancy: evidence for environmental inequity?

BACKGROUND: Inequities in the distribution of environmental exposures may add an extra burden to socially disadvantaged populations, especially when acting during vulnerable periods such as pregnancy and early life, but such inequities may be more complex and uncertain than is generally assumed. We therefore examine whether socioeconomic inequities exist in pregnancy exposures to multiple common environmental contaminants in air, water and food. METHODS: A Spanish population-based birth cohort study enrolled over 2000 pregnant women between 2004 and 2008. Questionnaires assessed parental education, occupation, country of birth, diet and many other factors. Environmental pollutant assessments included nitrogen dioxide as a marker of traffic-related air pollution, trihalomethanes as a marker of tap water disinfection by-products, organochlorine biomarkers measured in maternal serum during pregnancy (polychlorinated biphenyls (PCB), dichlorodiphenyl dichloroethylene (p,p'-DDE), hexachlorobenzene and ß-hexachlorocyclohexane) and mercury concentrations measured in cord blood. RESULTS: Associations between socioeconomic status indicators and nitrogen dioxide and trihalomethanes were generally weak and inconsistent in direction. Concentrations of PCB, hexachlorobenzene and mercury were higher in higher social classes than lower social classes. p,p'-DDE and ß-hexachlorocyclohexane were not related to social class. Social class explained between 1% and 5% of the variability in pollutant concentrations, much less than other variables such as region of residence, country of birth and maternal age. DISCUSSION: This study demonstrates that the general assumption that more disadvantaged populations have higher levels of exposure to environmental pollution does not always hold and requires further elucidation in different international settings.

Prenatal exposure to lead in Spain: cord blood levels and associated factors.

INTRODUCTION AND OBJECTIVE: Lead is a known neurotoxic. Fetuses and infants are very vulnerable to lead exposure, since their blood-brain barrier is not completely formed. Hence, there is an importance for monitoring of blood lead levels prenatally and during early infancy. The aim of this study is to evaluate the prenatal exposure to lead and its association with maternal factors in four population based mother-child cohorts in Spain. The present research was carried out within the framework of the INMA project INfancia y Medio Ambiente (Environment and Childhood). METHODS: A total of 1462 pregnant women were recruited between 2004 and 2008. Lead was analyzed in a sample of cord blood by thermal decomposition, amalgation, and Atomic Absorption Spectrometry. Maternal sociodemographic, lifestyle and dietary factors were obtained by questionnaires during pregnancy. A multivariate logistic regression model was constructed. The dependent variable was a dichotomous lead level variable (detected vs no detected, i.e. ≥ vs < 2µg/dL). RESULTS: A low percentage of cord blood samples with lead levels ≥ 2µg/dL were found (5.9%). Geometric mean and maximum were 1.06µg/dL and 19µg/dL, respectively. Smoking at the beginning of pregnancy, age, social class, weight gain during pregnancy, gravidity, and place of residence were the maternal factors associated with detectable cord blood lead levels. Mother's diet does not appear to be a determining factor of lead exposure. Nevertheless, daily intake of iron and zinc may act as a protective factor against having cord blood lead levels ≥ 2µg/dL. CONCLUSION: In the different regions of Spain taking part in this study, lead levels to which newborns are exposed are low. Mobilization of lead from bones may be the main contributor to the cord blood levels.