Maternal-Infant Research On Environmental Chemicals Research Articles

Flawed MIREC fluoride and intelligence quotient publications: A failed attempt to undermine community water fluoridation.

To assess the evidence presented in a set of articles that use the Canadian Maternal-Infant Research on Environmental Chemicals (MIREC) study database to claim that community water fluoridation (CWF) is associated with harm to foetal and infant cognitive development. Critical appraisal of measurements and processes in the MIREC database, and articles derived therefrom. MIREC's cohort is approximately 2000 pregnant women recruited in 10 centres across Canada, 2008-2011, leading to measuring 512 children aged 3-6 years in six cities. Fluoride exposure was measured by city fluoridation status, self-reports and maternal spot urine samples. Intelligence Quotient (IQ) was measured using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) by different assessors in each city. MIREC's fluoride and IQ measurements are invalid and therefore cannot support the claim that CWF is associated with IQ decline in children. The MIREC fluoride-IQ articles' results should be considered unacceptable for legal and policy purposes; other water fluoridation studies and systematic reviews show no effect of fluoridation on cognition.

Fluoride exposure and thyroid hormone levels in pregnancy: The MIREC cohort

BackgroundFluoride exposure may increase the risk of hypothyroidism, but results from previous studies are inconsistent at low-level fluoride exposure (i.e., ≤0.7 mg/L). Human studies of fluoride and thyroid hormone levels in pregnancy are scarce. ObjectivesWe examined associations between fluoride exposure and maternal thyroid hormone levels in a Canadian pregnancy cohort, with consideration for fetal sex-specific effects. MethodsWe measured fluoride concentrations in drinking water and spot urine samples collected during each trimester from 1876 pregnant women enrolled in the Maternal-Infant Research on Environmental Chemicals (MIREC) study. We also measured maternal thyroid stimulating hormone (TSH), free thyroxine (FT4), and total thyroxine (TT4) levels during the first trimester of pregnancy. We used linear and non-linear regression models to estimate associations between fluoride exposure and levels of TSH, FT4, and TT4. We explored effect modification by fetal sex and considered maternal iodine status as a potential confounder. ResultsA 1 mg/L increase in urinary fluoride was associated with a 0.30 (95 %CI: 0.08, 0.51) logarithmic unit (i.e., 35.0 %) increase in TSH among women pregnant with females, but not males (B = 0.02; 95 %CI: −0.16, 0.19). Relative to women with urinary fluoride concentrations in the first quartile (0.05–0.32 mg/L), those with levels in the third quartile (0.49–0.75 mg/L) had higher FT4 and TT4 (i.e., inverted J-shaped associations), but the association was not statistically significant after adjustment for covariates (p = 0.06). Water fluoride concentration showed a U-shaped association with maternal FT4, whereby women with water fluoride concentrations in the second (0.13–0.52 mg/L) and third (0.52–0.62 mg/L) quartiles had significantly lower FT4 compared to those with levels in the first quartile (0.04–0.13 mg/L). Adjustment for maternal iodine status did not change the results. DiscussionFluoride exposure was associated with alterations in maternal thyroid hormone levels, the magnitude of which appeared to vary by fetal sex. Given the importance of maternal thyroid hormones for fetal neurodevelopment, replication of findings is warranted.

Prenatal Exposure to Air Pollution and Respiratory Distress in Term Newborns: Results from the MIREC Prospective Pregnancy Cohort.

Respiratory distress is the leading cause of neonatal morbidity and mortality worldwide, and prenatal exposure to air pollution is associated with adverse long-term respiratory outcomes; however, the impact of prenatal air pollution exposure on neonatal respiratory distress has not been well studied. We examined associations between prenatal exposures to fine particular matter () and nitrogen dioxide () with respiratory distress and related neonatal outcomes. We used data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a prospective pregnancy cohort () recruited in the first trimester from 10 Canadian cities. Prenatal exposures to () and () were estimated using land-use regression and satellite-derived models coupled with ground-level monitoring and linked to participants based on residential location at birth. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between air pollution and physician-diagnosed respiratory distress in term neonates in hierarchical logistic regression models adjusting for detailed maternal and infant covariates. Approximately of newborns experienced respiratory distress. Neonates received clinical interventions including oxygen therapy (6%), assisted ventilation (2%), and systemic antibiotics (3%). Two percent received multiple interventions and 4% were admitted to the neonatal intensive care unit (NICU). Median and concentrations during pregnancy were and , respectively. Prenatal exposures to air pollution were not associated with physician-diagnosed respiratory distress, oxygen therapy, or NICU admissions. However, exposures were strongly associated with assisted ventilation (OR per increase in ; 95% CI: 1.02, 1.35), multiple clinical interventions (OR per increase in ; 95% CI: 1.07, 1.26), and systemic antibiotics, (OR per increase in ; 95% CI: 1.04, 1.21). These associations were consistent across exposure periods-that is, during prepregnancy, individual trimesters, and total pregnancy-and robust to model specification. exposure was associated with administration of systemic antibiotics (OR per 1-ppb increase in ; 95% CI: 1.00, 1.06). Prenatal exposures to increased the risk of severe respiratory distress among term newborns. These findings support the development and prioritization of public health and prenatal care strategies to increase awareness and minimize prenatal exposures to air pollution. https://doi.org/10.1289/EHP12880.

