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The solvents N-methyl-2-pyrrolidone (NMP) and N-ethyl-2-pyrrolidone (NEP) are established developmental toxicants; however, epidemiological data are lacking. We quantified associations between urinary NEP and NMP metabolites concentrations and pregnancy outcomes in participants enrolled in the pan-Canadian Maternal-Infant Research on Environmental Chemicals study (n = 1865) (2008-2011). Using discrete time survival analysis and logistic regression, we calculated the odds of preterm birth (PTB) and fetal loss. We used multivariable linear regression to quantify associations between metabolites and birth weight z-scores. Participants with quantifiable concentrations of the NEP metabolite 5-hydroxy-N-ethyl-2-pyrrolidone (5-HNEP) had a 41% increased odds of PTB (95% CI: 0.92-2.17). An interquartile range increase in concentrations of the NMP metabolite 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) was associated with a reduced odds of fetal loss (OR = 0.51 95% CI: 0.30,0.89). All other effect estimates were centered around the null value. We report widespread, low-level exposure to NMP metabolites yet no evidence of adverse effects on fetal health. Our analysis of fetal loss was most likely subject to selection bias resulting from conditioning on pregnancies with available first trimester urine samples Our finding that 5-HNEP exposure may increase risk of preterm birth provides impetus for further biomonitoring and etiological research in a pregnant population with contemporary NEP exposure., Competing Interests: Conflict of interest No authors have a conflict of interest., (Crown Copyright © 2025. Published by Elsevier GmbH. All rights reserved.)

Background: Gestational exposures to single toxic chemicals have been associated with cognitive deficits in children, but few studies have explored chemical mixtures., Objectives: To evaluate the associations between gestational chemical biomarker mixtures and cognitive abilities in children from two prospective cohorts., Methods: This study includes 617 birthing parent-child pairs from the Health Outcomes and Measures of the Environment (HOME) and Maternal-Infant Research on Environmental Chemicals (MIREC) Studies. We measured 29 chemical biomarkers (metals, persistent organic pollutants, perfluoroalkyl substances, organophosphate esters, phenols, phthalates, organophosphate pesticides, and parabens) in pregnant individuals during early pregnancy and their children's cognitive abilities at ages 3 to 5 years using Wechsler Intelligence Scales. We assessed linear associations using quantile g-computation and non-linear associations using Bayesian Kernel Machine Regression (BKMR) methods, adjusted for covariates., Results: Using quantile g-computation, we observed overall null associations between the chemical biomarker mixture and cognitive outcomes among preschool-age children. Although statistical significance was not attained for child sex as an effect modifier, our stratified analysis unveiled a moderate divergence in association trends. We noted a marginal inverse trend between the chemical biomarker mixture and cognitive scores [Full-Scale Intelligence Quotient (FSIQ) & Performance Intelligence Quotient (PIQ)] among males. Using quantile g-computation and BKMR methods, we observed that PBDE47, PFHxS, and di-ethyl organophosphates commonly contributed towards a decline in FSIQ scores in males. Among males, a quartile increase in the chemical biomarker mixture was associated with a 0.64-point decrease (95% CI: -2.59, 1.31) in the FSIQ score and a 1.59-point decrease (95% CI: -3.72, 0.54) in the PIQ score., Conclusion: In this study, we observed a weak negative trend between the gestational chemical biomarker mixture and cognitive scores (FSIQ/PIQ) among males. Further studies are needed to confirm the findings between the longitudinal chemical biomarkers and child cognitive scores at school ages., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Joseph Braun was compensated for serving as an expert witness for plaintiffs involved in litigation related to PFAS-contaminated drinking water. Other authors declare no competing financial interests to influence the findings in this study., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Context: During pregnancy, women who experience certain pregnancy complications show elevations in biomarkers of inflammation and insulin resistance; however, few studies have examined these cardiometabolic biomarkers in the decade following pregnancy., Objective: To examine the association between pregnancy complications and cardiometabolic biomarkers 9 years postpartum including: blood pressure, blood lipids, body fat percentage, insulin resistance (glucose, insulin, proinsulin, C-peptide, HOMA-IR, HbA1c, leptin, adiponectin) and inflammation (hs-C-reactive protein)., Methods: Using data from the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort study (2008-2021) we determined 3 groups of pregnancy complications: 1) hypertensive disorders of pregnancy (HDP) (n=35); any pregnancy complication in the index pregnancy, defined as preterm birth, HDP, impaired glucose tolerance or gestational diabetes mellitus (GDM) (n=55); or self-reported recurrence of one of these pregnancy complications (n=19). Our comparison group included 186 women with uncomplicated pregnancies., Results: In our adjusted linear regression results, all pregnancy complication groups showed significantly higher systolic and diastolic blood pressure 9 years later. HOMA-IR was 23% (95% CI: -4.4%, 57%), 26% (95% CI: 2.0%, 55%), and 51% (95% CI: 12%, 104%) higher at follow-up in participants who had experienced a prior HDP, an index pregnancy complication, or a recurrent pregnancy complication respectively. Elevations were also seen with HbA1c, insulin, C-peptide, and leptin especially among those with recurrent complications., Conclusion: This study contributes to the body of evidence that women with a history of certain pregnancy complications merit special attention in the prevention of CVD. We recommend further exploration into these associations in larger cohorts., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.)

