Clinical and economic burden of acute otitis media caused by Streptococcus pneumoniae in European children, after widespread use of PCVs-A systematic literature review of published evidence.

BACKGROUND: Acute otitis media (AOM) is a common childhood disease frequently caused by Streptococcus pneumoniae. Pneumococcal conjugate vaccines (PCV7, PCV10, PCV13) can reduce the risk of AOM but may also shift AOM etiology and serotype distribution. The aim of this study was to review estimates from published literature of the burden of AOM in Europe after widespread use of PCVs over the past 10 years, focusing on incidence, etiology, serotype distribution and antibiotic resistance of Streptococcus pneumoniae, and economic burden. METHODS: This systematic review included published literature from 31 European countries, for children aged ≤5 years, published after 2011. Searches were conducted using PubMed, Embase, Google, and three disease conference websites. Risk of bias was assessed with ISPOR-AMCP-NPC, ECOBIAS or ROBIS, depending on the type of study. RESULTS: In total, 107 relevant records were identified, which revealed wide variation in study methodology and reporting, thus limiting comparisons across outcomes. No homogenous trends were identified in incidence rates across countries, or in detection of S. pneumoniae as a cause of AOM over time. There were indications of a reduction in hospitalization rates (decreases between 24.5-38.8% points, depending on country, PCV type and time since PCV introduction) and antibiotic resistance (decreases between 14-24%, depending on country), following the widespread use of PCVs over time. The last two trends imply a potential decrease in economic burden, though this was not possible to confirm with the identified cost data. There was also evidence of an increase in serotype distributions towards non-vaccine serotypes in all of the countries where non-PCV serotype data were available, as well as limited data of increased antibiotic resistance within non-vaccine serotypes. CONCLUSIONS: Though some factors point to a reduction in AOM burden in Europe, the burden still remains high, residual burden from uncovered serotypes is present and it is difficult to provide comprehensive, accurate and up-to-date estimates of said burden from the published literature. This could be improved by standardised methodology, reporting and wider use of surveillance systems.

Metabolic Syndrome Traits Increase the Risk of Major Adverse Liver Outcomes in Type 2 Diabetes.

OBJECTIVE: Type 2 diabetes (T2D) increases the risk for major adverse liver outcomes (MALOs), including cirrhosis and its complications. Patients with T2D frequently have other traits of the metabolic syndrome (MetS). It remains uncertain whether there is a synergistic effect of accumulating MetS traits on future MALO risk. RESEARCH DESIGN AND METHODS: Patients with T2D without a history of liver disease were identified from national registers in Sweden from 1998 to 2021. MetS traits included hypertension, low HDL level, hypertriglyceridemia, obesity, and albuminuria, in addition to T2D. MALO events were identified based on administrative coding from national registers until 31 October 2022. Data were analyzed using Cox regression models. RESULTS: In total, 230,992 patients were identified (median age 64 years; 58% male), of whom 3,215 (1.39%) developed MALOs over a median follow-up of 9.9 years. Compared with patients with one MetS trait (only T2D) at baseline, those with more than one MetS trait had a higher rate of MALOs (adjusted hazard ratio [aHR] 2.33, 95% CI 1.53-3.54). The rate of MALOs increased progressively with increasing numbers of MetS traits at baseline (aHR 1.28 per added trait, 95% CI 1.23-1.33). During follow-up, patients who acquired additional MetS traits had a progressively higher rate of MALOs. The MetS trait with the largest association with incident MALOs was hypertension (aHR 2.06, 95% CI 1.57-2.71). CONCLUSIONS: Having or acquiring additional traits of MetS increase the rate of progression to MALOs in patients with T2D. These results could be used to inform screening initiatives for liver disease.

Arsenic exposure and increased C-reactive protein are independently associated with lower erythrocyte glutathione peroxidase activity in Bangladeshi children.

Toxic metal contaminants present in food and water have widespread effects on health and disease. Chalcophiles, such as arsenic, cadmium, and mercury, show a high affinity to selenium and exposure to these metals could have a modulating effect on enzymes dependent on selenocysteine in their active sites. The aim of this study was to assess the influence of these metals on the activity of the selenoprotein glutathione peroxidase 1 (GPX1) in erythrocytes of 100 children residing in rural Bangladesh, where drinking water often contains arsenic. GPX1 expression, as measured using high-throughput immunoblotting, showed little correlation with GPX activity (rs = 0.02, p = 0.87) in blood samples. Toxic metals and selenium measured in erythrocytes using inductively coupled plasma mass spectrometry (ICP-MS) and C-reactive protein (CRP) measured in plasma, were all considered as effectors of this divergence in GPX enzymatic activity. Arsenic concentrations in erythrocytes were most influential for GPX1 activity (rs = -0.395, p < 0.0001), and CRP levels also negatively impacted GPX1 activity (rs = -0.443, p < 0.0001). These effects appear independent of each other as arsenic concentrations and CRP showed no correlation (rs = 0.124, p = 0.2204). Erythrocyte selenium, cadmium, and mercury did not show any correlation with GPX1 activity, nor with CRP or arsenic. Our findings suggest that childhood exposure to inorganic arsenic, as well as inflammation triggering the release of CRP, may negatively affect GPX1 activity in erythrocytes.