Prenatal fluoride exposure, offspring visual acuity and autonomic nervous system function in 6-month-old infants

BackgroundPrenatal fluoride exposure can have adverse effects on children’s development; however, associations with visual and cardiac autonomic nervous system functioning are unknown. We examined associations between prenatal fluoride exposure and visual acuity and heart rate variability (HRV) in 6-month-old infants. MethodsWe used data from Canadian mother-infant pairs participating in the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort. We estimated prenatal fluoride exposure using: i) fluoride concentration in drinking water (mg/L), ii) maternal urinary fluoride adjusted for specific gravity (MUFSG; mg/L) and averaged across pregnancy, and iii) maternal fluoride intake (µg/kg/day) from consumption of water, tea, and coffee, adjusted for maternal body weight (kg). We used multivariable linear regression to examine associations between each measure of fluoride exposure and Teller Acuity Card visual acuity scores (n = 435) and assessed HRV (n = 400) using two measures: root mean square of successive differences (RMSSD) and the standard deviation of N-N intervals (SDNN) measured at 6-months of age. ResultsMedian (IQR) values for water fluoride, MUFSG, and daily fluoride intake were 0.20 (IQR: 0.13–0.56) mg/L; 0.44 (0.28–0.70) mg/L and 4.82 (2.58–10.83) µg/kg/day, respectively. After adjustment for confounding variables, water fluoride concentration was associated with poorer infant visual acuity (B = -1.51; 95 % CI: −2.14,-0.88) and HRV as indicated by lower RMSSD (B = -1.60; 95 % CI: −2.74,-0.46) but not SDNN. Maternal fluoride intake was also associated with poorer visual acuity (B = -0.82; 95 % CI: −1.35,-0.29) and lower RMSSD (B = -1.22; 95 % CI: −2.15,-0.30). No significant associations were observed between MUFSG and visual acuity or HRV. ConclusionFluoride in drinking water was associated with reduced visual acuity and alterations in cardiac autonomic function in infancy, adding to the growing body of evidence suggesting fluoride's developmental neurotoxicity.

Cohort profile update: The Canadian Maternal-Infant Research on Environmental Chemicals Child Development study (MIREC-CD PLUS).

The pan-Canadian Maternal-Infant Research on Environmental Chemicals (MIREC) study was established to determine whether maternal environmental chemical exposures were associated with adverse pregnancy outcomes in 2001 pregnant women. The MIREC-Child Development (CD PLUS) study followed this cohort with the goal of assessing the potential effects of prenatal exposures on anthropometry and neurodevelopment in early childhood. MIREC families with children between the ages of 15 months and 5 years who had agreed to be contacted for future research (n = 1459) were invited to participate in MIREC-CD PLUS which combines data collected from an online Maternal Self-Administered Questionnaire with biomonitoring and neurodevelopment data collected from two in-person visits. Between April 2013 and March 2015, 803 children participated in the Biomonitoring visit where we collected anthropometric measures, blood, and urine from the children. The Behavioural Assessment System for Children-2, Behaviour Rating Inventory of Executive Function, MacArthur-Bates Communicative Development Inventories and the Communication subscale of the Adaptive Behaviour Scale from the Bayley Scales of Infant and Toddler Development-III are available on close to 900 children. There were 610 singleton children who completed in-person visits for neurodevelopment assessments including the Social Responsiveness Scale, Wechsler Preschool Primary Scale of Intelligence-III and NEuroPSYchological assessments (NEPSY). Currently, we are following the cohort into early adolescence to measure the impact of early life exposures on endocrine and metabolic function (MIREC-ENDO). Data collection for the MIREC-CD PLUS study is complete and analysis of the data continues. We are now extending the follow-up of the cohort into adolescence to measure the impact of early life exposures on endocrine and metabolic function (MIREC-ENDO). MIREC-CD PLUS is limited by loss to follow-up and the fact that mothers are predominately of higher socioeconomic status and 'White' ethnicity, which limits our generalizability. However, the depth of biomonitoring and clinical measures in MIREC provides a platform to examine associations of prenatal, infancy and childhood exposures with child growth and development.