Exposure to per- and polyfluoroalkyl substances (PFAS) is ubiquitous and may be associated with neurodevelopmental toxicity. However, epidemiological studies report mixed results on the risks of gestational PFAS exposure for children's neurobehavioral impairment. We aimed to examine the associations between prenatal PFAS exposure and children's neurobehavioral and social problems. We measured plasma concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), and perfluorohexane sulphonate (PFHxS) in first-trimester blood from 757 women from the Canadian Maternal-Infant Research on Environmental Chemicals (MIREC) study. Children were assessed at 3-4 years with the Behavior Assessment System for Children-2 (BASC-2) and the Social Responsiveness Scale-2 (SRS-2) (n = 756 and 496, respectively). We used multivariable linear regression to examine associations between individual and summed log 2 -transformed PFAS and scores on these assessments. Effect modification by sex was evaluated through interaction terms and stratified analyses. In the sample combining both sexes, a doubling of maternal PFOA was significantly associated with lower T-scores on the following SRS-2 scales: Social Motivation, DSM-Social Communication, and SRS Total score (B ranging from -1.08 to -0.78), suggesting lesser impairments with higher exposure. In sex-stratified analysis, PFOA was related to significantly lower T-scores in boys for these BASC-2 scales: Behavioral Symptoms Index, Externalizing Problems, Aggression, and Hyperactivity (B ranging from -1.32 to -1.03). In girls, however, PFAS were associated with more problem behaviors, but most associations were small and the CIs included the null, with the exception of PFOA being significantly associated with higher T-scores for the BASC-2Anxiety scale (B = 1.84, 95% CI: 0.36, 3.32). In conclusion, we did not observe strong associations between prenatal exposure to the PFAS evaluated and children's neurobehavioral and social development in this population with low exposure levels. The results show mixed findings, depending on children's sex, neurodevelopmental outcome, and specific PFAS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Human milk (HM) composition data are widely used in clinical, regulatory, and public health initiatives. The existing HM profiles in United States and Canadian nutrient databanks are outdated and now considered inappropriate to estimate current nutrient intakes. Recent reviews have underscored the limited North American data available to generate a new profile., Objectives: To describe concentrations and sources of variability of nutrients in HM from a large cohort collected in Canada., Methods: The Maternal-Infant Research on Environmental Chemicals (MIREC) study recruited participants in the first trimester of pregnancy from 10 Canadian cities between 2008 and 2011. HM samples (n = 559-835, depending on nutrient) were collected 3-10 wk postpartum and analyzed for minerals (calcium, magnesium, phosphorus, potassium, sodium, manganese, molybdenum, zinc, copper, iodine, selenium), vitamin D [vitamin D 3 , 25-hydroxyvitamin D 3 ], folate vitamers (folic acid, 5-methyltetrahydrofolate, total folates), and fatty acids (panel). We examined associations between participant characteristics and log-transformed nutrient concentrations using linear regression., Results: Concentrations of HM components in MIREC samples were within the range observed in literature except for manganese, which was >100-fold lower than the value in the existing Canadian nutrient databank profile [2.43 (standard deviation 2.84) compared with 260 ng/g]. In multivariable models, concentrations of folate vitamers, vitamin D, and fatty acids demonstrated greater variability with maternal and sample characteristics than minerals. Factors such as relevant supplement use, body mass index, and for vitamin D, skin color and season, had a larger impact on nutrient concentrations than characteristics typically standardized in HM research, such as maternal or infant health, and method of collection., Conclusions: HM mineral concentrations from this study meet the methodological inclusion criteria for updating nutrient databank values and dietary reference intakes. Consideration of factors such as diet, skin color, and BMI will be important for selecting studies for developing representative reference values based on HM., Competing Interests: Conflict of interest AJM is an Associate Editor for The American Journal of Clinical Nutrition and played no role in the journal's evaluation of the manuscript. All other authors report no conflict of interest., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Background: Per- and polyfluoroalkyl substances (PFAS) are ubiquitous chemicals routinely detected in personal care products (PCPs). However, few studies have evaluated the impact of PCP use on PFAS concentrations in pregnant and lactating populations., Objective: We investigated associations between PCP use and PFAS concentrations in prenatal plasma and human milk., Methods: We leveraged the Maternal-Infant Research on Environmental Chemicals (MIREC) Study to evaluate the contribution of PCP use on PFAS concentrations in prenatal plasma (6 to 13 weeks' gestation; n = 1,940) and human-milk (2 to 10 weeks' postpartum; n = 664). Participants reported frequency of use across 8 PCP categories during the 1st and 3rd trimesters, 1 to 2 days postpartum, and 2 to 10 weeks' postpartum. We used adjusted linear regression models to quantify percent differences and corresponding 95 % confidence intervals., Results: In 1st trimester pregnant people, we found higher use of nailcare products (≥once a week vs. never: perfluorooctanoic acid (PFOA): 21 % [9.7 %, 32 %]; perfluorooctane-sulfonic acid (PFOS): 11 % [0.3 %, 23 %]), fragrances (daily vs. never: PFOA: 14 % [7.8 %, 21 %]; PFOS: 7.8 % [1.3 %, 15 %]), makeup (daily vs. never: PFOA: 14 % [5.8 %, 23 %]), hair dyes (never vs. 1-2 times during pregnancy: PFOA: 8.3 % [2.4 %, 15 %]), and hair sprays or gels (daily vs. never: PFOA: 12 % [5.0 %, 19 %], PFOS: 7.1 % [0.2 %, 15 %]) were associated with higher plasma PFAS concentrations. Similar results were observed for 3rd trimester PCP use and 2 to 10 weeks' postpartum human-milk PFAS concentrations. In addition, we also found that people using colored-permanent dye 1 to 2 days postpartum had higher Sm-PFOS (18 % [2.7 %, 35 %]), PFOA (16 % [4.3 %, 29 %]), and perfluorononanoic acid (17 % [3.6 %, 33 %]) postpartum human-milk concentrations., Conclusions: Our results show that PCP use may be a modifiable source of PFAS exposure in pregnant and lactating populations. These results along with growing scientific evidence can help inform PFAS regulation and guide individual choices to reduce PFAS exposure., Competing Interests: Declaration of competing interest Dr. Joseph Braun was compensated for serving as an expert witness on behalf of plaintiffs in litigation related to PFAS-contaminated drinking water. No other authors have any conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Folic acid (FA) supplementation may attenuate the associations between gestational exposure to certain chemicals and autism or autistic-like behaviors, but to our knowledge, this has not been assessed for lead., Objectives: We examined whether the relationship between gestational blood-lead levels (BLLs) and autistic-like behaviors was modified by gestational plasma total folate concentrations, FA supplementation, and maternal methylenetetrahydrofolate reductase ( MTHFR ) 677C>T genotype., Methods: We used data from the Maternal-Infant Research on Environmental Chemicals study (2008-2011), a Canadian pregnancy and birth cohort study. Childhood autistic-like behaviors were documented in 601 children 3-4 y of age with the Social Responsiveness Scale-2 (SRS-2), where higher scores denote more autistic-like behaviors. We measured BLLs and plasma total folate concentrations during the first and third trimesters of pregnancy. We also estimated gestational FA supplementation via surveys and genotyped the maternal MTHFR 677C>T single nucleotide polymorphism (SNP). We estimated the confounder-adjusted associations between log 2 -transformed BLLs and SRS-2 scores by two indicators of folate exposure and maternal MTHFR 677C>T genotype using linear regression., Results: Third-trimester BLLs were associated with increased SRS-2 scores [ β a d j = 3.3 ; 95% confidence interval (CI): 1.1, 5.5] among participants with low ( < 10 th percentile), third-trimester, plasma total folate concentrations, but BLL-SRS-2 associations were null ( β a d j = - 0.3 ; 95% CI: - 1.2 , 0.5) among those in the middle category ( ≥ 10 th and < 80 th percentiles) ( p -interaction < 0.001 ). FA supplementation also attenuated these associations. Both folate indicators modified first-trimester BLL-SRS-2 associations, but to a lesser extent. Third-trimester BLL-SRS-2 associations were slightly stronger among participants who were homozygous for the T (minor) allele of the MTHFR 677C>T SNP ( β a d j = 0.9 ; 95% CI: - 1.2 , 3.1) than those without the T allele ( β a d j = - 0.3 ; 95% CI: - 1.3 , 0.7), but the difference was not statistically significant ( p -interaction = 0.28 )., Discussion: Folate may modify the associations between gestational lead exposure and childhood autistic-like behaviors, suggesting that it mitigates the neurotoxic effects of prenatal lead exposure. https://doi.org/10.1289/EHP14479.

Background: Few high-quality studies have evaluated associations between urinary glyphosate or its environmental degradate (aminomethylphosphonic acid (AMPA)] and preterm birth (PTB)., Objectives: To quantify associations between urinary glyphosate and AMPA and preterm birth in the pan-Canadian Maternal-Infant Research on Environmental Chemicals (MIREC) study and determine if associations differ by fetal sex., Methods: We measured first trimester urinary glyphosate and AMPA concentrations in MIREC participants who were recruited between 2008-2011 from 10 Canadian cities. Of the 1880 participants whose first trimester urine samples were analyzed for glyphosate or AMPA, 1765 delivered a singleton, live birth. Our primary outcome was preterm birth (PTB) defined as births occurring between 20 and <37 weeks. Secondary outcomes were spontaneous preterm births (sPTB) and gestational age. We modelled the hazard of PTB and sPTB using discrete time survival analysis with multivariable logistic regression to calculate odds ratios (OR). We used multivariable linear regression models to quantify associations between analytes and gestational age. To assess effect modification by fetal sex, we stratified all models and calculated interaction terms. In the logistic regressions models we additionally calculated the relative excess risk due to interaction., Results: Six percent (n = 106) of the study population delivered preterm, and 4.7% (n = 83) had a spontaneous preterm birth. Median specific-gravity standardized concentrations of glyphosate and AMPA were 0.25 and 0.21 µg/L. Associations between both glyphosate or AMPA and PTB, sPTB, and gestational age centered around the null value. The adjusted ORs of PTB for each doubling of glyphosate and AMPA concentrations were 0.98 (95% CI: 0.94, 1.03) and 0.99 (95% CI: 0.92, 1.06) respectively. We observed no evidence of differences by fetal sex., Conclusions: In this Canadian pregnancy cohort, neither glyphosate nor AMPA urinary concentrations was associated with PTB or reduced gestational length., (© 2024. Crown.)