Assessment of Joint Impact of Iodine, Selenium, and Zinc Status on Women's Third-Trimester Plasma Thyroid Hormone Concentrations.

BACKGROUND: Iodine is essential for synthesizing thyroid hormones, but other micronutrients are also required for optimal thyroid function. However, there is a lack of data on combined micronutrient status in relation to thyroid hormones in pregnancy. OBJECTIVES: We aimed to assess the joint associations of iodine, selenium, and zinc status with plasma concentrations of thyroid hormones and thyroid-stimulating hormone (TSH) in pregnancy. METHODS: We included 531 pregnant women (aged 22-40 y) participating in a Swedish birth cohort who provided blood and spot urine samples in gestational weeks 27-33 (mean: 29). Associations of urinary iodine concentration (UIC), plasma selenium concentration, and plasma zinc concentration (measured by inductively coupled plasma mass spectrometry) with plasma hormone concentrations [total and free thyroxine (tT4, fT4), total and free triiodothyronine (tT3, fT3), and TSH] were explored with Bayesian kernel machine regression (BKMR; n = 516; outliers excluded) and multivariable-adjusted linear regression (n = 531; splined for nonlinear associations). RESULTS: Median (IQR) micronutrient concentrations were 112 µg/L (80-156 µg/L) for UIC, 67 µg/L (58-76 µg/L) for plasma selenium, and 973 µg/L (842-1127 µg/L) for plasma zinc; the former 2 median values were below recommended concentrations (150 µg/L and 70 µg/L, respectively). Mean ± SD TSH concentration was 1.7 ± 0.87 mIU/L, with 98% < 4 mIU/L. BKMR showed a positive trend of joint micronutrient concentrations in relation to TSH. Plasma zinc was most influential for all hormones but tT3, for which plasma selenium was most influential. In adjusted linear regression models, zinc was positively associated with tT4, tT3, and TSH, and <1200 µg/L also with fT4 and fT3. Selenium was inversely associated with fT3, and <85 µg/L with tT3. CONCLUSIONS: Pregnant women's plasma TSH concentrations in the early third trimester increased with increasing joint status of iodine, selenium, and zinc. Zinc and selenium were more influential than iodine for the hormone concentrations. Multiple micronutrients need consideration in future studies of thyroid hormone status.

Shift and night work during pregnancy and preterm birth-a cohort study of Swedish health care employees.

BACKGROUND: Previous studies of preterm birth (PTB) concerning night work have been inconclusive and partly limited by imprecise data on working schedules. This study investigated the risk of PTB in relation to detailed, registry-based data on working hours. METHODS: In a register-based prospective cohort study, we identified 4970 singleton births with information on PTB from the Swedish Medical Birth Register of health care employees in Stockholm. Day-by-day information on working hours 2008-16 was obtained from a computerized employee register. Odds ratios (ORs) of PTB according to work hour characteristics were analysed by logistic regression adjusted for mother's age, stature, body mass index (BMI), parity, smoking habits, education, profession and country of birth. RESULTS: There was an increased risk of PTB among those who frequently worked night shifts (>25 times) [OR, 1.62; 95% confidence interval (CI), 1.03-2.53] and who ever worked ≥3 consecutive night shifts (OR, 1.43; 95% CI, 1.03-1.99) during the first trimester. Frequently (> 8 times) working 3 or more consecutive nights, and frequently (>18 times) having quick returns from night shifts (<28 h) during the first trimester showed 3-4 fold increased risk of PTB. Moreover, working frequent (>20 times) long shifts (≥10 h) (OR 1.63; 95% CI, 1.07-2.49) during the first trimester and working any Week >40 h (OR 2.05; 95% CI, 1.31-3.22) during the third trimester were associated with PTB. CONCLUSIONS: In this cohort of Swedish health care employees with registry-based data on working hours, night work, especially working frequent consecutive nights, and quick returns from night shifts during the first trimester were associated with increased risk of PTB among pregnant women.

Thyroid hormones in relation to toxic metal exposure in pregnancy, and potential interactions with iodine and selenium.

