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Context: Maternal oxidative stress in pregnancy can arise through a multitude of sources and may have lifelong consequences for the child. Animal studies suggest that prenatal oxidative stress may contribute to metabolic dysfunction and excessive weight gain in the offspring. However, this relationship has been studied minimally in humans., Objective: Determine the association between prenatal oxidative stress biomarkers and child weight and body mass index (BMI) z-scores from birth to age 6., Methods: Within The Infant Development and the Environment Study (TIDES) prospective pregnancy cohort, we calculated age- and sex-specific Z-scores for child weight and BMI, measured between birth and age 6 (N = 736). Three oxidative stress biomarkers were quantified in third-trimester urine, including 8-iso-prostaglandin F2α (8-iso-PGF2α), its primary metabolite, and prostaglandin F2α (PGF2α). We examined associations between each biomarker and Z-scores using linear regression as well as group-based trajectory modeling., Results: Prenatal 8-iso-PGF2α and its metabolite were associated with lower birth weight and higher weight at age 4. For example, an ln-unit increase in 8-iso-PGF2α was associated with 0.17 SD higher weight at age 4 (95% CI 0.01, 0.33). These biomarkers were also associated with higher BMI at age 4. Finally, within 4 unique weight trajectories (low, normal, high, and low-high), children of mothers with higher 8-iso-PGF2α were 2.56 times more likely (95% CI 1.22, 5.41) to be in the low-high trajectory than children in the normal group., Conclusion: We observed associations between third-trimester oxidative stress and lower birth weight as well as higher early childhood weight and BMI. These findings have important implications for understanding the developmental origins of childhood weight gain and metabolic disease., (Published by Oxford University Press on behalf of the Endocrine Society 2021.)

Background: Inflammation during pregnancy is hypothesized to influence fetal growth. Eicosanoids, an important class of lipid mediators derived from polyunsaturated fatty acids, can act as both direct influences and biomarkers of inflammation through a variety of biological pathways. However, quantifying these distinct inflammatory pathways has proven difficult. We aimed to characterize a comprehensive panel of plasma eicosanoids longitudinally across gestation in pregnant women and to determine whether levels differed by infant size at delivery., Methods and Findings: Our data come from a case-control study of 90 pregnant women nested within the LIFECODES prospective birth cohort study conducted at Brigham and Women's Hospital in Boston, Massachusetts. This study included 31 women who delivered small for gestational age (SGA) babies (SGA, ≤10th percentile), 28 who delivered large for gestational age (LGA) babies (≥90th percentile), and 31 who delivered appropriate for gestational age (AGA) babies (controls, >10th to <90th percentile). All deliveries occurred between 2010 and 2017. Most participants were in their early 30s (median age: 33 years), of white (60%) or black (20%) race/ethnicity, and of normal pre-pregnancy BMI (median BMI: 23.5 kg/m2). Women provided non-fasting plasma samples during 3 prenatal study visits (at median 11, 25, and 35 weeks gestation) and were analyzed for a panel of eicosanoids. Eicosanoids were grouped by biosynthetic pathway, defined by (1) the fatty acid precursor, including linoleic acid (LA), arachidonic acid (AA), docosahexaenoic acid (DHA), or eicosapentaenoic acid (EPA), and (2) the enzyme group, including cyclooxygenase (COX), lipoxygenase (LOX), or cytochrome P450 (CYP). Additionally, the concentrations of the 4 fatty acids (LA, AA, DHA, and EPA) were measured in maternal plasma. Analytes represent lipids from non-esterified plasma. We examined correlations among eicosanoids and trajectories across pregnancy. Differences in longitudinal concentrations between case groups were examined using Bayesian linear mixed effects models, which included participant-specific random intercepts and penalized splines on gestational age. Results showed maternal plasma levels of eicosanoids and fatty acids generally followed U-shaped curve patterns across gestation. Bayesian models showed that associations between eicosanoids and case status varied by biosynthetic pathway. Eicosanoids derived from AA via the CYP and LOX biosynthetic pathways were positively associated with SGA. The adjusted mean concentration of 12-HETE, a LOX pathway product, was 56.2% higher (95% credible interval 6.6%, 119.1%) among SGA cases compared to AGA controls. Eicosanoid associations with LGA were mostly null, but negative associations were observed with eicosanoids derived from AA by LOX enzymes. The fatty acid precursors had estimated mean concentrations 41%-97% higher among SGA cases and 33%-39% lower among LGA cases compared to controls. Primary limitations of the study included the inability to explore the potential periods of susceptibility of eicosanoids on infant size due to limited sample size, along with the use of infant size at delivery instead of longitudinal ultrasound measures to estimate fetal growth., Conclusions: In this nested case-control study, we found that eicosanoids and fatty acids systematically change in maternal plasma over pregnancy. Eicosanoids from specific inflammation-related pathways were higher in mothers of SGA cases and mostly similar in mothers of LGA cases compared to controls. These findings can provide deeper insight into etiologic mechanisms of abnormal fetal growth outcomes., Competing Interests: The authors have declared that no competing interests exist.