Background: PM 2.5, NO 2 , and O 3 contribute to the development of adverse pregnancy complications. While studies have investigated the independent effects of these exposures, literature on their combined effects is limited. Our objective was to study the multipollutant effects of PM 2.5 , NO 2 , and O 3 on maternal systemic C-reactive protein (CRP) levels., Methods: We used data from 1170 pregnant women enrolled in the Maternal-Infant Research on Environmental Chemicals Study (MIREC) study in Canada. Air pollution exposures were assigned to each participant based on residential location. CRP was measured in third-trimester blood samples. We fit multipollutant linear regression models and evaluated the effects of air pollutant mixtures (14-day averages) using repeated-holdout Weighted Quantile Sum (WQS) regression and by calculating the Air Quality Health Index (AQHI)., Results: In multipollutant models adjusting for NO 2, O 3 , and green space, each interquartile range (IQR) increase in 14-day average PM 2.5 (IQR: 6.9 µg/m 3 ) was associated with 27.1% (95% confidence interval [CI] = 6.2, 50.7) higher CRP. In air pollution mixture models adjusting for green space, each IQR increase in AQHI was associated with 37.7% (95% CI = 13.9, 66.5) higher CRP; and an IQR increase in the WQS index was associated with 78.6% (95% CI = 29.7, 146.0) higher CRP., Conclusion: PM 2.5 has the strongest relationship of the individual pollutants examined with maternal blood CRP concentrations. Mixtures incorporating all three pollutants, assessed using the AQHI and WQS index, showed stronger relationships with CRP compared with individual pollutants and illustrate the importance of conducting multipollutant analyses., Competing Interests: The authors declare that they have no conflicts of interest with regard to the content of this report., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The Environmental Epidemiology. All rights reserved.)

Objective: To study the association between maternal exposure to arsenic, cadmium, lead, manganese and mercury, time-to-pregnancy (TTP) and infertility., Design: Pregnancy-based retrospective TTP cohort study., Setting: Hospitals and clinics from ten cities across Canada., Population: A total of 1784 pregnant women., Methods: Concentrations of arsenic, cadmium, lead, manganese and mercury were measured in maternal whole blood during the first trimester of pregnancy as a proxy of preconception exposure. Discrete-time Cox proportional hazards models generated fecundability odds ratios (FOR) for the association between metals and TTP. Logistic regression generated odds ratios (OR) for the association between metals and infertility. Models were adjusted for maternal age, pre-pregnancy body mass index, education, income, recruitment site and plasma lipids., Main Outcome Measures: TTP was self-reported as the number of months of unprotected intercourse to become pregnant. Infertility was defined as TTP longer than 12 months., Results: A total of 1784 women were eligible for the analysis. Mean ± SD maternal age and gestational age at interview were 32.2 ± 5.0 years, and 11.6 ± 1.6 weeks, respectively. Exposure to arsenic, cadmium, manganese or mercury was not associated with TTP or infertility. Increments of one standard deviation of lead concentrations resulted in a shorter TTP (adjusted FOR 1.09, 95% CI 1.02-1.16); however, the association was not linear when exposure was modelled in tertiles., Conclusion: Blood concentrations of metals at typical levels of exposure among Canadian pregnant women were not associated with TTP or infertility. Further studies are needed to assess the role of lead, if any, on TTP., (© 2024 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

In 2022, approximately one out of six people globally experienced infertility at some point in their life. Environmental chemicals, particularly those with endocrine disrupting activity, may contribute to impaired fecundity and infertility. We review existing prospective cohort studies of environmental chemicals and fecundity, identify methodological challenges and biases, and outline future research priorities. Studies of preconception environmental chemical exposures and fecundity have occurred in US, Singapore, China and Denmark with recruitment as early as 1982-1986, as recent as 2015-2017 and sample sizes ranging from 99 to 936. Higher exposure to certain chemicals (e.g. heavy metals, perfluoroalkyl substances) was associated with longer time to pregnancy; yet the literature is scarce or nonexistent for many chemicals. Furthermore, prospective studies face challenges and potential biases related to recruiting participants prior to conception, measuring environmental chemicals during critical windows of exposure, and ascertaining when pregnancy occurred. Research priorities include expanding the scope of biomonitoring data collected during the preconception period, continuing to develop and validate analytic methods for self-sampled biospecimens in traditional and novel matrices, collecting data in male partners and investigating etiologic associations according to indicators of marginalization., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: To discuss the potential biological mechanisms between vitamin D and toxic metals and summarize epidemiological studies examining this association in pregnant women., Recent Findings: We identified four plausible mechanisms whereby vitamin D and toxic metals may interact: nephrotoxicity, intestinal absorption of metals, endocrine disruption, and oxidative stress. Few studies have examined the association between vitamin D and toxic metals in pregnant women. North American studies suggest that higher vitamin D status early in pregnancy are associated with lower blood metals later in pregnancy. However, a trial of vitamin D supplementation in a pregnant population, with higher metal exposures and lower overall nutritional status, does not corroborate these findings., Summary: Given ubiquitous exposure to many toxic metals, nutritional intervention could be a means for prevention of adverse outcomes. Future prospective studies are needed to establish a causal relationship and clarify the directionality of vitamin D and metals., Supplementary Information: The online version contains supplementary material available at 10.1007/s40471-024-00348-0., Competing Interests: Competing InterestsThe authors declare no competing interests or funding.Conflict of InterestWe acknowledge that one of the authors (AM Jukic) is a section editor of this journal, however they did not act as editor for this particular submission. All other authors declare that they have no conflict of interest., (© Crown 2024.)

Background: 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., Objectives: 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., Population: 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., Preliminary Results: 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)., Conclusions: 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., (© 2023 His Majesty the King in Right of Canada and The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd. Reproduced with the permission of the Minister of Health.)