Childhood exposure to pyrethroids and neurodevelopment in Canadian preschoolers

BackgroundPyrethroid insecticides are used both residentially and agriculturally and their toxicity targets the nervous system of insects. They might also interfere with development and function of the human brain. A few epidemiological studies suggest that exposure to pyrethroids may be associated with neurobehavioral problems in children but there is little data on potential associations with cognitive outcomes. Furthermore, many studies showed that the neurotoxic effects of several pesticides are modified by sex, hence, considerations of potential sex-differences are important to investigate. ObjectiveTo study the cross-sectional association between urinary levels of pyrethroid metabolites and neurodevelopment, including neurobehavioral and cognitive outcomes, in preschool-age children, and to examine whether sex might modify these associations. MethodsWe used data from a follow-up examination of the Maternal-Infant Research on Environmental Chemicals (MIREC), the MIREC Child Development study (MIREC-CD Plus) on children at age 3–4 years living in 6 Canadian cities. For each participant, we collected a urine sample for measurements of pyrethroids metabolites (cis-DBCA, cis-DCCA, trans-DCCA, 3-PBA, 4-F-3-PBA). We assessed neurodevelopment with the Wechsler Primary and Preschool Scale of Intelligence–III (WPPSI-III) and two scales of the Behavior Rating Inventory of Executive Function–Preschool (BRIEF-P). Parents reported children’s behavior using the Behavior Assessment System for Children–2 (BASC-2) and the Social Responsiveness Scale-2 (SRS-2). We examined associations between children’s urinary pyrethroid metabolite concentrations and neurodevelopmental scores with multiple linear regression models, adjusting for confounders, in boys and girls separately. ResultsThe study included 179 children (mean age: 3.2 y, range 2.8–4.0). The detection frequencies were high for most pyrethroid metabolites (83–100%), but lower for 4-F-3-PBA (36%). Higher concentrations of cis-DBCA were significantly associated with lower verbal, performance and full-scale IQ scores in boys (e.g., for a 2-fold increase in cis-DBCA, β = −2.0; 95% CI: −3.4, −0.6 for full-scale IQ). In girls, the only metabolite associated with cognitive scores was 3-PBA, which was associated with lower verbal IQ scores (β = −1.3, 95% CI: −2.6, −0.1). For neurobehavioral outcomes in boys, there were associations between poorer BASC-2 Adaptive Skills scores with higher concentrations of cis-DCCA (β = −1.6, 95% CI: −2.3, −0.9), trans-DCCA (β = −1.5, 95% CI: −2.2, −0.8), 3-PBA (β = −1.7, 95% CI: −2.5, −0.9), and sum of pyrethroid metabolites (β = −1.8, 95% CI: −2.6, −0.9). In girls, we observed a significant association between higher concentration of cis-DCCA and better BASC-2 Adaptive Skills score (β = 1.0; 95% CI, 0.2, 1.8), but not with other urinary pyrethroids metabolites. Scores on the SRS-2 and BRIEF-P were not associated with pyrethroid metabolites. ConclusionThere were associations between some pyrethroid pesticide metabolites and indicators of neurodevelopmental disorder, especially among boys. These associations are in agreement with previous studies and could suggest that exposure to pyrethroid pesticides represents a risk of potential toxicity for the cognitive development of children, and a risk for behavioral development. However, the cross-sectional nature of this study limits causal inferences.

A descriptive analysis of first trimester urinary concentrations of 14 bisphenol analogues in the MIREC Canadian pregnancy cohort

BackgroundConcern over the health effects of BPA, particularly for the developing fetus, has led to an increasing use of bisphenol analogues in industrial and consumer products, which may be as hormonally active as BPA. Biomonitoring data for many bisphenol analogues, especially in pregnant populations, are limited. MethodsWe measured concentrations of 14 bisphenol analogues in 1st trimester urine samples (n = 1851) from the Maternal-Infant Research on Environmental Chemicals (MIREC) Canadian pregnancy cohort (2008–2011). We examined patterns of exposure according to sociodemographic and sampling characteristics as well as occupation and frequency of consumption of canned fish within the previous 3 months. ResultsBPA was detected in 89% of participants with a specific gravity standardized geometric mean concentration of 0.990 μg/L. Biphenol 4,4’ (BP 4,4′), 4,4′-dihydroxydiphenyl ether (DHDPE), and bisphenol E (BPE) were detected in >97% of participants. Bisphenol F (BPF) and bisphenol S (BPS) were detected in >60% of participants. Specific gravity standardized geometric mean concentrations of these 5 compounds ranged from 0.024 to 0.564 μg/L. Nine bisphenol analogues were detected in <9% of participants. Concentrations of BP 4,4′, DHDPE, and BPE were higher in younger women and those with higher pre-pregnancy BMI, lower household income, lower education, and among smokers. We found a similar pattern of differences in BPF for age, education, and smoking status while BPS similarly differed across categories of pre-pregnancy BMI. Participants who were unemployed or working in the service industry had higher molar sum of 7 bisphenol analogues than those working in healthcare, education, or an office setting. Canned fish consumption was not related to bisphenol analogue concentrations. ConclusionBP 4,4’, DHDPE, BPE, BPF, and BPS were highly detected in 1st trimester urine samples in this large pan-Canadian pregnancy cohort. This suggests widespread exposure to these analogues around 2008–2011 and warrants further investigation into associations with health outcomes.