Background: Preterm birth is a global public health issue and rates in Puerto Rico are consistently among the highest in the USA. Exposures to environmental contaminants might be a contributing factor., Methods: In a preliminary analysis from the Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) cohort (n = 1090), we investigated the association between urinary phthalate metabolite concentrations measured at three study visits (targeted at 20, 24, and 28 weeks of gestation) individually and averaged over pregnancy with gestational age at delivery and preterm birth. We additionally assessed differences in associations by study visit and among preterm births with a spontaneous delivery., Results: Compared to women in the general USA population, urinary concentrations of metabolites of di-n-butyl phthalate (DBP) and di-isobutyl phthalate (DiBP) were higher among pregnant women in Puerto Rico. Interquartile range (IQR) increases in pregnancy-averages of urinary metabolites of DBP and DiBP were associated with shorter duration of gestation and increased odds of preterm birth. An IQR increase in mono-n-butyl phthalate (MBP), a metabolite of DBP, was associated with 1.55 days shorter gestation (95% confidence interval [CI] = -2.68, -0.42) and an odds ratio (OR) of 1.42 (95% confidence interval [CI]: 1.07, 1.88) for preterm birth. An IQR increase in mono-isobutyl phthalate (MiBP), a metabolite of DiBP, was associated with 1.16 days shorter gestation (95% CI = -2.25, -0.08) and an OR of 1.32 (95% CI: 1.02, 1.71) for preterm birth. Associations were greatest in magnitude for urinary concentrations measured at the second study visit (median 23 weeks gestation). DiBP metabolite associations were greatest in magnitude in models of spontaneous preterm birth. No associations were detected with other phthalate metabolites, including those of di-2-ethylhexyl phthalate., Conclusion: Among pregnant women in the PROTECT cohort, DBP and DiBP metabolites were associated with increased odds of preterm birth. These exposures may be contributing to elevated rates of preterm birth observed in Puerto Rico., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Prenatal exposure to some phenols and parabens has been associated with adverse birth outcomes. Hormones may play an intermediate role between phenols and adverse outcomes. We examined the associations of phenol and paraben exposures with maternal reproductive and thyroid hormones in 602 pregnant women in Puerto Rico. Urinary triclocarban, phenol and paraben biomarkers, and serum hormones (estriol, progesterone, testosterone, sex-hormone-binding globulin (SHBG), corticotropin-releasing hormone (CRH), total triiodothyronine (T3), total thyroxine (T4), free thyroxine (FT4) and thyroid-stimulating hormone (TSH)) were measured at two visits during pregnancy., Methods: Linear mixed models with a random intercept were constructed to examine the associations between hormones and urinary biomarkers. Results were additionally stratified by study visit. Results were transformed to hormone percent changes for an inter-quartile-range difference in exposure biomarker concentrations (%Δ)., Results: Bisphenol-S was associated with a decrease in CRH [(%Δ -11.35; 95% CI: -18.71, - 3.33), and bisphenol-F was associated with an increase in FT4 (%Δ: 2.76; 95% CI: 0.29, 5.22). Butyl-, methyl- and propylparaben were associated with decreases in SHBG [(%Δ: -5.27; 95% CI: -9.4, - 1.14); (%Δ: -3.53; 95% CI: -7.37, 0.31); (%Δ: -3.74; 95% CI: -7.76, 0.27)]. Triclocarban was positively associated with T3 (%Δ: 4.08; 95% CI: 1.18, 6.98) and T3/T4 ratio (%Δ: 4.67; 95% CI: -1.37, 6.65), and suggestively negatively associated with TSH (%Δ: -10.12; 95% CI: -19.47, 0.32). There was evidence of susceptible windows of vulnerability for some associations. At 24-28 weeks gestation, there was a positive association between 2,4-dichlorophenol and CRH (%Δ: 9.66; 95% CI: 0.67, 19.45) and between triclosan and estriol (%Δ: 13.17; 95% CI: 2.34, 25.2); and a negative association between triclocarban and SHBG (%Δ: -9.71; 95% CI:-19.1, - 0.27) and between bisphenol A and testosterone (%Δ: -17.37; 95% CI: -26.7, - 6.87)., Conclusion: Phenols and parabens are associated with hormone levels during pregnancy. Further studies are required to substantiate these findings.