BACKGROUND: Several endocrine-disrupting metals may affect thyroid function, but the few available studies of exposure during pregnancy and thyroid hormones are inconclusive. OBJECTIVE: To explore if environmental exposure to cadmium (Cd), lead (Pb), and methylmercury (MeHg) impacts thyroid function in pregnancy, and interacts with iodine and selenium status. METHODS: Women in a Swedish birth cohort provided blood and urine samples in early third trimester. Concentrations of erythrocyte Cd, Pb, and Hg (n = 544), urinary Cd and iodine (n = 542) and plasma selenium (n = 548) were measured using inductively coupled plasma-mass spectrometry.Free and total thyroxine (fT4, tT4) and triiodothyronine (fT3, tT3), and thyroid stimulating hormone (TSH), were measured in plasma (n = 548) with electrochemiluminescence immunoassays. Metal-hormone associations were assessed in regression models, and metal mixture effects and metal-nutrient interactions were explored in Bayesian kernel machine regression (BKMR). RESULTS: In multivariable-adjusted regression models, a doubling of urinary Cd was associated with a mean increase in tT4 of 2.7 nmol/L (95% CI: 0.78, 4.6), and in fT3 and tT3 of 0.06 pmol/L (0.02, 0.10) and 0.09 nmol/L (0.05, 0.13), respectively. A doubling of urinary Cd was associated with a -0.002 (-0.003, -0.001) and -0.03 (-0.05, -0.02) decrease in the fT4:tT4 and fT3:tT3 ratio, respectively. A doubling of erythrocyte Hg (>1 µg/kg) was associated with a decrease in fT3 and tT3 by -0.11 pmol/L (-0.16, -0.05) and -0.11 nmol/L (-0.16, -0.06), respectively, and a -0.013 (-0.02, -0.01) decrease in the fT3:fT4 ratio. BKMR did not indicate any mixture effect of toxic metals or interactions between metals and iodine or selenium in relation to the hormones. CONCLUSION: Our findings suggest that exposure to Cd and Hg, at levels globally prevalent through the diet, may affect thyroid function during pregnancy, independently of iodine and selenium levels. Further studies on potential implications for maternal and child health are warranted.

Working life, health and well-being of parents: a joint effort to uncover hidden treasures in European birth cohorts.

OBJECTIVE: Birth cohorts collect valuable and under-utilized information on employment and health of parents before and during pregnancy, at birth, and sometimes after birth. In this discussion paper, we examine how these data could be exploited to study the complex relationships and interactions between parenthood, work, and health among parents themselves. METHODS: Using a web-based database of birth cohorts, we summarize information on maternal employment and health conditions and other potentially related variables in cohorts spread throughout Europe. This provided information on what data are available and could be used in future studies, and what was missing if specific questions are to be addressed, exploiting the opportunity to explore work-health associations across heterogenous geographical and social contexts. RESULTS: We highlight the many potentialities provided by birth cohorts and identify gaps that need to be addressed to adopt a life-course approach and investigate topics specific to the peri-pregnancy period, such as psychosocial aspects. We address the technical difficulties implied by data harmonization and the ethical challenges related to the repurposing of data, and provide scientific, ecological and economic arguments in favor of improving the value of data already available as a result of a serious investment in human and material resources. CONCLUSIONS: There is a hidden treasure in birth cohorts that deserves to be brought out to study the relationships between employment and health among working parents in a time when the boundaries between work and life are being stretched more than ever before.

Infant Iodine and Selenium Status in Relation to Maternal Status and Diet During Pregnancy and Lactation.

Iodine and selenium are essential trace elements. Recent studies indicate that pregnant and lactating women often have insufficient intake of iodine and selenium, but the impact on fetal and infant status is unclear. Here, we assessed iodine and selenium status of infants in relation to maternal intake and status of these trace elements in the birth cohort NICE, conducted in northern Sweden (n = 604). Iodine was measured in urine (UIC) in gestational week 29, and in breast milk and infant urine 4 months postpartum, while selenium was measured in maternal plasma and erythrocytes in gestational week 29, and in breast milk and infant erythrocytes 4 months postpartum, in both cases using ICP-MS. Maternal intake was assessed with semi-quantitative food frequency questionnaires in gestational week 34 and at 4 months postpartum. The median intake of iodine and selenium during pregnancy (98 and 40 µg/d, respectively) and lactation (108 and 39 µg/d, respectively) was below recommended intakes, reflected in insufficient status (median UIC of 113 µg/L, median plasma selenium of 65 µg/L). Also, breast milk concentrations (median iodine 77 µg/L, median selenium 9 µg/L) were unlikely to meet infant requirements. Median UIC of the infants was 114 µg/L and median erythrocyte selenium 96 µg/kg, both similar to the maternal concentrations. Infant UIC correlated strongly with breast milk levels (rho = 0.64, p < 0.001). Their erythrocyte selenium correlated with maternal erythrocyte selenium in pregnancy (rho = 0.38, p < 0.001), but not with breast milk selenium, suggesting formation of prenatal reserves. Our results indicate that the transport of iodine and selenium to the fetus and infant is prioritized. Still, it is uncertain whether most infants had sufficient intakes. Further, the results might indicate an involvement of iodine in asthma development during the first year of life, which is essential to follow up. The low maternal and infant dietary intake of both iodine and selenium, especially when the mothers did not use supplements or iodized table salt, suggest a need for a general screening of women and young children.