Measurement of 24 phthalate metabolites in 1st trimester urine samples: The MIREC study

Phthalates are non-persistent chemicals measured as metabolites in urine. Over time, new metabolites have been identified. In the original Maternal-Infant Research on Environmental Chemicals (MIREC) study (2008–2011), we measured 11 phthalate metabolites in first trimester urine samples. The goal of the present study was to develop a method to measure new metabolites, to increase the sensitivity for some previously measured metabolites, and to measure these new metabolites in biobanked urine samples from MIREC participants.Using Ultra Performance Liquid Chromatography with a tandem mass spectrometer, we developed a method to measure 24 metabolites from 10 different parent phthalates. Chromatographic interpretation of some of the di-iso-decyl phthalate metabolites (mono-(2-propyl-6oxoheptyl) phthalate (MOiDP), mono-(2,7-methyl-7-carboxyheptyl) phthalate (MCiNP), mono-(2-propyl-6-hydroxy-heptyl) phthalate (MHiDP)) and di-iso-nonyl phthalate metabolites (mono(oxo-isononyl) phthalate (MOiNP), mono(carboxy-isooctyl) phthalate (MCiOP), mono(hydroxy-isononyl) phthalate (MHiNP) and mono-isononyl phthalate (MiNP)) was challenging as these are complex isomeric mixtures.To validate and confirm our quantitation peaks, an assay using a high-resolution detection technique was developed on a Quadrupole Time-of-Flight (QToF) system. This system has a mass resolution of at least 0.005 amu, compared to 0.5 amu for the MS/MS detector. Using the QToF system, the distinction between an isomer and possible interference was achieved with the use of the exact mass.In about 1800 MIREC samples, mono-cyclo-hexyl phthalate (MCHP), mono-(7-carboxy-n-heptyl) phthalate (MCHpP), mono-iso-decyl phthalate (MiDP), and mono-n-octyl phthalate (MnOP) were rarely detected, while detection of MMP was improved. MCiOP, MiNP and MCiNP had to be reported semi-quantitatively.Given the complexity of isomeric mixtures of some phthalates, researchers must be careful in their determination of the analytes and the approach used in their quantification when generating biomonitoring data.This study produced biomonitoring data for a large population of pregnant people that can be used in risk assessment of phthalates. Future work will examine associations with birth and child outcomes.

Prenatal exposure to legacy PFAS and neurodevelopment in preschool-aged Canadian children: The MIREC cohort

BackgroundExposure to perfluoroalkyl substances (PFAS) has been shown to be neurotoxic in experimental studies, but epidemiological evidence linking prenatal PFAS exposure to child neurodevelopment is equivocal and scarce. ObjectiveTo quantify associations between prenatal exposure to legacy PFAS and children's intelligence (IQ) and executive functioning (EF) in a Canadian pregnancy and birth cohort and to determine if these associations differ by child sex. MethodsWe measured first-trimester plasma concentrations of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS) in the Maternal-Infant Research on Environmental Chemicals (MIREC) study and assessed children's full-scale (n = 522), performance (n = 517), and verbal (n = 519) IQ using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III). Children's working memory (n = 513) and ability to plan and organize (n = 514) were assessed using a parent-reported questionnaire, the Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P). We quantified associations between individual log2-transformed PFAS exposure and children's IQ and EF using multiple linear regression analyses and evaluated effect modification by child sex. We also used Repeated Holdout Weighted Quantile Sum (WQS) regression models with effect modification by child sex to quantify the effect of combined exposure to all three PFAS chemicals on IQ and EF. All models were adjusted for key sociodemographic characteristics. ResultsGeometric mean plasma concentrations (IQR) for PFOA, PFOS and PFHxS were 1.68 (1.10–2.50), 4.97 (3.20–6.20) and 1.09 (0.67–1.60) μg/L respectively. We found evidence of effect modification by child sex in all models examining performance IQ (p < .01). Specifically, every doubling of PFOA, PFOS, and or PFHxS was inversely associated with performance IQ, but only in males (PFOA: B = −2.80, 95% CI: −4.92, −0.68; PFOS: B = −2.64, 95% CI: −4.77, −0.52; PFHxS: B = −2.92, 95% CI: −4.72, −1.12). Similarly, every quartile increase in the WQS index was associated with poorer performance IQ in males (B = −3.16, 95% CI: −4.90, −1.43), with PFHxS contributing the largest weight to the index. In contrast, no significant association was found for females (B = 0.63, 95% CI: −0.99, 2.26). No significant associations were found for EF in either males or females. ConclusionsHigher prenatal PFAS exposure was associated with lower performance IQ in males, suggesting that this association may be sex- and domain-specific.