Environmental phenols are used commonly in personal care products and exposure is widespread in pregnant women. In this study, we sought to assess the association between maternal urinary phenol concentrations in pregnancy and fetal growth. The study population included 476 mothers who participated in the prospective LIFECODES birth cohort between 2006 and 2008 at Brigham and Women's Hospital in Boston, Massachusetts, USA. Dichlorophenols (DCPs), benzophenone-3, parabens, triclosan, triclocarban, and bisphenol-S were measured in urine from three time points during pregnancy and averaged. Outcome measures were all standardized to create gestational-age specific z-scores and included: 1) birth weight; 2) ultrasound parameters measured at up to two time points in pregnancy (head and abdominal circumference and femur length); and 3) ultrasound estimates of fetal weight from two time points in combination with birth weight. Models were stratified to investigate sex differences. Inverse associations were observed between average 2,4- and 2,5-DCP concentrations and birth weight z-scores in males. For example, an interquartile range difference in 2,4-DCP was associated with a 0.18 standard deviation decrease in birth weight z-score (95% confidence interval [CI]=-0.33, -0.02). These associations were observed in models that included repeated ultrasound estimates of fetal weight during gestation as well. Also in males, we noted inverse associations between average triclosan exposure over pregnancy and estimated fetal weight combined with birth weight in repeated measures models. For females, associations were generally null. However, mothers with a detectable concentration of bisphenol-S at any of the study visits had lower weight females. In conclusion, we observed inverse associations between indicators of maternal phenol exposure during pregnancy and fetal growth, with several differences observed by sex., (Published by Elsevier Ltd.)

Background: Maternal supply of thyroid hormones during pregnancy serves a critical role in fetal development. Although animal and in vitro studies provide evidence for thyroid hormone disruption as a result of bisphenol A (BPA) exposure, there is still a lack of evidence in human studies, particularly in the context of pregnancy., Objectives: We aimed to explore the associations between urinary BPA concentrations and plasma thyroid hormone parameters during gestation in pregnant women, and also investigated potential windows of vulnerability during gestation., Methods: Our study population included 116 cases of preterm birth and 323 controls from a nested case-control study. We measured BPA in urine and thyroid hormone parameters in plasma samples collected at up to four study visits during pregnancy (median for each visit: 9.64, 17.9, 26.0, and 35.1weeks gestation). We used linear mixed models for repeated measures analyses, and multivariate linear regression models stratified by study visit to explore potential windows of susceptibility., Results: In our repeated measures analysis, BPA and thyrotropin (TSH) were inversely associated. An interquartile range (IQR) increase in BPA was associated with an 8.21% decrease in TSH (95% confidence interval [CI]: -14.2, -1.83), and a 4.79% increase in free T4 (95% CI: 0.82, 8.92). BPA and TSH were also inversely associated in our cross-sectional analyses at visits 3 and 4., Conclusions: Our results suggest that TSH is inversely associated with urinary BPA in a consistent manner across pregnancy. Disruption of TSH levels during pregnancy can potentially impact child development and interfere with normal birth outcomes., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Bisphenol-A (BPA) exposure occurs commonly and may adversely impact pregnancy. Endocrine disruption is posited as the primary mechanism of action, but oxidative stress and inflammation pathways may also be important. We investigated associations between BPA exposure and oxidative stress and inflammation in 482 pregnant women. Participants were recruited early in pregnancy and provided urine and plasma at up to four visits. We measured total BPA and two biomarkers of oxidative stress (8-hydroxydeoxyguanosine and 8-isoprostane) in urine from each visit. Inflammation markers, including C-reactive protein and four cytokines were measured in plasma from the same time points. In adjusted models, an interquartile range increase in BPA was associated with significant increases in both oxidative stress biomarkers (5-9% increase). Additionally, we observed significantly higher IL-6 concentrations in association with an interquartile range increase in BPA (8.95% increase). These systemic changes consequent to BPA exposure may mediate adverse birth outcomes and/or fetal development., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Increasing scientific evidence suggests that exposure to phthalates during pregnancy may be associated with an elevated risk of adverse reproductive outcomes such as preterm birth. Maternal endocrine disruption across pregnancy may be one pathway mediating some of these relationships. We investigated whether urinary phthalate metabolites were associated with maternal serum thyroid (free thyroxine [FT4], free triiodothyronine [FT3], and thyroid-stimulating hormone [TSH]), and sex (estradiol, progesterone, and sex hormone-binding globulin [SHBG]) hormone levels at multiple time points during pregnancy., Methods: Preliminary data (n = 106) were obtained from an ongoing prospective birth cohort in Northern Puerto Rico. We collected urine and serum sample at the first and third study visits that occurred at 18 +/- 2 and 26 +/- 2 weeks of gestation, respectively. To explore the longitudinal relationships between urinary phthalate metabolites and serum thyroid and sex hormone concentrations, we used linear mixed models (LMMs) adjusted for prepregnancy body mass index (BMI) and maternal age. An interaction term was added to each LMM to test whether the effect of urinary phthalate metabolites on serum thyroid and sex hormone levels varied by study visit. In cross-sectional analyses, we stratified BMI- and age-adjusted linear regression models by study visit., Results: In adjusted LMMs, we observed significant inverse associations between mono-3-carboxypropyl phthalate (MCPP) and FT3 and between mono-ethyl phthalate (MEP) and progesterone. In cross-sectional analyses by study visit, we detected stronger and statistically significant inverse associations at the third study visit between FT3 and MCPP as well as mono-carboxyisooctyl phthalate (MCOP); also at the third study visit, significant inverse associations were observed between FT4 and metabolites of di-(2-ethylhexyl) phthalate (DEHP). The inverse association between MEP and progesterone was consistent across study visits., Conclusions: In this group of pregnant women, urinary phthalate metabolites may be associated with altered maternal serum thyroid and sex hormone levels, and the magnitude of these effects may depend on the timing of exposure during gestation.