Occupational exposure to whole-body vibrations and pregnancy complications: a nationwide cohort study in Sweden.

OBJECTIVES: Pregnancy complications are common contributors to perinatal mortality and morbidity. Still, the cause(s) of gestational hypertensive disorders and diabetes are largely unknown. Some occupational exposures have been inconsistently associated with pregnancy complications, but exposure to whole-body vibrations (WBV) has been largely overlooked even though it has been associated with adverse birth outcomes. Therefore, the aim was to assess whether occupational WBV exposure during pregnancy is associated with pregnancy complications in a nationwide, prospective cohort study. METHODS: The Fetal Air Pollution Exposure cohort was formed by merging multiple Swedish, national registers containing information on occupation during pregnancy and diagnosis codes, and includes all working women who gave birth between 1994 and 2014 (n=1 091 044). WBV exposure was derived from a job-exposure matrix and was divided into categories (0, 0.1-0.2, 0.3-0.4 and ≥0.5 m/s2). ORs with 95% CIs were calculated using logistic regression adjusted for potential confounders. RESULTS: Among women working full time (n=646 490), we found increased risks of all pregnancy complications in the highest exposure group (≥0.5 m/s2), compared with the lowest. The adjusted ORs were 1.76 (95% CI 1.41 to 2.20), 1.55 (95% CI 1.26 to 1.91) and 1.62 (95% CI 1.07 to 2.46) for preeclampsia, gestational hypertension and gestational diabetes, respectively, and were similar in all sensitivity analyses. There were no clear associations for part-time workers. CONCLUSIONS: The results suggest that women should not be exposed to WBV at/above the action limit value of 0.5 m/s2 (European directive) continuously through pregnancy. However, these results need further confirmation.

Prenatal and childhood arsenic exposure through drinking water and food and cognitive abilities at 10 years of age: A prospective cohort study.

BACKGROUND: Our studies of children in a rural Bangladeshi area, with varying concentrations of arsenic in well-water, indicated modest impact on child verbal cognitive function at 5 years of age. OBJECTIVES: Follow-up of arsenic exposure and children's cognitive abilities at school-age. METHODS: In a nested sub-cohort of the MINIMat supplementation trial, we assessed cognitive abilities at 10 years of age (n = 1523), using Wechsler Intelligence Scale for Children (WISC-IV). Arsenic in maternal urine and erythrocytes in early pregnancy, in child urine at 5 and 10 years, and in hair at 10 years, was measured using Inductively Coupled Plasma Mass Spectrometry. RESULTS: Median urinary arsenic at 10 years was 58 µg/L (range 7.3-940 µg/L). Multivariable-adjusted regression analysis showed that, compared to the first urinary arsenic quintile at 10 years (<30 µg/L), the third and fourth quintiles (30-45 and 46-73 µg/L, respectively) had 6-7 points lower Full developmental raw scores (B: -7.23, 95% CI -11.3; -3.18, and B: -6.37, 95% CI -10.5; -2.22, respectively), corresponding to ~0.2 SD. Verbal comprehension and Perceptual reasoning seemed to be affected. Models with children's hair arsenic concentrations showed similar results. Maternal urinary arsenic in early pregnancy, but not late pregnancy, showed inverse associations with Full developmental scores (quintiles 2-4: B: -4.52, 95% CI -8.61; -0.43, B: -5.91, 95% CI -10.0; -1.77, and B: -5.98, 95%CI -10.2; -1.77, respectively, compared to first quintile), as well as with Verbal comprehension, Perceptual reasoning, and Processing speed, especially in girls (p < 0.05 for interaction of sex with Full developmental scores and Perceptual reasoning). In models with all exposure time points included, both concurrent exposure at 10 years and early prenatal exposure remained associated with cognitive abilities. CONCLUSIONS: Both early prenatal and childhood arsenic exposure, even at low levels (about 50 µg/L in urine), was inversely associated with cognitive abilities at school-age, although the estimates were modest.