Descriptive analysis of organophosphate ester metabolites in a pan-Canadian pregnancy cohort

Organophosphate esters (OPEs) are widely used in numerous consumer products for their flame retardant and plasticizing properties. Despite potential widespread exposure, biomonitoring data during critical windows of development are scarce and limited to the most widely studied metabolites. We quantified urinary concentrations of multiple OPE metabolites in a vulnerable Canadian population. Using data and biobanked specimens from the Maternal-Infant Research on Environmental Chemicals (MIREC) study (2008–2011), we measured first trimester urinary concentrations of 15 OPE metabolites as well as one flame retardant metabolite and quantified associations with sociodemographic and sample collection characteristics in 1865 pregnant participants. We applied 2 different analytical methods to quantify OPEs, one using UItra-Performance Liquid Chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) and the other using Atmospheric Pressure Gas Chromatography coupled to mass spectrometry (APGC-MS/MS) with sensitive limits of detection (0.008–0.1 μg/L). We modelled associations between sociodemographic and sample collection characteristics and specific gravity-standardized chemical concentrations. Six OPE metabolites were detected in the majority (68.1–97.4 %) of participants. Bis-(2-chloroethyl) hydrogen phosphate had the highest detection rate (97.4 %). Diphenyl phosphate had the highest geometric mean concentration (0.657 μg/L). Metabolites of tricresyl phosphate were detected in few participants. Associations between sociodemographic characteristics varied according to each OPE metabolite. Pre-pregnancy body mass index tended to be positively associated with OPE metabolite concentrations whereas age tended to be inversely associated with OPE concentrations. OPE concentrations were, on average, higher in urine samples collected in the summer than other seasons the winter. We present the largest biomonitoring study of OPE metabolites in pregnant people to date. These findings demonstrate widespread exposure to OPEs and their metabolites and identify subpopulations who may experience heightened exposure.

Relationships of First-Trimester Body Mass Index and Weight Change with Persistent Organic Pollutant Concentrations in Pregnant Canadian Individuals

Persistent organic pollutants (POPs) are toxic chemicals with demonstrable effects on pregnancy and neonatal outcomes. The associations of early pregnancy body mass index (BMI) and antenatal weight changes with circulating POP concentrations are poorly understood in the Canadian context. The aim of this study was to explore the relationship between maternal BMI in the first trimester, weight change from pre-pregnancy to 6–13 weeks of pregnancy, and first-trimester plasma POP concentrations among Canadian pregnant women. We analyzed data collected as part of the Maternal-Infant Research on Environmental Chemicals (MIREC) study and evaluated POP concentrations based on first-trimester BMI and early gestational weight change categories. We tested for overall differences using Kruskal-Wallis tests. The associations between first-trimester maternal BMI, weight change, and plasma concentrations of 41 POPs were evaluated using censored regression models. After controlling for potential confounders, first-trimester plasma levels of multiple POPs differed significantly across BMI categories, with the highest concentrations in underweight/normal-weight individuals and the lowest in class III obese individuals. Our findings provide preliminary evidence of higher circulating POP levels in individuals with obesity and align with previous findings of an inverse relationship between circulating POP concentrations and BMI in pregnancy. Future studies should prospectively evaluate the interplay between weight change and POP concentrations throughout pregnancy to inform gestational weight gain recommendations for pregnant individuals with obesity.

Differences in mirex [dechlorane] and dechlorane plus [syn- and anti-] concentrations observed in Canadian human milk

As part of the pan-Canadian Maternal-Infant Research on Environmental Chemicals (MIREC) study, human milk samples were collected between 2008 and 2011, and analyzed for mirex, an organochlorine insecticide and flame retardant, in addition to dechlorane plus (syn- and anti-DDC-CO), the flame retardant replacement for mirex. Mirex was analyzed separately, using a method for the analysis of existing organochlorine insecticides, while the presence of DDC-CO isomers was determined using a method developed for the detection of emerging flame retardants. Mirex was detected in all samples analyzed (n = 298), while syn- and anti-DDC-CO were present in 61.0% and 79.5% of the samples, respectively (n = 541). Mirex concentrations have declined in human milk since the 1990s. Since this is the first pan-Canadian dataset reporting DDC-CO concentrations in human milk, no temporal comparisons can be made. Maternal age was correlated with concentrations of both compounds although parity did not impact concentrations of either analyte. Given the presence of this relatively recently identified flame retardant (DDC-CO) in human milk from women across Canada, studies to identify dominant sources of this compound are critical. Despite low concentrations of environmental chemicals in human milk from Canadian women, Health Canada supports breastfeeding of infants because of the important health benefits to both the mothers and their infants.