Problem: Previous studies have investigated the utility of inflammation markers as predictors of preterm birth, but none have compared trends in levels between uncomplicated and preterm pregnancy., Method of Study: We explored longitudinal changes in plasma cytokines, including IL-1β, IL-6, IL-10, and TNF-α, as well as C-reactive protein in pregnant women from a nested case-control study., Results: IL-6 was associated with increased odds of spontaneous preterm birth, defined by presentation of spontaneous preterm labor and/or preterm premature rupture of the membranes. Associations were strongest later in pregnancy. IL-10 was associated with increased odds of placentally mediated preterm birth, defined by presentation with preeclampsia or intrauterine growth restriction, and odds ratios were also highest near the end of pregnancy., Conclusion: Maternal inflammation markers were associated with increased risk of preterm birth, and relationships differed by etiology of preterm delivery and gestational age at sample collection., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

BackgroundPhthalate exposures are ubiquitous during pregnancy and may contribute to racial and ethnic disparities in preterm birth.ObjectivesWe investigated race and ethnicity in the relationship between biomarkers of phthalate exposure and preterm birth by examining: a) how hypothetical reductions in racial and ethnic disparities in phthalate metabolites might reduce the probability of preterm birth; and b) exposure-response models stratified by race and ethnicity.MethodsWe pooled individual-level data on 6,045 pregnancies from 16 U.S. cohorts. We investigated covariate-adjusted differences in nine urinary phthalate metabolite concentrations by race and ethnicity [non-Hispanic White (White, 43%), non-Hispanic Black (Black, 13%), Hispanic/Latina (38%), and Asian/Pacific Islander (3%)]. Using g-computation, we estimated changes in the probability of preterm birth under hypothetical interventions to eliminate disparities in levels of urinary phthalate metabolites by proportionally lowering average concentrations in Black and Hispanic/Latina participants to be approximately equal to the averages in White participants. We also used race and ethnicity-stratified logistic regression to characterize associations between phthalate metabolites and preterm birth.ResultsIn comparison with concentrations among White participants, adjusted mean phthalate metabolite concentrations were consistently higher among Black and Hispanic/Latina participants by 23%-148% and 4%-94%, respectively. Asian/Pacific Islander participants had metabolite levels that were similar to those of White participants. Hypothetical interventions to reduce disparities in metabolite mixtures were associated with lower probabilities of preterm birth for Black [13% relative reduction; 95% confidence interval (CI): -34%, 8.6%] and Hispanic/Latina (9% relative reduction; 95% CI: -19%, 0.8%) participants. Odds ratios for preterm birth in association with phthalate metabolites demonstrated heterogeneity by race and ethnicity for two individual metabolites (mono-n-butyl and monoisobutyl phthalate), with positive associations that were larger in magnitude observed among Black or Hispanic/Latina participants.ConclusionsPhthalate metabolite concentrations differed substantially by race and ethnicity. Our results show hypothetical interventions to reduce population-level racial and ethnic disparities in biomarkers of phthalate exposure could potentially reduce the probability of preterm birth. https://doi.org/10.1289/EHP12831.