Exposure assessment of inorganic arsenic is challenging due to the existence of multiple species, complexity of arsenic metabolism, and variety of exposure sources. Exposure assessment of arsenic during pregnancy is further complicated by the physiological changes that occur to support fetal growth. Given the well-established toxicity of inorganic arsenic at high concentrations, continued research into the potential health effects of low-level exposure on maternal and fetal health is necessary. Our objectives were to review the value of and challenges inherent in measuring inorganic arsenic species in pregnancy and highlight related research priorities. We discussed how the physiological changes of pregnancy influence arsenic metabolism and necessitate the need for pregnancy-specific data. We reviewed the biomonitoring challenges according to common and novel biological matrices and discussed how each matrix differs according to half-life, bioavailability, availability of laboratory methods, and interpretation within pregnancy. Exposure assessment in both established and novel matrices that accounts for the physiological changes of pregnancy and complexity of speciation is a research priority. Standardization of laboratory method for novel matrices will help address these data gaps. Research is particularly lacking in contemporary populations of pregnant women without naturally elevated arsenic drinking water concentrations (i.e. <10 µg/l)., (© 2022. Crown.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

Background: Prenatal and childhood mercury (Hg) exposures have been associated with negative impacts on child neurodevelopment. It is unclear if associations persist at the low Hg exposures typical in Western countries., Objective: To examine associations between prenatal/childhood blood Hg concentrations and child IQ in Canadian male and female children while considering the potential modifying role of prenatal fish consumption., Methods: We analyzed data from the Maternal-Infant Research on Environmental Chemicals study. Hg was measured in first trimester (n = 527), cord (n = 430), and child (at 3-4 years of age, n = 355) blood and examined sex-stratified associations between blood Hg and children's Full Scale IQ (FSIQ), Verbal IQ (VIQ), Performance IQ (PIQ), and General Language Composite (GLC) scores (assessed with WPPSI-III). Prenatal Hg analyses were further stratified by prenatal fish consumption (low: 0-2, moderate: 3-7, or high: ≥8 times/month)., Results: Higher cord blood Hg concentrations were associated with lower PIQ (ß = -3.27; 95%CI: 6.44, -0.09) in male children with the lowest prenatal fish consumption. Progressively stronger positive associations were observed with PIQ in male children for moderate (ß = 1.08; 95%CI: 0.10, 2.26) and high (ß = 3.07; 95%CI: 1.95, 4.19) prenatal fish consumption. Cord blood Hg concentrations were positively associated with female children's FSIQ (ß = 1.29; 95% CI: 0.77, 1.81) and PIQ (ß = 2.01; 95% CI: 1.19, 2.83); however, when stratified only in the highest fish consumption subgroup. Among female children, higher child blood Hg concentrations were associated with an approximately 1-point increase in FSIQ, VIQ, and GLC., Conclusions: Prenatal exposure to low levels of Hg was associated with lower PIQ scores in male children with low prenatal fish intake. Positive associations between cord and child blood Hg concentrations and IQ were primarily observed in female children and may be due to beneficial effects of prenatal fish intake., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Copyright His Majesty the King in Right of Canada, as represented by the Minister of Health, 2023. Published by Elsevier Inc. All rights reserved.)

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants that induce immunotoxicity in experimental studies; however, epidemiological evidence-particularly during pregnancy-is scarce. We quantified associations between first trimester plasma perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorohexane sulfonate (PFHxS) concentrations and third trimester concentrations of inflammatory biomarkers and determined if these associations were modified by fetal sex., Methods: We analyzed data from 1411 participants, recruited between 2008 and 2011, in the Maternal-Infant Research on Environmental Chemicals study. Our primary outcome was a composite inflammatory index derived by summing the z-scores of eight proinflammatory biomarkers. Using multivariable linear regression models, we quantified associations between each PFAS and the inflammatory index and individual biomarkers. We quantified the effects of the PFAS mixture using weighted quantile sum regression, and evaluated effect modification using product terms and sex-stratified models., Results: Each doubling of PFOA and PFHxS was associated with a 0.38 (95% CI, 0.09, 0.67) and 0.21 (95% CI, 0.01, 0.41) SD increase in the proinflammatory index, respectively. A one-quartile increase in the PFAS mixture was associated with a 0.40 (95% CI, 0.09, 0.71) SD increase in the proinflammatory index. In individual models, we observed positive associations between PFAS and concentrations of monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and matrix metalloproteinases-9; however, the magnitude and precision varied according to the specific PFAS. Sex-specific findings were identified in few PFAS-biomarker associations., Conclusions: PFOA, PFOS, and PFHxS, individually and as a mixture, were positively associated with proinflammatory biomarkers during pregnancy., Competing Interests: The authors declare that they have no conflicts of interest with regard to the content of this report. The MIREC Study was supported by Health Canada’s Chemicals Management Plan at Health Canada, the Ontario Ministry of the Environment, and the Canadian Institutes for Health Research (grant MOP-81285). This study was also supported by a 2022 Carleton University Research Achievement Award. Data ussed in this analysis are confidential and not available for distribution. Some analytical code may be provided upon request., (Copyright @ His Majesty the King in Right of Canada as represented by the Minister of Health, 2023. Published by Wolters Kluwer Health, Inc. on behalf of The Environmental Epidemiology. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

Background: Exposure 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., Objective: To 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., Methods: We 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., Results: Geometric 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., Conclusions: Higher prenatal PFAS exposure was associated with lower performance IQ in males, suggesting that this association may be sex- and domain-specific., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Background: Toxic metals, like lead, are risk factors for preterm birth (PTB), but few studies have examined low levels found in most Canadians. Vitamin D, which may have antioxidant activity, protects against PTB., Objectives: In this study, we investigated the impact of toxic metals (lead, mercury, cadmium and arsenic) on PTB and examined if maternal plasma vitamin D concentrations modify these associations., Methods: We investigated whether concentrations of metals in whole blood measured in early and late pregnancy were associated with PTB (<37 weeks) and spontaneous PTB in 1851 live births from the Maternal-Infant Research on Environmental Chemicals Study using discrete time survival analysis. We also investigated whether the risk of PTB was modified by first-trimester plasma 25-hydroxyvitamin D (25OHD) concentrations., Results: Of 1851 live births, 6.1% (n = 113) were PTBs and 4.9% (n = 89) were spontaneous PTB. A 1 μg/dL increase in blood lead concentrations during pregnancy was associated with an increased risk of PTB (relative risk [RR] 1.48, 95% confidence interval [CI] 1.00, 2.20) and spontaneous PTB (RR 1.71, 95% CI 1.13, 2.60). The risk was higher in women with insufficient vitamin D concentrations (25OHD <50 nmol/L) for both PTB (RR 2.42, 95% CI 1.01, 5.79) and spontaneous PTB (RR 3.04, 95% CI 1.15, 8.04). However, an interaction on the additive scale was not present. Arsenic was associated with a higher risk of PTB (RR 1.10, 95% CI 1.02, 1.19) and spontaneous PTB (RR 1.11, 95% CI 1.03, 1.20) per 1 μg/L., Conclusions: Gestational exposure to low levels of lead and arsenic may increase the risk of PTB and spontaneous PTB; individuals with insufficient vitamin D may be more susceptible to the adverse effects of lead. Given our relatively small number of cases, we encourage testing of this hypothesis in other cohorts, especially those with vitamin D-deficient populations., (© 2023 His Majesty the King in Right of Canada and The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd. Reproduced with the permission of the Minister of Health.)