Associations between folic acid supplement use and folate status biomarkers in the first and third trimesters of pregnancy in the Maternal–Infant Research on Environmental Chemicals (MIREC) Pregnancy Cohort Study

Achieving optimal folate status during early gestation reduces the risk of neural tube defects (NTDs). While inadequate folate intake remains a concern, it is becoming increasingly common for individuals to consume higher than recommended doses of folic acid (FA) with minimal additional benefit. Here, we sought to investigate the determinants, including FA supplement dose and use, of plasma total and individual folate vitamer concentrations in the first and third trimesters of pregnancy. Using data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a cohort exposed to mandatory FA fortification, we measured plasma total folate and individual folate vitamer [5-methyltetrahydrofolate (5-methylTHF), unmetabolized FA (UMFA), and non-methyl folates (sum of THF, 5-formylTHF, 5,10-methenyl-THF)] concentrations in the first and third trimesters (n=1,893). Using linear mixed models, we estimated associations between plasma folate concentrations, total daily supplemental FA intake, plasma vitamin B-12 concentrations, and multiple demographic, maternal, and reproductive factors. Almost 95% of MIREC study participants met or exceeded the recommended daily supplemental FA intake from supplements (≥400 μg/d), with approximately 25% consuming more than the Tolerable Upper Intake Level (>1000 μg/d). Over 99% of MIREC participants had a plasma total folate status indicative of maximal NTD risk reduction (25.5nmol/L) regardless of FA supplement dose. UMFA was detected in almost all participants, with higher concentrations associated with higher FA doses. Determinants of adequate FA supplement intake and folate status associated with reduced NTD risk included indicators of higher socioeconomic position, higher maternal age, nulliparity, and lower prepregnancy BMI. In the context of mandatory FA fortification, our data indicate that higher-than-recommended FA doses are unwarranted, with the exception of individuals at higher risk for NTDs. Ideally, prenatal supplements would contain 400 rather than 1000µg FA, thereby enabling the consumption of optimal and safe FA doses.

Urinary concentrations and determinants of glyphosate and glufosinate in pregnant Canadian participants in the MIREC study

BackgroundGlyphosate is the most widely applied herbicide in agriculture. Glufosinate is a broad spectrum herbicide used to manage glyphosate-resistant weeds. Despite the widespread use of these herbicides, biomonitoring data – which inform risk assessment and management – are sparse. ObjectivesTo identify determinants of urinary concentrations of these herbicides and their metabolites in pregnancy. MethodsWe measured urinary concentrations of glyphosate, glufosinate, and their primary metabolites aminomethylphosphonic acid (AMPA) and 3-methylphosphinicopropionic acid (3-MPPA) in a single spot urine specimen collected during the first trimester of pregnancy from the Maternal-Infant Research on Environmental Chemicals (MIREC) study. MIREC recruited about 2000 pregnant women from 10 Canadian cities between 2008 and 2011. We used UItra-Performance Liquid Chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) with sensitive limits of detection to quantify analyte concentrations. We examined urinary concentrations according to maternal sociodemographics, sample collection characteristics, reported pesticide use, and consumption of fruits, vegetables, legumes, and grain products. We used ANOVA models with specific gravity-standardized chemical concentrations as the dependent variable to determine associations with maternal and sample determinants. ResultsAmong women with biobanked urine samples (n = 1829–1854), 74% and 72% had detectable concentrations of glyphosate and AMPA, respectively. In contrast, one and six percent of women had detectable concentrations of glufosinate and 3-MPPA, respectively. The specific gravity-standardized geometric mean (95% CI) concentrations of glyphosate and AMPA were 0.112 (0.099–0.127) μg/L and 0.159 (0.147–0.172) μg/L, respectively. We observed a dose-response relationship between consumption of whole grain bread and higher urinary glyphosate concentrations. Season of urine collection and self-reported pesticide use were not associated with increased concentrations of any analyte. ConclusionsWe detected glyphosate and AMPA in the majority of pregnant women from this predominantly urban Canadian cohort. Diet was a probable route of exposure.

Using Latent Profile Analysis to Identify Associations Between Gestational Chemical Mixtures and Child Neurodevelopment.

Unsupervised machine learning techniques have become increasingly popular for studying associations between gestational exposure mixtures and human health. Latent profile analysis is one method that has not been fully explored. We estimated associations between gestational chemical mixtures and child neurodevelopment using latent profile analysis. Using data from the Maternal-Infant Research on Environmental Chemicals (MIREC) research platform, a longitudinal cohort of pregnant Canadian women and their children, we generated latent profiles from 27 gestational exposure biomarkers. We then examined the associations between these profiles and child Verbal IQ, Performance IQ, and Full-Scale IQ, measured with the Wechsler Preschool and Primary Scale of Intelligence, Third Edition (WPPSI-III). We validated our findings using k-means clustering. Latent profile analysis detected five latent profiles of exposure: a reference profile containing 61% of the study participants, a high monoethyl phthalate (MEP) profile with moderately low persistent organic pollutants (POPs) containing 26%, a high POP profile containing 6%, a low POP profile containing 4%, and a smoking chemicals profile containing 3%. We observed negative associations between both the smoking chemicals and high MEP profiles and all IQ scores and between the high POP profile and Full-Scale and Verbal IQ scores. We also found a positive association between the low POP profile and Full-Scale and Performance IQ scores. All associations had wide 95% confidence intervals. Latent profile analysis is a promising technique for identifying patterns of chemical exposure and is worthy of further study for its use in examining complicated exposure mixtures.