BackgroundPreterm birth is the leading cause of infant morbidity and mortality worldwide. Elevated levels of oxidative stress have been associated with an increased risk of delivering before term. However, most studies testing this hypothesis have been conducted in racially and demographically homogenous study populations, which do not reflect the diversity within the United States.ObjectiveWe leveraged 4 cohorts participating in the Environmental Influences on Child Health Outcomes Program to conduct the largest study to date examining biomarkers of oxidative stress and preterm birth (N=1916). Furthermore, we hypothesized that elevated oxidative stress would be associated with higher odds of preterm birth, particularly preterm birth of spontaneous origin.Study designThis study was a pooled analysis and meta-analysis of 4 birth cohorts spanning multiple geographic regions in the mainland United States and Puerto Rico (208 preterm births and 1708 full-term births). Of note, 8-iso-prostaglandin-F2α, 2,3-dinor-5,6-dihydro-8-iso-prostaglandin-F2α (F2-IsoP-M; the major 8-iso-prostaglandin-F2α metabolite), and prostaglandin-F2α were measured in urine samples obtained during the second and third trimesters of pregnancy. Logistic regression was used to calculate adjusted odds ratios and 95% confidence intervals for the associations between averaged biomarker concentrations for each participant and all preterm births, spontaneous preterm births, nonspontaneous preterm births (births of medically indicated or unknown origin), and categories of preterm birth (early, moderate, and late). Individual oxidative stress biomarkers were examined in separate models.ResultsApproximately 11% of our analytical sample was born before term. Relative to full-term births, an interquartile range increase in averaged concentrations of F2-IsoP-M was associated with higher odds of all preterm births (odds ratio, 1.29; 95% confidence interval, 1.11-1.51), with a stronger association observed for spontaneous preterm birth (odds ratio, 1.47; 95% confidence interval, 1.16-1.90). An interquartile range increase in averaged concentrations of 8-iso-prostaglandin-F2α was similarly associated with higher odds of all preterm births (odds ratio, 1.19; 95% confidence interval, 0.94-1.50). The results from our meta-analysis were similar to those from the pooled combined cohort analysis.ConclusionHere, oxidative stress, as measured by 8-iso-prostaglandin-F2α, F2-IsoP-M, and prostaglandin-F2α in urine, was associated with increased odds of preterm birth, particularly preterm birth of spontaneous origin and delivery before 34 completed weeks of gestation.

BackgroundLower socioeconomic status (SES) and elevated psychosocial stress are known contributors to adverse pregnancy outcomes; however, biological mechanisms linking these factors to adverse pregnancy outcomes are not well-characterized. Oxidative stress may be an important, yet understudied mechanistic pathway. We used a pooled study design to examine biological, behavioral, and social factors as predictors of prenatal oxidative stress biomarkers.MethodsLeveraging four pregnancy cohorts from the Environmental influences on Child Health Outcomes (ECHO) Program spanning multiple geographic regions across the United States (U.S.) (N = 2082), we measured biomarkers of oxidative stress in urine samples at up to three time points during pregnancy, including 8-isoprostane-prostaglandin F2α (8-isoPGF2α), its major metabolite, 2,3-dinor-5,6-dihydro-15-F2t-isoprostane, and prostaglandin F2α (PGF2α). Maternal age, pre-pregnancy body mass index, marital/partnered status, parity, and smoking status were included as biological and behavioral factors while race/ethnicity, maternal education, and stressful life events were considered social factors. We examined associations between each individual biological, behavioral, and social factor with oxidative stress biomarkers using multivariable-adjusted linear mixed models.ResultsNumerous biological, behavioral, and social factors were associated with elevated levels of 8-isoPGF2α, its major metabolite, and PGF2α. Pregnant people who were current smokers relative to non-smokers or had less than a high school education relative to a college degree had 11.04% (95% confidence interval [CI] = -1.97%, 25.77%) and 9.13% (95% CI = -1.02%, 20.32%) higher levels of 8-isoPGF2α, respectively.ConclusionsOxidative stress biomarkers are elevated among pregnant people with higher socioeconomic disadvantage and may represent one pathway linking biological, behavioral, and social factors to adverse pregnancy and child health outcomes, which should be explored in future work.

BackgroundPrenatal phthalate exposure has been linked to reductions in fetal growth in animal and laboratory studies, but epidemiologic evidence is equivocal.ObjectiveExamine the association between prenatal phthalate metabolite mixtures and fetal growth and evaluate whether that association is modified by fetal sex or omega-3 intake during pregnancy.MethodsAnalyses included 604 singleton pregnancies from TIDES, a prospective pregnancy cohort with spot urine samples and questionnaires collected in each trimester. Pregnancy-averaged phthalate exposure estimates were calculated as the geometric means of specific-gravity corrected phthalate metabolites. Fetal growth outcomes included birthweight and length, and ultrasound-derived size and velocity of estimated fetal weight, femur length, abdominal and head circumferences in the second and third trimesters. We used a novel application of quantile g-computation to estimate the joint association between pregnancy-averaged phthalate exposure and fetal growth, and to examine effect modification of that association by infant sex or omega-3 intake during pregnancy.ResultsThere were few statistically significant differences in birth size and fetal growth by exposure. A one-quartile increase in the phthalate mixture was modestly associated with reduced birthweight(β [95% confidence interval)]: -54.6 [-128.9, 19.7] grams; p = 0.15) and length (-0.2 [-0.6, 0.2] centimeters; p = 0.40). A one-quartile increase in the phthalate mixture was associated with reduced birth length in males (-0.5 [-1.0, 0.0] centimeters) but not for females (0.1 [-0.2, 0.3] centimeters); interaction p = 0.05. The phthalate metabolite mixture was inversely associated with ultrasound-derived fetal growth among those with adequate omega-3 intake. For example, a one-quartile increase in the phthalate mixture was associated with reduced abdominal circumference in the third trimesters in those with adequate omega-3 intake (-3.3 [-6.8, 0.1] millimeters) but not those with inadequate omega-3 intake (1.8 [-0.8, 4.5] millimeters); interaction p = 0.01.ConclusionPrenatal phthalate exposure was not significantly associated with fetal growth outcomes, with some exceptions for certain subgroups.