Predictors of selenium biomarker kinetics in 4-9-year-old Bangladeshi children.

BACKGROUND: Biomarker selenium concentrations vary greatly between studies. Concentrations in erythrocytes, urine, and hair vary even at similar plasma concentrations, suggesting that unknown factors influence the distribution of selenium between body compartments. OBJECTIVE: To assess predictors of the different selenium biomarkers in children. DESIGN: We used a mother-child cohort, nested in a population-based supplementation trial in rural Bangladesh (MINIMat), established for evaluation of arsenic toxicity. Selenium was measured in plasma (n = 223), erythrocytes, urine, and hair at 9 years (n = 395) and in erythrocytes and urine at 4.5 years (n = 259) using inductively coupled plasma mass spectrometry. We also measured concentrations of arsenic (all biospecimen) and cadmium (erythrocytes and urine). Genotyping for INMT, a methyltransferase involved in selenium metabolism, was performed using TaqMan probes. RESULTS: At 9 years, the selenium concentrations ranged 51-139 µg/L in plasma, 128-281 µg/L in erythrocytes, 2.2-55 µg/L in urine, and 258-723 µg/kg in hair. Correlations (rS) between biomarkers ranged 0.12-0.37, and were strongest between blood compartments and between erythrocytes and hair (long-term markers). In multivariable-adjusted linear regression analyses, plasma selenium differed by sampling season (highest in food-secure pre-monsoon season) and was inversely associated with plasma arsenic (range < 0.0080-20 µg/L; B = -1.1, 95% CI: -1.8, -0.41). In contrast, erythrocyte selenium was positively associated with erythrocyte arsenic (range 0.95-50 µg/L; B = 0.58, 95% CI: 0.26, 0.91) and inversely associated with erythrocyte cadmium (range 0.27-3.1 µg/L; B = -12, 95% CI: -17, -6.9). These associations were similar at 4.5 years. Only selenium in hair and urine were influenced by INMT polymorphisms. Finally, chronic malnutrition seemed to increase selenium retention, measured as the ratio plasma/urinary selenium. CONCLUSIONS: Selenium biomarkers seem to be influenced by malnutrition, genetics, and exposure to metal pro-oxidants. This might affect the evaluation of deficiency/sufficiency, normally assessed by selenium in plasma/serum.

Arsenite methyltransferase (AS3MT) polymorphisms and arsenic methylation in children in rural Bangladesh.

BACKGROUND: Arsenic methylation efficiency, a susceptibility factor for arsenic toxicity, is in adults partly explained by variation in arsenite methyltransferase (AS3MT) gene. Little is known about the role of AS3MT for children's arsenic methylation. OBJECTIVES: Evaluating associations between AS3MT polymorphisms and children's arsenic methylation efficiency. METHODS: Bangladeshi children's arsenic exposure (9-years; n = 424) was assessed as sum urinary concentration of inorganic arsenic (iAs) and its metabolites (monomethylarsonic acid [MMA] and dimethylarsinic acid [DMA]) using HPLC-HG-ICPMS. Arsenic methylation efficiency was assessed by the individual metabolite fractions (%). AS3MT polymorphisms (rs7085104, rs3740400, rs3740393 and rs1046778) were genotyped using TaqMan SNP genotyping assays. RESULTS: We found higher %iAs and %MMA, and lower %DMA in urine, among rs1046778 TT carriers (median 8.8%, 9.6% and 81.1% for iAs, MMA and DMA, respectively), compared to CC carriers (median 7.0%, 8.3% and 84.9%). These associations were significant in multivariable-adjusted linear regression models: B-coefficients for TT vs CC were 1.26, 1.33 and -2.59 for iAs, MMA and DMA, respectively. Effect estimates were slightly stronger when restricting the analyses to children with urinary arsenic ≥58 µg/L (reducing the impact of ingested DMA). Estimates in girls were slightly stronger than in boys, although there were no significant differences between boys and girls. No clear associations were found for the other AS3MT polymorphisms. CONCLUSIONS: One out of four AS3MT polymorphisms, previously associated with arsenic methylation in adults, was associated with arsenic methylation in children. Thus, AS3MT variation seems to influence arsenic methylation efficiency in children to a lesser extent than in adults.

Prenatal arsenic exposure is associated with increased plasma IGFBP3 concentrations in 9-year-old children partly via changes in DNA methylation.