Background: Toxic metals, such as lead (Pb), cadmium (Cd), arsenic (As), and mercury (Hg), may be associated with a higher risk of gestational hypertension and preeclampsia, whereas manganese (Mn) is an essential metal that may be protective., Objectives: We estimated the individual, independent, and joint associations of Pb, Cd, As, Hg, and Mn on the risk of developing gestational hypertension and preeclampsia in a cohort of Canadian women., Methods: Metal concentrations were analyzed in first and third trimester maternal blood ( n = 1,560 ). We measured blood pressure after 20 wk gestation to diagnose gestational hypertension, whereas proteinuria and other complications defined preeclampsia. We estimated individual and independent (adjusted for coexposure) relative risks (RRs) for each doubling of metal concentrations and examined interactions between toxic metals and Mn. We used quantile g-computation to estimate the joint effect of trimester-specific exposures., Results: Each doubling of third trimester Pb ( RR = 1.54 ; 95% CI: 1.06, 2.22) and first trimester blood As ( RR = 1.25 ; 95% CI: 1.01, 1.58) was independently associated with a higher risk of developing preeclampsia. First trimester blood As ( RR = 3.40 ; 95% CI: 1.40, 8.28) and Mn ( RR = 0.63 ; 95% CI: 0.42, 0.94) concentrations were associated with a higher and lower risk, respectively, of developing gestational hypertension. Mn modified the association with As such that the deleterious association with As was stronger at lower concentrations of Mn. First trimester urinary dimethylarsinic acid concentrations were not associated with gestational hypertension ( RR = 1.31 ; 95% CI: 0.60, 2.85) or preeclampsia ( RR = 0.92 ; 95% CI: 0.68, 1.24). We did not observe overall joint effects for blood metals., Discussion: Our results confirm that even low blood Pb concentrations are a risk factor for preeclampsia. Women with higher blood As concentrations combined with lower Mn in early pregnancy were more likely to develop gestational hypertension. These pregnancy complications impact maternal and neonatal health. Understanding the contribution of toxic metals and Mn is of public health importance. https://doi.org/10.1289/EHP10825.

Background: Glyphosate 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., Objectives: To identify determinants of urinary concentrations of these herbicides and their metabolites in pregnancy., Methods: We 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., Results: Among 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., Conclusions: We detected glyphosate and AMPA in the majority of pregnant women from this predominantly urban Canadian cohort. Diet was a probable route of exposure., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Warren G. Foster reports a relationship with Hollingsworth LLC that includes: paid expert testimony., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Gestational arsenic exposure adversely impacts child health. Folate-mediated 1-carbon metabolism facilitates urinary excretion of arsenic and may prevent arsenic-related adverse health outcomes. We investigated the potential for maternal folate status to modify associations between gestational arsenic exposure and child health. We used data from 364 mother-child pairs in the MIREC study, a prospective pan-Canadian cohort. During pregnancy, we measured first trimester urinary arsenic concentrations, plasma folate biomarkers, and folic acid supplementation intake. At age 3 years, we evaluated twelve neurodevelopmental and anthropometric features. Using latent profile analysis and multinomial regression, we developed phenotypic profiles of child health, estimated covariate-adjusted associations between arsenic and these phenotypic profiles, and evaluated whether folate status modified these associations. We identified three phenotypic profiles of neurodevelopment and three of anthropometry, ranging from less to more optimal child health. Gestational arsenic was associated with decreased odds of optimal neurodevelopment. Maternal folate status did not modify associations of arsenic with neurodevelopmental phenotypic profiles, but gestational arsenic was associated with increased odds of excess adiposity among those who exceed recommendations for folic acid (>1000 μg/day). However, arsenic exposure was low and folate status was high. Gestational arsenic exposure may adversely impact child neurodevelopment and anthropometry, and maternal folate status may not modify these associations; however, future work should examine these associations in more arsenic-exposed or lower folate-status populations.

Objectives: To measure heavy metal concentrations among Kenyan youth and quantify associations with sociocultural, demographic, and health factors as well as anthropometry., Methods: Using data from a study of semi-nomadic pastoralists in Samburu County, Kenya, we measured blood concentrations of lead (Pb), mercury (Hg), and cadmium (Cd) in 161 adolescents. We identified sociocultural, demographic and health characteristics associated with each metal and quantified the association between metals and adolescent anthropometry., Results: Median blood concentrations of Pb, Cd, and Hg were 1.82 µg/dL, 0.24 µg/L and 0.16 µg/L, respectively. Place of residence (highlands vs lowlands) was a determinant of metal concentrations. Hg was inversely related to anemia, and metals were not associated with anthropometry., Conclusions: In this population of Samburu adolescents, median Pb and Cd blood concentrations were higher than other North American or European biomonitoring studies. These findings motivate further investigation into the environmental sources of metals in this community.

Low 25-hydroxyvitamin D (25OHD), a biomarker of vitamin D status, is associated with reduced immune function and adverse pregnancy outcomes, such as preterm birth. Observational studies indicate that long-term, high level exposure to metals such as cadmium (Cd) and lead (Pb) can impact a person's vitamin D status. However, the directionality of the association is uncertain, particularly for low-level exposures. We used three distinct longitudinal data analysis methods to investigate cross-sectional, longitudinal and bidirectional relationships of Cd and Pb biomarkers with 25-hydroxyvitamin D (25OHD) in a Canadian pregnancy cohort. Maternal whole blood Cd and Pb and plasma 25OHD concentrations were measured in the 1st (n = 1905) and 3rd (n = 1649) trimester and at delivery (25OHD only, n = 1542). Our multivariable linear regression analysis showed weak inverse associations between Cd and 25OHD concentrations cross-sectionally and longitudinally while the latent growth curve models showed weak associations with Pb on the 25OHD intercept. In the bidirectional analysis, using cross lagged panel models, we found no association between 1st trimester metals and 3rd trimester 25OHD. Instead, 1st trimester 25OHD was associated with 9% (-15%, -3%) lower 3rd trimester Cd and 3% (-7, 0.1%) lower Pb. These findings suggest the 25OHD may modify metal concentrations in pregnancy and demonstrates the value of controlling for contemporaneous effects and the persistence of a biomarker over time, in order to rule out reverse causation., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Background: Bisphenol A (BPA) is typically measured in urine using an indirect method that involves enzymatic deconjugation and extraction. In contrast, the direct method measures free and conjugated BPA concurrently and sums them to estimate urinary BPA concentrations. Statistical comparison of total BPA results using the direct and indirect methods is necessary to accurately interpret biomonitoring data for risk assessments., Objectives: To compare urinary BPA concentrations estimated from the indirect and direct methods in duplicate first trimester urine samples collected from 1879 pregnant women from the MIREC Study., Methods: For the indirect method, we measured urinary BPA concentrations using GC-MS/MS. For the direct method, we summed free and conjugated BPA concentrations measured using LC-MS/MS. We evaluated deviation between the two methods using the Bland-Altman analysis in the total sample and stratified (1) by specific gravity and (2) at the limit of quantification (LOQ)., Results: Median urinary BPA concentrations for the direct and indirect methods were 0.89 µg BPA equivalents/L and 0.81 µg/L respectively. Concentrations from the direct method were, on average, 8.6% (95% CI: 6.7%, 10.5%) higher than the indirect method in a Bland-Altman analysis. The percent differences between the two methods was 4.0% in urines with specific gravities < 1.02 (n = 1348, 72%) and 20.3% in urine with specific gravity ≥ 1.02. In values below the LOQ (n = 663, 35%), we observed smaller average percent deviation (4.8%) between the two methods but wider limits of agreement., Discussion: Results from this study, based on the largest statistically rigorous comparison of the direct and indirect methods of BPA measurement, contrast previous findings reporting that the indirect method underestimates total BPA exposure. The difference in urinary BPA concentrations we observed with the indirect and direct methods is unlikely to alter the interpretation of health outcome data., (Copyright © 2021. Published by Elsevier Ltd.)