BackgroundPrenatal phthalate exposure has been associated with lower birth weight but also higher weight in childhood. Few studies have examined weight or adiposity from birth to childhood and thus cannot assess growth trajectories associated with exposure.ObjectiveWe assessed associations between maternal phthalate exposures in pregnancy and child weight and adiposity measured prenatally through childhood (3-6 years of age).MethodsWithin The Infant Development and the Environment Study (TIDES), a prospective pregnancy cohort, we analyzed a panel of phthalate metabolites in urine collected at two visits from early and late gestation (N=780). We estimated average phthalate metabolite associations with child weight z-scores from ∼20wk gestation (estimated by ultrasound), birth, and 1, 3, 4, and 6 years of age using linear mixed-effects (LME) models. We also modeled associations with adiposity z-scores from birth (weight for length) and 1, 3, 4, and 6 years of age [body mass index (BMI)] using LME models.ResultsFor weight, we observed inverse associations between several phthalate metabolites and birth weight z-scores, but no associations were observed with postnatal weight z-scores in LME models. Regarding adiposity, we observed inverse associations between phthalate metabolites and weight-for-length z-scores at birth, but positive associations were observed with BMI z-scores at 3-4 years of age in LME models. For example, mono-ethyl phthalate was associated with a 0.17-unit decrease in birth weight-for-length z-score [95% confidence interval (CI): -0.29, -0.05] and a 0.18-unit increase in 4-years-of-age BMI z-score (95% CI: 0.04, 0.32).DiscussionWe observed associations between prenatal exposure to phthalates and lower weight at birth but not at childhood follow-up visits. However, for adiposity, we observed an interesting pattern of association with low adiposity at delivery as well as high adiposity at 3-4 years of age. Although it is not clear from our results whether these associations occur within the same children, such a pattern of adiposity in early life has been linked to cardiometabolic disease in adulthood and deserves special attention as an outcome in the study of prenatal exposures in the developmental origins of health and disease. https://doi.org/10.1289/EHP10077.

The purpose of this study was to determine whether maternal urinary phthalate metabolite concentrations are associated with the development of higher blood pressure or pregnancy-induced hypertension (PIH). Participants were women without chronic hypertension who enrolled in The Infant Development and the Environment Study, a prospective pregnancy cohort conducted at four U.S. academic medical centers from 2010-2012. Prenatal records were reviewed to obtain blood pressure measurements and diagnoses of PIH (gestational hypertension, preeclampsia, eclampsia, and HELLP syndrome, defined as hemolysis, elevated liver enzymes, and low platelet count). Complete-case analyses used multivariable linear and logistic regression for analysis of blood pressure measurements and PIH diagnoses, respectively. In the final dataset (N = 668), higher concentrations of first-trimester monoethyl phthalate (MEP) and mono-3-carboxypropyl phthalate (MCPP) and third-trimester mono-isobutyl phthalate (MiBP) were significantly associated with a medical chart diagnosis of PIH. First-trimester mono-n-butyl phthalate (MBP) and MEP along with the sum of di-(2-ethylhexyl) phthalate metabolites (∑DEHP) were each associated with increased systolic blood pressure across pregnancy. In conclusion, several phthalate metabolite concentrations were significantly associated with PIH and greater increases in systolic blood pressure across pregnancy.

Oxidative stress is a biological imbalance in reactive oxygen species and antioxidants. Increased oxidative stress during pregnancy has been associated with adverse birth outcomes. Omega-3 fatty acid (n-3 FA) supplementation may decrease oxidative stress; however, this relationship is seldom examined during pregnancy. This study assessed the association between n-3 FA supplement use during pregnancy and urinary oxidative stress biomarker concentrations. Data came from The Infant Development and the Environment Study (TIDES), a prospective cohort study that recruited pregnant women in 4 US cities between 2010-2012. Third trimester n-3 FA intake was self-reported. Third trimester urinary 8-iso-prostaglandin F2α (8-iso-PGF2α) was measured as an oxidative stress biomarker. Additionally, we measured the major metabolite of 8-iso-PGF2α and Prostaglandin F2α (PGF2α) and utilized the 8-iso-PGF2α to PGF2α ratio to calculate the change in 8-iso-PGF2α reflecting oxidative stress versus inflammation. Adjusted linear models were used to determine associations with control for confounding. Of 725 women, 165 reported n-3 FA supplement use in the third trimester. In adjusted linear models, n-3 FA use was associated with 10.2% lower levels of 8-iso-PGF2α (95% Confidence Interval [CI]: -19.6, 0.25) and 10.3% lower levels of the metabolite (95% CI: -17.1, -2.91). No associations were observed with PGF2α. The lower levels of 8-iso-PGF2α appeared to reflect a decrease in oxidative stress (percent change with supplement use: -18.7, 95% CI: -30.1, -5.32) rather than inflammation. Overall, third trimester n-3 FA intake was associated with lower concentrations of 8-iso-PGF2α and its metabolite, suggesting a decrease in maternal oxidative stress during pregnancy.