Exposure to inorganic arsenic (As), a carcinogen and epigenetic toxicant, has been associated with lower circulating levels of insulin-like growth factor 1 (IGF1) and impaired growth in children of pre-school age. The aim of this study was to assess the potential impact of exposure to As on IGF1 and insulin-like growth factor-binding protein 3 (IGFBP3) as well as DNA methylation changes in 9-year-old children. To this end, we studied 9-year-old children from a longitudinal mother-child cohort in rural Bangladesh (n = 551). Prenatal and concurrent exposure to As was assessed via concentrations in maternal urine at gestational week 8 and in child urine at 9 years, measured by HPLC-HG-ICPMS. Plasma IGF1 and IGFBP3 concentrations were quantified with immunoassays. DNA methylation was measured in blood mononuclear cells at 9 years in a sub-sample (n = 113) using the Infinium HumanMethylation450K BeadChip. In multivariable-adjusted linear regression models, prenatal As (natural log-transformed), but not children's concurrent urinary As, was positively associated with IGFBP3 concentrations (ß = 76, 95% CI 19, 133). As concentrations were not associated with IGF1. DNA methylation analysis revealed CpGs associated with both prenatal As and IGFBP3. Mediation analysis suggested that methylation of 12 CpG sites for all children was mediator of effect for the association between prenatal As and IGFBP3. We also found differentially methylated regions, generally hypermethylated, that were associated with both prenatal As and IGFBP3. In all, our study revealed that prenatal exposure to As was positively associated with IGFBP3 concentrations in children at 9 years, independent of IGF1, and this association may, at least in part, be epigenetically mediated.

Associations between Methylated Metabolites of Arsenic and Selenium in Urine of Pregnant Bangladeshi Women and Interactions between the Main Genes Involved.

BACKGROUND: It has been proposed that interactions between selenium and arsenic in the body may affect their kinetics and toxicity. However, it is unknown how the elements influence each other in humans. OBJECTIVES: We aimed to investigate potential interactions in the methylation of selenium and arsenic. METHODS: Urinary selenium (U-Se) and arsenic (U-As) were measured using inductively coupled plasma mass spectrometry (ICPMS) in samples collected from pregnant women (n=226) in rural Bangladesh at gestational weeks (GW) 8, 14, 19, and 30. Urinary concentrations of trimethyl selenonium ion (TMSe) were measured by HPLC-vapor generation-ICPMS, as were inorganic arsenic (iAs), methylarsonic acid (MMA), and dimethylarsinic acid (DMA). Methylation efficiency was assessed based on relative amounts (%) of arsenic and selenium metabolites in urine. Genotyping for the main arsenite and selenium methyltransferases, AS3MT and INMT, was performed using TaqMan probes or Sequenom. RESULTS: Multivariable-adjusted linear regression analyses indicated that %TMSe (at GW8) was positively associated with %MMA (ß=1.3, 95% CI: 0.56, 2.0) and U-As, and inversely associated with %DMA and U-Se in producers of TMSe (INMT rs6970396 AG+AA, n=74), who had a wide range of urinary TMSe (12-42%). Also, %TMSe decreased in parallel to %MMA during pregnancy, especially in the first trimester (-0.58 %TMSe per gestational week). We found a gene-gene interaction for %MMA (p-interaction=0.076 for haplotype 1). In analysis stratified by INMT genotype, the association between %MMA and both AS3MT haplotypes 1 and 3 was stronger in women with the INMT GG (TMSe nonproducers, 5th-95th percentile: 0.2-2%TMSe) vs. AG+AA genotype. CONCLUSIONS: Our findings for Bangladeshi women suggest a positive association between urinary %MMA and %TMSe. Genes involved in the methylation of selenium and arsenic may interact on associations with urinary %MMA. https://doi.org/10.1289/EHP1912.

Selenium status during pregnancy: Influential factors and effects on neuropsychological development among Spanish infants.

Selenium (Se) has been positively associated with neurodevelopment in early life. However, its margin of safety is rather narrow, and few prospective studies have evaluated its potential neurotoxic effects at intermediate levels. We aimed to explore the association between maternal Se concentrations and child neuropsychological development, including the genetic effect modification of the Se metabolizing gene INMT. Study subjects were 650 mother-child pairs from the Spanish Childhood and Environment Project (INMA, 2003-2005). Infant neuropsychological development was assessed around 12months of age by the Bayley Scales of Infant Development. Sociodemographic and dietary characteristics were collected by questionnaire at the first and third trimester of gestation. Se was measured in serum samples at the first trimester. The mean serum Se concentration was 79.7 (standard deviation=7.9) µg/L. In multivariate analysis, nonsignificant inverse linear associations were found between Se concentrations and standardized mental and psychomotor development scores (ß (95% CI)=-0.13 (-0.29, 0.03) and ß (95% CI)=-0.08 (-0.24, 0.07), respectively). Generalized additive models indicated inverted U-shaped relationships between Se concentrations and both scales. Using segmented regression, the turning point for the associations was estimated at 86µg/L for both scales. The association between Se and neuropsychological development was inverted U-shaped for children with the AG+AA genotype for rs6970396 INMT but a descending curve was suggested for the GG genotype. Further studies would be necessary in order to disentangle the complex equilibrium between the toxicity and benefits of Se exposure during the prenatal period.