Research Question: How do anti-Müllerian hormone (AMH) concentrations in women with and without arthritis compare? Is there an association between AMH and arthritis drug regimen?, Design: In this prospective cohort study, AMH was measured at two time points (T 0 and T 1 ) in 129 premenopausal women with arthritis. AMH at T 0 was compared with that from a bank of serum samples from 198 premenopausal women without arthritis. Primary outcomes were: (i) diminished ovarian reserve (DOR) (AMH <1.1 ng/ml) and (ii) annual rate of AMH decrease. Univariate, multivariable and Firth logistic regression identified variables associated with annual AMH decrease in excess of the 75th percentile., Results: Median time between T 0 and T 1 was 1.72 years. At time T 0 , median age-adjusted AMH in women with arthritis was significantly lower than that of women without arthritis (median 2.21 ng/ml versus 2.78 ng/ml; P = 0.009). Women with arthritis at highest risk for DOR had a history of tubal sterilization or were over the age of 35. Those with highest odds of having an annual AMH decrease in excess of the 75th percentile (over 28% decrease per year) were those: over the age of 35 or who sought care for infertility. Women with arthritis taking methotrexate alone (OR 0.08, 95% CI 0.01-0.67) or methotrexate plus tumour necrosis factor-alpha antagonists (OR 0.13, 95% CI 0.02-0.89) were less likely to be in the highest quartile of annual AMH decrease than women with arthritis not taking medication., Conclusions: Women with arthritis had lower AMH than healthy controls. Long-term methotrexate use was not associated with an annual AMH decrease., (Copyright © 2021 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Childhood exposure to phthalates, a class of chemicals with known reproductive and developmental effects, has been hypothesized to increase the risk of obesity, but this association is not well understood in preschool children. We examined the association between urinary concentrations of phthalate metabolites and concurrently measured body mass index (BMI) and skinfolds among children between the ages of two and five years. We collected anthropometric measures and biomonitoring data on approximately 200 children enrolled in the Maternal-Infant Research on Environmental Chemicals Child Development Plus study. We measured 22 phthalate metabolites in children's urine and used the 19 metabolites detected in at least 40% of samples. Our primary outcome was BMI z-scores calculated using the World Health Organization growth standards. Skinfold z-scores were secondary outcomes. We used multivariable linear regression to evaluate the association between tertiles of phthalate concentrations and each anthropometric measure. We also used weighted quantile sum regression to identify priority exposures of concern. Our analytic sample included 189 singleton-born children with complete anthropometric data. Children with concentrations of the parent compound di-n-butyl phthalate (∑DnBP) in the third tertile had 0.475 (95% CI: 0.068, 0.883) higher BMI z-scores than those in the lower tertile. ∑DnBP was identified as a priority exposure in the weighted quantile sum regression BMI model. In this population of Canadian preschool aged children, we identified DnBP as a potential chemical of concern in regard to childhood obesity. Future research with serial phthalate measurements and anthropometric measurements in young children will help confirm these findings., (Crown Copyright © 2021. Published by Elsevier GmbH. All rights reserved.)

Our objective was to determine if maternal first trimester urinary phthalate concentrations are associated with reduced penile length (PL) or width (PW) at birth in full term singletons. First trimester phthalate metabolite urinary concentrations were obtained from mothers participating in a Canadian pregnancy cohort study (MIREC). PL and PW were measured shortly after birth in the male offspring. Univariate and multivariable linear regressions were performed to study associations between maternal phthalate exposure and penile measurements, adjusting for confounders. On univariate analysis of 170 mother-infant pairs, PW showed an inverse relationship with the concentration of mono-3-carboxypropyl phthalate (MCPP-p = 0.016), which was not confirmed on multivariable analysis. On multivariable analysis controlling for infant's size and other confounders, no statistically signficant associations between phthalate metabolite concentrations and PL or PW were identified. In this population of Canadian women, there was no strong evidence to suggest an association between maternal first trimester urinary phthalates with PL or PW in term singletons., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

The objective of the present study was to examine the association between birth by Caesarean section (CS) and otitis media (OM) in childhood. We assembled a retrospective cohort of children born between 2003 and 2007 in Nova Scotia and followed them through to 2014. The cohort was derived through a linkage of the Nova Scotia Atlee Perinatal Database with provincial administrative health data. Cox proportional hazards, negative binomial regression and logistic regression were used to examine the association between CS and OM. Among the 36,318 children, 27% were born by CS, and 78% had at least one OM episode (median 2 episodes). Children born by CS were at a slightly higher risk of OM (hazard ratio 1.06, 95% confidence interval (CI) 1.03, 1.09), had more OM episodes in the first 7 years of life (incidence rate ratio 1.04, 95% CI 1.01, 1.07), and were more likely to be above the 95th percentile for OM episodes than children born vaginally (odds ratio 1.10, 95% CI 0.99, 1.23). Our study shows that birth by CS is weakly associated with OM in childhood, but the clinical and public health impact of these findings is small.

Background: The negative impact of exposures such as maternal obesity, excessive gestational weight gain, and hypertension in pregnancy on the health of the next generation has been well studied. Evidence from animal studies suggests that the effects of in utero exposures may persist into the second generation, but the epidemiological literature on the influence of pregnancy-related exposures across three generations in humans is sparse., Objectives: This cohort was established to investigate associations between antenatal and perinatal exposures and health outcomes in women and their offspring., Population: The cohort includes women who were born and subsequently had their own pregnancies in the Canadian province of Nova Scotia from 1980 onward., Design: Intergenerational linkage of data in the Nova Scotia Atlee Perinatal Database was used to establish a population-based dynamic retrospective cohort., Methods: The cohort has prospectively collected information on sociodemographics, maternal health and health behaviours, pregnancy health and complications, and obstetrical and neonatal outcomes for two generations of women and their offspring., Preliminary Results: As of October 2018, the 3G cohort included 14 978 grandmothers (born 1939-1986), 16 766 mothers or cohort women (born 1981-2003), and 28 638 children (born 1996-2018). The cohort women were generally younger than Nova Scotian women born after 1980, and as a result, characteristics associated with pregnancy at a younger age were more frequently seen in the cohort women; sampling weights will be created to account for this design effect. The cohort will be updated annually to capture future deliveries to women who are already in the cohort and women who become eligible for inclusion when they deliver their first child., Conclusions: The 3G Multigenerational Cohort is a population-based cohort of women and their mothers and offspring, spanning a time period of 38 years, and provides the opportunity to study inter- and transgenerational associations across the maternal line., (© 2020 John Wiley & Sons Ltd.)

Background: Though the physiological roles of adipokines in metabolism, insulin resistance and satiety are clear, literature regarding associations between cord blood adipokine levels and childhood adiposity is equivocal., Objectives: To determine whether cord blood levels of leptin and adiponectin are associated with adiposity in children 2 to 5 years of age, and whether such associations are modified by sex., Methods: Leptin and adiponectin levels were measured in cord blood and anthropometric measures were completed on 550 children enrolled in the Maternal-Infant Research on Environmental Chemicals Child Development Plus study (MIREC-CD Plus). We used multivariable linear and Poisson regression models to determine associations between cord blood adipokine levels and child body mass index (BMI), triceps and subscapular skinfold thickness and risk of overweight/obesity and to assess effect modification by child sex., Results: Cord blood adiponectin was significantly associated with modest increases in BMI and the sum of triceps and subscapular skinfold z-scores in boys but not girls. A doubling of adiponectin levels was associated with a 30% increased risk of overweight/obesity in boys (RR = 1.30; 95% CI: 1.02, 1.64). Leptin was not associated with anthropometric measures in either sex., Conclusions: The observed associations between adiponectin and adiposity in boys were statistically significant, of moderate magnitude, and underscore the value of considering sex-specific patterns., (© 2019 Her Majesty the Queen in Right of Canada Pediatric Obesity © 2019 World Obesity Federation.)