Perfluorinated alkyl substances in Canadian human milk as part of the Maternal-Infant Research on Environmental Chemicals (MIREC) study

Perfluorinated alkyl substances (PFAS) were determined in human milk samples (n = 664) from participants in the Maternal-Infant Research on Environmental Chemicals (MIREC) study. ΣPFAS concentrations (sum of seven PFAS) ranged from 3.1 ng L−1 to 603 ng L−1, with a median concentration of 106 ng L−1 in the Canadian mothers' milk analyzed. These data comprise the first pan-Canadian dataset of PFAS in human milk. Perfluorooctanoic acid (PFOA) and linear perfluorooctanesulfonate (L-PFOS) were the dominant contributors to ΣPFAS in human milk samples. An inverse relationship between ΣPFAS concentrations and age was observed (Spearman correlation - 0.184). Primiparous women had elevated PFAS concentrations in milk relative to women who had children previously (p < 0.001). In contrast, the region of maternal birth did not influence ΣPFAS concentrations (p = 0.156). Although China and Norway have observed consistently detectable levels of perfluoroundecanoic acid (PFUdA) in human milk, PFAS with long carbon chains (n ≥ 11) were not present above method detection limits in Canadian human milk samples analyzed as part of the MIREC study. In conclusion, despite the presence of low levels of environmental contaminants in human milk, Health Canada supports breastfeeding due to the benefits to both infants and mothers.

Maternal fluoride exposure, fertility and birth outcomes: The MIREC cohort

ObjectiveFluoride exposure >1.5 mg/L from water has been associated with adverse pregnancy and birth outcomes. Little is known, however, about the effect of fluoride at levels consistent with water fluoridation (i.e., 0.7 mg/L) on pregnancy and birth outcomes. We examined the relationship between maternal fluoride exposure, fertility, and birth outcomes in a Canadian pregnancy cohort living in areas where municipal drinking water fluoride concentrations ranged from 0.04 to 0.87 mg/L. MethodsUsing data from the Maternal-Infant Research on Environmental Chemicals (MIREC) study, we estimated fluoride exposure during pregnancy using three different metrics: (1) maternal urinary fluoride concentrations standardized for specific gravity (MUFSG) and averaged across all three trimesters (N = 1566), (2) water fluoride concentration (N = 1370), and (3) fluoride intake based on self-reported consumption of water, coffee, and tea, adjusted for body weight (N = 1192). Data on fertility, birth weight, gestational age, preterm birth, and small-for-gestational age (SGA) were assessed. We used multiple linear regression to examine associations between fluoride exposure, birth weight and gestational age, and logistic regression to examine associations with fertility, preterm birth, and SGA, adjusted for relevant covariates. ResultsMedian (IQR) MUFSG was 0.50 (0.33–0.76) mg/L, median water fluoride was 0.52 (0.17–0.64) mg/L, and median fluoride intake was 0.008 (0.003–0.013) mg/kg/day. MUFSG, water fluoride concentrations, and fluoride intake were not significantly associated with fertility, birth weight, gestational age, preterm birth, or SGA. Fetal sex did not modify any of the associations. ConclusionFluoride exposure during pregnancy was not associated with fertility or birth outcomes in this Canadian cohort.

Early prenatal use of a multivitamin diminishes the risk for inadequate vitamin D status in pregnant women: results from the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort study

ABSTRACTBackgroundReports on the adequacy of vitamin D status of pregnant women are not available in Canada.ObjectivesThe objectives of this study were to examine vitamin D status across pregnancy and identify the correlates of vitamin D status of pregnant women in Canada.MethodsPregnant women (≥18 years) from 6 provinces (2008–2011) participating in a longitudinal cohort were studied. Sociodemographic data, obstetrical histories, and dietary and supplemental vitamin D intakes were surveyed. Plasma 25-hydroxyvitamin D (25OHD) was measured using an immunoassay standardized to LC-MS/MS from samples collected during the first (n = 1905) and third trimesters (n = 1649) and at delivery (n = 1543). The proportion of women with ≥40 nmol/L of plasma 25OHD (adequate status) was estimated at each time point, and factors related to achieving this cut point were identified using repeated-measures logistic regression. Differences in 25OHD concentrations across trimesters and at delivery were tested a using repeated-measures ANOVA with a post hoc Tukey's test.ResultsIn the first trimester, 93.4% (95% CI: 92.3%–94.5%) of participants had 25OHD ≥40 nmol/L. The mean plasma 25OHD concentration increased from the first to the third trimester and then declined by delivery (69.8 ± 0.5 nmol/L, 78.6 ± 0.7 nmol/L, and 75.7 ± 0.7 nmol/L, respectively; P < 0.0001). A lack of multivitamin use early in pregnancy reduced the odds of achieving 25OHD ≥40 nmol/L (ORadj = 0.33; 95% CI: 0.25–0.42) across all time points. Factors associated with not using a prenatal multivitamin included multiparity (ORadj = 2.08; 95% CI: 1.42–3.02) and a below-median income (ORadj = 1.39; 95% CI: 1.02–1.89).ConclusionsThe results from this cohort demonstrate the importance of early multivitamin supplement use to achieve an adequate vitamin D status in pregnant women.