Early-Life Selenium Status and Cognitive Function at 5 and 10 Years of Age in Bangladeshi Children.

BACKGROUND: In older adults, selenium status has been positively associated with cognitive function. We recently reported a positive association between maternal selenium status in pregnancy and children's cognitive function at 1.5 y. OBJECTIVE: We followed up the children to assess if prenatal and childhood selenium status was associated with cognitive abilities at 5 and 10 y. METHODS: This longitudinal cohort study was nested in Maternal and Infant Nutrition Interventions in Matlab (MINIMat), a population-based, randomized supplementation trial in pregnancy in rural Bangladesh. Selenium in maternal blood [erythrocyte fraction (Ery-Se) at baseline] and in child hair and urine was measured using inductively coupled plasma mass spectrometry. Children's cognition at 5 and 10 y was assessed using the Wechsler Preschool and Primary Scale of Intelligence™ and the Wechsler Intelligence Scale for Children®, respectively. In total, 1,408 children were included. RESULTS: Multivariable-adjusted linear regression analyses showed that prenatal selenium status was positively associated with children's cognitive function at 5 and 10 y. An increase in maternal Ery-Se from the fifth to the 95th percentile [median: 0.44µg/g hemoglobin (Hb)] was associated with an increase in full developmental score of 3.5 [95% confidence interval (CI): 0.1, 7.0], corresponding to 0.16 standard deviation (SD) at 5 y, and 8.1 (95% CI: 3.8, 13), corresponding to 0.24 SD at 10 y. In addition, urine and hair selenium concentrations at 5 and 10 y of age were positively associated with cognitive function at 10 y, although associations were inverse for concentrations ≥98th percentile. Some associations were slightly stronger for girls than for boys. CONCLUSIONS: Measures of prenatal and childhood (below the 98th percentile) selenium status were associated with higher cognitive function scores at 5 and 10 y of age. https://doi.org/10.1289/EHP1691.

Major Limitations in Using Element Concentrations in Hair as Biomarkers of Exposure to Toxic and Essential Trace Elements in Children.

BACKGROUND: Hair is a commonly used exposure biomarker for metals and other trace elements, but concern has been raised regarding its appropriateness for assessing the internal dose. OBJECTIVES: The aim of the present study was to evaluate children's hair as biomarker of internal dose for toxic (As, Mn, Cd, Pb) and essential elements (Mg, Ca, Fe, Co, Cu, Zn, Se, Mo). METHODS: In 207 children (9-10 years of age), originating from a population-based cohort in rural Bangladesh, we measured concentrations of the selected elements in hair ( closest to the scalp) using ICP-MS. We compared these with previously measured concentrations in erythrocytes, urine, and water. For a subset of children (n=19), we analyzed four consecutive 2 cm pieces of hair. RESULTS: There were strong associations between hair As and the other biomarkers (erythrocytes: rs=0.73, p<0.001; urine: rS=0.66, p<0.001); and water (rs=0.60, p<0.001); and there were significant correlations between Se in hair and erythrocytes (overall rs=0.38, p<0.001), and urine (rs=0.29, p<0.001). Hair Co and Mo showed weak correlations with concentrations in erythrocytes. Hair Mn was not associated with Mn in erythrocytes, urine, or water, and the geometric mean concentration increased almost five times from the 2 cm closest to the head to the 7th­8th cm (p<0.001). Also Mg, Ca, Co, Cd, and Pb increased from the scalp outward (>50% higher in 7th­8th cm compared with 1st­2nd cm, p<0.001). CONCLUSIONS: Hair was found to be a useful exposure biomarker of absorbed As and Se only. Of all measured elements, hair Mn seemed the least reflective of internal dose. https://doi.org/10.1289/EHP1239.

Prenatal lead exposure and childhood blood pressure and kidney function.