Fetal exposure to some toxic metals has been associated with reduced fetal growth, but the impact of contemporary, low-level metals on anthropometric measures in childhood is not well understood. Our primary objective was to quantify associations between childhood levels of toxic metals and concurrently measured body mass index (BMI) in a population of Canadian preschool-aged children. We collected biomonitoring data and anthropometric measures on 480 children between the ages of two and five years in the Maternal-Infant Research on Environmental Chemicals (MIREC) Child Development Plus study. Concentrations of four toxic metals (lead, arsenic, cadmium, and mercury) were measured in whole blood collected from pregnant women and their children. Blood levels of key essential elements were also measured in children. Children's weight, height, and BMI z-scores were calculated using the World Health Organization growth standards. We used a series of linear regression models, adjusted for potential parental confounders, concurrently measured metals and elements, and prenatal blood metal levels, to evaluate associations between tertiles of each toxic metal and anthropometric measures. We tested for effect modification by sex. Of the 480 children, 449 (94%) were singleton births and had complete biomonitoring and anthropometric data. The majority of children had detectable concentrations of metals. In the adjusted models, girls with blood lead concentrations in the highest tertile (>0.82 μg/dL) had, on average, 0.26 (95% Cl: -0.55, 0.03) lower BMI z-scores than those in the referent category. In contrast, boys with lead levels in the highest tertile had, on average, 0.14 higher BMI z-scores (95% Cl: -0.14, 0.41) (p-value heterogeneity = 0.04). In this population of Canadian preschool-aged children with low-level blood lead concentrations, we observed effect modification by sex in the association between Pb and BMI but no statistically significant associations in the sex-specific strata. Child blood levels of As, Cd, and Hg were not associated with childhood BMI, weight, or height in boys or girls., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Objective: To model the development of the tri-ponderal mass index (TMI, kg/m 3 ) throughout childhood and adolescence and to compare the utility of the TMI with that of the body mass index (BMI, kg/m 2 ) to predict cardiometabolic risk in a population-based sample of Canadian children and youth., Methods: We used data from the Canadian Health Measures Survey to model TMI from 6 to 19 years of age. Percentile curves were developed using the LMS method. Logistic regression was used to predict abnormal levels of cardiometabolic markers; predictive accuracy was assessed using the area under the ROC curve (AUC)., Results: Mean TMI was relatively stable from ages 6 to 19 years for both sexes, but variability increased with age. There was no notable difference in AUC values for prediction models based on BMI z-score compared with TMI for any of the outcomes. For both BMI z-score and TMI, prediction accuracy was good for homeostasis model assessment insulin resistance and having ≥3 abnormal tests (AUC>0.80), fair for C-reactive protein and poor for the remainder of the outcomes., Conclusions: The use of a single sex-specific TMI cut-off for overweight or obesity is hampered by the increasing variability of the measure with age. Weight-for-height indices likely have only limited ability to predict cardiometabolic marker levels, and changing the scaling power of height is unlikely to improve predictive accuracy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Epidemiological and toxicological evidence suggests that maternal total arsenic (As) levels are associated with an elevated risk of gestational diabetes (GDM). Uncertainty remains regarding the metabolic toxicity of specific arsenic species, comprised of both organic and inorganic sources of arsenic exposure., Objectives: We assessed associations between speciated As and GDM using data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study., Methods: Concentrations of speciated As [(inorganic (trivalent, pentavalent)), methylated arsenic species metabolites (monomethylarsonic acid (MMA), dimethylarsinic acid (DMA)), and organic (arsenobetaine)] were measured in first trimester maternal urine samples. GDM cases were identified in accordance with Canadian guidelines. Multivariable regression models were used to estimate associations between speciated As and GDM, evaluate potential interaction between speciated As exposures, and assess fetal sex-specific findings., Results: Among 1243 women who had a live, singleton birth and no previous history of diabetes, 4% met the diagnostic criteria for GDM. Our analyses focused on DMA and arsenobetaine as these were the subtypes with detectable concentrations in at least 40% of samples. Compared to women in the lowest tertile of DMA (<1.49 μg As/L), women with concentrations exceeding 3.52 μg As/L (3rd tertile) experienced an increased risk of GDM (aOR = 3.86; 95% CI: 1.18, 12.57) (p-value for trend across tertiles = 0.04). When restricted to women carrying male infants, the magnitude of this association increased (aOR 3rd tertile = 4.71; 95% CI: 1.05, 21.10)., Conclusions: These results suggest a positive relation between DMA and GDM; potential differences in risk by fetal sex requires further investigation., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

Epidemiological studies have hypothesized that both insufficient and excess blood manganese (Mn) levels during pregnancy are associated with reduced fetal growth. This literature is characterized by inconsistent results and a limited focus on women with exposures representative of the general North American population. We examined the relationship between maternal and cord blood Mn levels and fetal growth among women enrolled in the Maternal-Infant Research on Environmental Chemicals Study (MIREC). Mothers with singleton, term infants and complete maternal first and third trimester blood Mn data were eligible for inclusion in the present study (n = 1519). Mean birth weight and odds ratios of small for gestational age (SGA) births according to maternal and cord blood Mn levels (low (<10), referent (10-<90), high (≥90) percentiles) were estimated. We also evaluated the association between the ratio of cord and maternal blood Mn and birth weight. Women with low (<0.82 μg/dL) maternal blood third trimester Mn levels had infants that weighed an average of 64.7 g (95% CI: -142.3,12.8) less than infants born to women in the referent exposure group. This association was strengthened and became statistically significant when adjusted for toxic metals (lead, mercury, arsenic, and cadmium) [-83.3 g (95% CI: -162.4, -4.1)]. No statistically significant associations were observed in models of maternal first trimester or cord blood Mn. A one unit increase in the cord/maternal blood Mn ratio was associated with a 29.4 g (95% CI: -50.2, -8.7), when adjusted for maternal and neonatal characteristics. Our findings motivate additional research regarding the relation between Mn exposure and fetal growth. Further inquiry is necessary to determine whether an exposure threshold exists, how growth related effects of maternal and fetal Mn may differ, and how concurrent exposure to other toxic metals may impact the association between Mn and growth., (Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Triclosan is a phenolic biocide used in a multitude of consumer products and in health care settings. It is widely detected in the American and Canadian populations and has been shown in animal models to act as an endocrine disrupting agent. However, there has been little examination to date of the effects of triclosan exposure in pregnancy on perinatal metabolic outcomes in human populations., Methods: Using data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a Canadian pregnancy cohort, we measured associations of first-trimester urinary triclosan concentrations with total gestational weight gain, gestational diabetes mellitus and impaired glucose tolerance in pregnancy, and fetal markers of metabolic function. Leptin and adiponectin were measured in plasma from umbilical cord blood samples in term neonates and categorized into low (< 10th percentile), intermediate (10th-90th percentile) and high (> 90th percentile) levels. Triclosan concentrations were grouped into quartiles and associations with study outcomes were examined using logistic regression models with adjustment for maternal age, race/ethnicity, pre-pregnancy BMI, education and urinary specific gravity. Restricted cubic spline analysis was performed to help assess linearity and shape of any dose-response relationships. All analyses for leptin and adiponectin levels were performed on the entire cohort as well as stratified by fetal sex., Results: Triclosan measures were available for 1795 MIREC participants with a live born singleton birth. Regression analyses showed a non-significant inverse association between triclosan concentrations and leptin levels above the 90th percentile that was restricted to female fetuses (OR for highest quartile of triclosan compared to lowest quartile = 0.4 (95% CI 0.2-1.1), p-value for trend across quartiles = 0.02). Triclosan concentrations in the second quartile were associated with elevated odds of adiponectin below the 10th percentile in male fetuses (OR for Q2 compared to Q1 = 2.5, 95% CI 1.1-5.9, p-value for trend across quartiles = 0.93). No significant linear associations between triclosan concentrations and leptin or adiponectin levels in overall or sex-specific analyses were observed from restricted cubic spline analyses. No significant associations were observed in adjusted analyses between triclosan concentrations and gestational diabetes mellitus, impaired glucose tolerance or gestational weight gain., Conclusions: This study does not support an association between triclosan concentrations in pregnancy and fetal metabolic markers, glucose disorders of pregnancy, or excessive gestational weight gain., (Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.)