Associations Between Prenatal Fluoride Exposure and Performance IQ in Canadian Preschool Aged Children: A Multilevel Modeling Approach

BACKGROUND AND AIM: Prenatal fluoride exposure is associated with reduced IQ in children, especially Performance IQ (PIQ; nonverbal intelligence), but studies have not accounted for hierarchical clustering. We examined the association between sex-specific prenatal fluoride exposure and PIQ using multilevel modeling (MLM) to account for nesting of 448 mother-child pairs within 184 postal codes and six cities. METHODS: Our sample was from the Maternal-Infant Research on Environmental Chemicals (MIREC) prospective Canadian birth cohort. Variables included maternal urinary fluoride (MUF; adjusted for dilution), PIQ scores at age 3-4 years from the WPPSI, and participant level covariates (HOME scores, maternal education level, and maternal race). A series of three-level MLMs were fit to estimate associations between within-postal code and within-city centered MUF and PIQ. RESULTS:Median MUF concentration was 0.44 mg/L (IQR= 0.35), with average PIQ of 102 (SD= 14) for boys and 105 (SD= 14) for girls. A three-level intra-class correlation revealed that 3.8% and 9.1% of the variance in PIQ was accounted for by nesting of dyads in postal codes and cities, respectively. The interaction between child sex and MUF and the covariate effects were fixed across postal codes and cities in the optimal model. The interaction between child sex and within-postal-code MUF was significant (p .05).For boys, a 1 mg/L increase in within-postal-code MUF was significantly associated with PIQ, B= -7.9 (95% CI: -13.6, -2.2); for girls, the association was not significant, B= 1.7 (95% CI: -5.0, 8.5). Centering MUF within city resulted in a weaker effect among boys (B= -5.7 95% CI: -10.2, -1.2), and a stronger, but nonsignificant effect among girls (B= 3.3, 95% CI: -2.7, 9.3). CONCLUSIONS:For boys, the stronger effect of MUF in postal codes than cities shows the importance of accounting for hierarchical clustering in the MIREC cohort to examine associations between prenatal fluoride exposure and PIQ. KEYWORDS: biomarkers of exposure, children’s environmental health, epidemiology, fluoride, neurodevelopmental outcomes

Prenatal Fluoride Exposure and Autism Spectrum Disorder-Like Behaviors in a Sample of Canadian Preschool Aged Children: The MIREC Study

BACKGROUND AND AIM: A growing body of evidence indicates that prenatal exposure to fluoride is neurotoxic to child development. However, epidemiologic research examining fluoride’s effect on autism spectrum disorder (ASD) is lacking. Our aim was to examine the association of prenatal fluoride exposure with ASD-like behaviors in a sample of preschool aged children living in regions with fluoridated and non-fluoridated community water. METHODS: We analyzed 502 mother-child pairs from the Maternal-Infant Research on Environmental Chemicals (MIREC), a prospective multicentered Canadian birth cohort, with available data on prenatal fluoride exposure, ASD-like behaviors, and covariates. We measured fluoride exposure by averaging maternal urinary fluoride adjusted for specific gravity (MUFsg) across three trimesters. We assessed children’s ASD-like behaviors at 3-4 years of age using the parent-reported Social Responsiveness Scale-2 (SRS-2) Preschool Form, with higher scores indicating more behavioral symptomology. Covariate adjusted linear and quantile regression models were used to estimate the difference in the relationship between MUFsg and SRS-2 conditional mean and quantile subscale T-scores, respectively. We adjusted all regression models for baseline maternal age, second-hand smoke, marital status, parity, child sex, study site, and the HOME score that was assessed at child follow-up visit. RESULTS:Mean MUFsg concentration was 0.53 mg/L (SD=0.38), and mean SRS-2 Total T-score was 45.3 (SD=6.2). In multiple linear regression, a 1 mg/L increase in MUFsg concentration was not statistically associated with SRS-2 Total T-score (β=0.12; 95% CI, -1.36, 1.60; P=0.87). Likewise, we observed no statistical association for all other SRS-2 subscale T-scores. In quantile regression, there was no statistical association between MUFsg and SRS-2 Total T-score across percentiles: 0.1, 0.3, 0.5, 0.7 and 0.9. Effect modification by sex was not observed. CONCLUSIONS:In this Canadian cohort, we found no evidence of a statistical association between prenatal fluoride exposure and ASD-like behaviors among preschool aged children. KEYWORDS: biomarkers of exposure, children’s environmental health, epidemiology, fluoride, neurodevelopmental outcomes