BACKGROUND: Exposure to lead, a common environmental pollutant, is known to cause cardiovascular and nephrotoxic effects in adults. Potential effects of early-life lead exposure on these functions are, however, less well characterized. OBJECTIVES: To assess blood pressure and kidney function in preschool-aged children in relation to prenatal lead exposure. METHODS: This prospective study in rural Bangladesh measured children's systolic and diastolic blood pressure in triplicate at the follow-up at 4.5±0.11 years. Their kidney function was assessed by the estimated glomerular filtration rate (eGFR), calculated based on serum cystatin C concentrations, and by kidney volume, measured by sonography. Exposure to lead was assessed by concentrations in the mothers' blood (erythrocyte fraction; Ery-Pb) in gestational weeks (GW) 14 and 30, the effects of which were evaluated separately in multivariable-adjusted linear regression analyses. RESULTS: We found no associations between maternal exposure to lead [n~1500 for GW14 and 700 for GW30] and children's blood pressure or eGFR. However, we found an inverse association between late gestation lead and kidney volume, although the sample size was limited (n=117), but not with early gestation lead (n=573). An increase of 85µg/kg in Ery-Pb (median concentration at GW30) was associated with a 6.0cm3/m2 decrease in kidney volume (=0.4SD; p=0.041). After stratifying on gender, there seemed to be a somewhat stronger association in girls. CONCLUSIONS: Prenatal lead exposure may cause long-lasting effects on the kidney. This warrants follow-up studies in older children, as well as additional studies in other populations.

Elevated childhood exposure to arsenic despite reduced drinking water concentrations--A longitudinal cohort study in rural Bangladesh.

OBJECTIVES: The aim of this study was to evaluate the massive efforts to lower water arsenic concentrations in Bangladesh. METHODS: In our large mother-child cohort in rural Matlab, we measured the arsenic concentrations (and other elements) in drinking water and evaluated the actual exposure (urinary arsenic), from early gestation to 10 years of age (n=1017). RESULTS: Median drinking water arsenic decreased from 23 (2002-2003) to <2 µg/L (2013), and the fraction of wells exceeding the national standard (50 µg/L) decreased from 58 to 27%. Still, some children had higher water arsenic at 10 years than earlier. Installation of deeper wells (>50 m) explained much of the lower water arsenic concentrations, but increased the manganese concentrations. The highest manganese concentrations (~900 µg/L) appeared in 50-100 m wells. Low arsenic and manganese concentrations (17% of the children) occurred mainly in >100 m wells. The decrease in urinary arsenic concentrations over time was less apparent, from 82 to 58 µg/L, indicating remaining sources of exposure, probably through food (mean 133 µg/kg in rice). CONCLUSION: Despite decreased water arsenic concentrations in rural Bangladesh, the children still have elevated exposure, largely from food. Considering the known risks of severe health effects in children, additional mitigation strategies are needed.

Selenium metabolism to the trimethylselenonium ion (TMSe) varies markedly because of polymorphisms in the indolethylamine N-methyltransferase gene.

BACKGROUND: Selenium is an essential element, but its metabolism in humans is not well characterized. A few small studies indicate that the trimethylselenonium ion (TMSe) is a common selenium metabolite in humans. OBJECTIVE: This study aimed to elucidate the human metabolism of selenium to TMSe. DESIGN: Study individuals constituted subsamples of 2 cohorts: 1) pregnant women (n = 228) and their 5-y-old children (n = 205) in rural Bangladesh with poor selenium status [median urinary selenium (U-Se): 6.4 µg/L in mothers, 14 µg/L in children] and 2) women in the Argentinian Andes (n = 83) with adequate selenium status (median U-Se: 24 µg/L). Total U-Se and blood selenium were measured by inductively coupled plasma mass spectrometry (ICPMS), and urinary concentrations of TMSe were measured by high-performance liquid chromatography/vapor generation/ICPMS. A genomewide association study (GWAS) was performed for 1,629,299 (after filtration) single nucleotide polymorphisms (SNPs) in the Bangladeshi women (n = 72) by using Illumina Omni5M, and results were validated by using real-time polymerase chain reaction. RESULTS: TMSe "producers" were prevalent (approximately one-third) among the Bangladeshi women and their children, in whom TMSe constituted ∼10-70% of U-Se, whereas "nonproducers" had, on average, 0.59% TMSe. The TMSe-producing women had, on average, 2-µg U-Se/L higher concentrations than did the nonproducers. In contrast, only 3 of the 83 Andean women were TMSe producers (6-15% TMSe in the urine); the average percentage among the nonproducers was 0.35%. Comparison of the percentage of urinary TMSe in mothers and children indicated a strong genetic influence. The GWAS identified 3 SNPs in the indolethylamine N-methyltransferase gene (INMT) that were strongly associated with percentage of TMSe (P < 0.001, false-discovery rate corrected) in both cohorts. CONCLUSIONS: There are remarkable population and individual variations in the formation of TMSe, which could largely be explained by SNPs in INMT. The TMSe-producing women had higher U-Se concentrations than did nonproducers, but further elucidation of the metabolic pathways of selenium is essential for the understanding of its role in human health. The MINIMat trial was registered at isrctn.org as ISRCTN16581394.