Study Objective: To examine the association between gestational weight gain (GWG) and interpregnancy weight change (IPWC) in adolescent mothers (younger than 20 years), and to determine if this association differs from adult women (aged 20-35 years)., Design: Retrospective cohort study., Setting and Participants: We included 3055 adolescents and 17,090 adult women with singleton pregnancies recorded in the Nova Scotia Atlee Perinatal Database with a subsequent pregnancy occurring between 2003 and 2014., Interventions and Main Outcome Measures: GWG in the first pregnancy was categorized as below, within, or above the current Institute of Medicine recommendations. IPWC was defined as the difference between the prepregnancy weights of the 2 pregnancies. Analyses were adjusted for parity, body mass index in the first pregnancy, and time between pregnancies., Results: Relative to adolescents with GWG within the recommendations, those who gained below had a 2.7 kg (95% confidence interval [CI], 1.4-3.9) lower mean IPWC whereas those who gained above had a 4.2 kg (95% CI, 3.3-5.1) higher mean IPWC. Smaller differences in IPWC between GWG categories were observed in adult women; relative to those with GWG within the recommendations, adults who gained below had a 1.3 kg (95% CI, 0.9-1.7) lower mean IPWC and those who gained above had a 2.9 kg (95% CI, 2.6-3.2) higher mean IPWC., Conclusion: Mean IPWC differed across GWG categories and the differences were greater in adolescents than in adult women. This difference should be considered when assessing whether specific GWG recommendations are needed for adolescents., (Copyright © 2017 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Perfluoroalkyl substances (PFAS) are ubiquitous, persistent chemicals that have been widely used in the production of common household and consumer goods for their nonflammable, lipophobic, and hydrophobic properties. Inverse associations between maternal or umbilical cord blood concentrations of perfluorooctanoic acid and perfluorooctanesulfonate and birth weight have been identified. This literature has primarily examined each PFAS individually without consideration of the potential influence of correlated exposures. Further, the association between PFAS exposures and indicators of metabolic function (i.e., leptin and adiponectin) has received limited attention. We examined associations between first-trimester maternal plasma PFAS concentrations and birth weight and cord blood concentrations of leptin and adiponectin using data on 1,705 mother-infant pairs from the Maternal Infant Research on Environmental Chemicals (MIREC) Study, a trans-Canada birth cohort study that recruited women between 2008 and 2011. Bayesian hierarchical models were used to quantify associations and calculate credible intervals. Maternal perfluorooctanoic acid concentrations were inversely associated with birth weight z score, though the null value was included in all credible intervals (log10 β = −0.10, 95% credible interval: −0.34, 0.13). All associations between maternal PFAS concentrations and cord blood adipocytokine concentrations were of small magnitude and centered around the null value. Follow-up in a cohort of children is required to determine how the observed associations manifest in childhood.

Objectives: We aimed to determine whether average and trimester-specific exposures to ambient measures of nitrogen dioxide (NO2) and particular matter (PM2.5) were associated with elevated cord blood concentrations of immunoglobulin E (IgE) and two epithelial cell produced cytokines: interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP)., Methods: This study utilized data and biospecimens from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study. There were 2001 pregnant women recruited between 2008 and 2011 from 10 Canadian cities. Maternal exposure to NO2 and PM2.5 was estimated using land use regression and satellite-derived models., Results: We observed statistically significant associations between maternal NO2 exposure and elevated cord blood concentrations of both IL-33 and TSLP among girls but not boys., Conclusions: Maternal NO2 exposure may impact the development of the newborn immune system as measured by cord blood concentrations of two cytokines.

Background. Skinfold thickness (SFT) measurements are a reliable and feasible method for assessing body fat in children but their use and interpretation is hindered by the scarcity of reference values in representative populations of children. The objective of the present study was to develop age- and sex-specific percentile curves for five SFT measures (biceps, triceps, subscapular, suprailiac, medial calf) in a representative population of Canadian children and youth. Methods. We analyzed data from 3,938 children and adolescents between 6 and 19 years of age who participated in the Canadian Health Measures Survey cycles 1 (2007/2009) and 2 (2009/2011). Standardized procedures were used to measure SFT. Age- and sex-specific centiles for SFT were calculated using the GAMLSS method. Results. Percentile curves were materially different in absolute value and shape for boys and girls. Percentile girls in girls steadily increased with age whereas percentile curves in boys were characterized by a pubertal centered peak. Conclusions. The current study has presented for the first time percentile curves for five SFT measures in a representative sample of Canadian children and youth.

Iron, vitamin D, and calcium intakes in the prenatal period are important determinants of maternal and fetal health. The objective of this study was to examine iron, vitamin D, and calcium intakes from diet and supplements in relation to maternal characteristics. Data were collected in a subsample of 1186 pregnant women from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a cohort study including pregnant women recruited from 10 Canadian sites between 2008 and 2011. A food frequency questionnaire was administered to obtain rankings of iron, calcium, and vitamin D intake (16-21 weeks of pregnancy). Intakes from supplements were obtained from a separate questionnaire (6-13 weeks of pregnancy). Women were divided into 2 groups according to the median total intake of each nutrient. Supplement intake was an important contributor to total iron intake (median 74%, interquartile range (IQR) 0%-81%) and total vitamin D intake (median 60%, IQR 0%-73%), while the opposite was observed for calcium (median 18%, IQR 0%-27%). Being born outside of Canada was significantly associated with lower total intakes of iron, vitamin D, and calcium (p ≤ 0.01 for all). Consistent positive indicators of supplement use (iron, vitamin D, and calcium) were maternal age over 30 years and holding a university degree. In conclusion, among Canadian women, the probability of having lower iron, vitamin D, and calcium intakes is higher among those born outside Canada; supplement intake is a major contributor to total iron and vitamin D intakes; and higher education level and age over 30 years are associated with supplement intake.

Triclosan is widely used as an antimicrobial agent and preservative that has been hypothesized to play a role in asthma and allergic disease. The limited body of literature regarding the allergenicity of triclosan has not evaluated prenatal exposure and subsequent potential effects on the developing immune system. The objective of the present study was to determine the association between prenatal urinary triclosan concentrations and cord blood immune system biomarker concentrations. Umbilical cord blood samples were obtained from the Maternal-Infant Research on Environmental Chemicals (MIREC) Biobank and were tested for three immune system biomarkers: immunoglobulin E (IgE), thymic stromal lymphopoietin (TSLP), and interleukin-33 (IL-33). Triclosan concentrations were measured in urine at 6-13 weeks gestation. No statistically significant associations were observed between prenatal triclosan concentrations and elevated concentrations of any immune system biomarker (n=1219 participants). Longitudinal studies are necessary to determine how the observed findings at birth translate into childhood., (Copyright © 2016 The Authors. Published by Elsevier GmbH.. All rights reserved.)