BackgroundUrinary phthalate metabolites and psychosocial stress in pregnancy have each been associated with preterm birth (PTB), but no study has examined the joint impact of these two environmental exposures. We hypothesized that there would be stronger associations between phthalate exposure and PTB in mothers with higher stress in pregnancy compared to mothers with lower stress.MethodsWe addressed this question using data from The Infant Development and the Environment Study (TIDES), a prospective birth cohort conducted at four US sites (N = 783). We examined urinary phthalate metabolite concentrations measured in samples collected from up to three trimesters of pregnancy. Mothers reported their exposure to stressful life events (SLE) in each trimester in a questionnaire administered in the third trimester. PTB was defined as delivery before 37 weeks completed gestation (n = 71, 9.1%). We examined associations between urinary phthalate metabolite concentrations (individual time points and on average) and PTB using logistic regression models adjusted for maternal race, age, pre-pregnancy body mass index, education, specific gravity, and gestational age at sample collection. In addition, we created models stratified by whether or not mothers were exposed to any or no SLE in pregnancy.ResultsSummed di-2-ethylhexyl phthalate (ΣDEHP) metabolites measured in urine samples from the third trimester, but not the first trimester, were associated with an increased odds ratio (OR) of PTB (OR = 1.44, 95% confidence interval [CI] = 1.06, 1.95). In models stratified by SLE, associations between third trimester ΣDEHP concentrations and PTB were significant only for women experiencing one or more SLE during pregnancy (OR for ΣDEHP: 2.09, 95% CI: 1.29, 3.37) but not for women with no SLE during pregnancy (OR for ΣDEHP: 1.04, 95% CI: 0.66, 1.63) (p for interaction = 0.07).ConclusionsWe observed an association between urinary ΣDEHP levels and PTB that was modified by whether a mother was exposed to one or more psychosocial stressors during pregnancy. Additional research to understand the joint impacts of chemical and non-chemical exposures, with an emphasis on timing of exposure, is needed in order to advance the state of the science on how the environment influences pregnancy.

BackgroundPhthalates are common plasticizer chemicals that have been linked to glucose intolerance in the general population, but there is only limited research on their association with gestational diabetes (GDM).ObjectiveWe evaluated the association between 11 urinary phthalate metabolites and GDM, impaired glucose tolerance (IGT), and continuous blood glucose concentration during pregnancy in The Infant Development and Environment Study (TIDES). Based on prior study results, our primary analyses focused on monoethyl phthalate (MEP) in relation to our outcomes of interest.Study designWe used multi-variable logistic regression to examine the odds of GDM and IGT in relation to an interquartile-range (IQR) increase in natural log (ln)-transformed, specific gravity (SG)-adjusted first trimester (T1) and average of T1 and third trimester (T3) ("T1T3avg") phthalate metabolite concentrations. We fit linear regression models to examine the percent change in blood glucose per IQR increase in ln-transformed, SG-adjusted T1 and T1T3avg phthalates. In sensitivity analyses, we examined interactions between exposure and race. We adjusted for maternal age, maternal body mass index, study center, race/ethnicity, parity, and gestational age at glucose testing.ResultsIn our sample of 705 pregnant women, we observed 60 cases of GDM, 90 cases of IGT, and an average GLT blood glucose of 113.6 ± 27.7 mg/dL. In our primary analysis, T1T3avg MEP was positively associated with GDM ([OR (95% CI) per IQR increase] T1T3avg MEP: 1.61 (1.10, 2.36)). In secondary analyses, most other phthalates were not found to be related to study outcomes, though some associations were noted. Sensitivity analyses indicated possible strong race-specific associations in Asians, though these results are based on a small sample size (n = 35).ConclusionIn alignment with our a priori selection, we documented an association between T1T3avg MEP and GDM. Additional phthalate metabolites were also found to be linked to glucose intolerance, with possible stronger associations in certain racial/ethnic subgroups. Given the prevalence of phthalate exposures and the growing evidence of associations with metabolic outcomes, future studies should continue to examine this question in diverse cohorts of pregnant women, particularly in those who may be at higher risk for GDM and IGT.

BackgroundOxidative stress has been implicated in numerous birth outcomes, including spontaneous preterm birth. However, the relationship with presentation at delivery has been less well studied. We assessed the relationship between oxidative stress biomarkers and gestational duration with a focus on spontaneous presentation for delivery.MethodsOur sample included 740 women from a multi-center prospective cohort study, recruited from 2010 to 2012. Resultant measures of oxidative stress in pregnancy prostaglandin F2α (PGF2α), 8-iso-prostaglandin F2α (8-iso-PGF2α), and the primary 8-iso-PGF2α metabolite were measured in third trimester urine samples. Information on presentation for delivery was abstracted from medical records. We examined associations with preterm birth using adjusted logistic models. Time to event (overall delivery and spontaneous delivery) was examined using adjusted accelerated failure time models.ResultsThe 8-iso-PGF2α metabolite was associated with increased odds of overall preterm birth (OR: 1.44 [95% CI: 1.00, 2.06]), and the association with spontaneous preterm birth was similar in magnitude but not statistically significant (OR: 1.45 [95% CI: 0.96, 2.20]). We did not detect associations between other biomarkers and preterm birth, or between biomarkers and timing of overall or spontaneous delivery in accelerated failure time models.ConclusionsOur data suggest that increased oxidative stress, as indicated by the 8-iso-PGF2α metabolite, may be associated with preterm birth. In contrast to previous studies, associations were similar among individuals with spontaneous versus non-spontaneous presentation for delivery.

BACKGROUND:Prenatal psychological stress during pregnancy has been associated with adverse reproductive outcomes. A growing animal literature supports an association between psychological stress and oxidative stress. We assessed this relationship in pregnant women, hypothesising that psychological stress is associated with higher concentrations of oxidative stress biomarkers during pregnancy. METHODS:Psychosocial status and stressful life events (SLE) were self-reported. 8-iso-prostaglandin F2α (8-iso-PGF2α ) was measured as a biomarker of oxidative stress in urine samples at median 32 weeks' gestation. We examined SLEs individually (ever vs never) and in summary (any vs none) and psychosocial status as measured by individual subscales and in summary (poor vs good). Linear models estimated associations between these parameters and urinary 8-iso-PGF2α concentrations after adjusting for covariates. RESULTS:The geometric mean of 8-iso-PGF2α was significantly higher among pregnant women who were non-White, smokers, had less than a college education, higher pre-pregnancy BMI and were unmarried. Having ever had a death in the family (n = 39) during pregnancy was associated with a 22.9% increase in 8-iso-PGF2α in unadjusted models (95% confidence interval [CI] 1.50, 48.8). Poor psychosocial status was associated with a 13.1% (95% CI 2.43, 25.0) greater mean 8-iso-PGF2α in unadjusted analyses. Associations were attenuated, but remained suggestive, after covariate adjustment. CONCLUSIONS:These data suggest that 8-iso-PGF2α is elevated in pregnant women with who are at a sociodemographic disadvantage and who have higher psychological stress in pregnancy. Previous studies have observed that 8-iso-PGF2α levels are associated with adverse birth outcomes, oxidative stress could be a mediator in these relationships.

BACKGROUND: Gestational phthalate and phenol exposure disrupts adipogenesis, contributing to obesity in mice. Whether gestational phthalate or phenol exposure is associated with infant body composition has not been investigated in humans. OBJECTIVE: We examined associations between biomarkers of phthalate and phenol exposure in midpregnancy and infant size and body composition at birth and at 5 months of age. METHODS: Analyses were conducted among 438 infants from the Healthy Start prospective pregnancy cohort. Sixteen phthalate and phenol biomarkers were quantified in spot urine samples collected at 24–28 wk of gestation. Infant outcomes measured at birth and at 5 months of age included size [weight (in grams)] and body composition [fat and lean masses (in grams); percentage fat mass]. Single- (linear) and multipollutant (quantile g-computation) models were used to estimate associations of phthalate and phenol biomarkers with infant outcomes at birth and at 5 months of age. Models were adjusted for sociodemographics, sample collection timing, and lifestyle factors and used to examine for effect modification by infant sex. RESULTS: In single-pollutant models, mono-benzyl phthalate and di-n-butyl phthalate were inversely associated with percentage fat mass [ß: -0.49 (95% CI: -0:91, -0:08) and -0:51 (95% CI: -1.02, 0.01), respectively] in male but not female infants at birth. Similar, but less precise, associations were observed at 5 months of age. In multipollutant models, a 1-quartile increase in the phthalate and phenol biomarker mixture was inversely associated with percentage fat mass at birth [-1.06 (95% CI: -2.21, 0.1)] and at 5 months of age [-2.14 (95% CI: -3.88, -0.39)] among males, but associations were null among females [0.48 (95% CI: -0.78, 1.75) and -0.64 (95% CI: -2.68, 1.41), respectively]. Similar associations were observed with infant weight. CONCLUSION: In this U.S.-based prospective cohort, gestational phthalate and phenol biomarkers were inversely associated with infant weight and fat mass, particularly in males. [ABSTRACT FROM AUTHOR]

Our objective was to identify metabolites associated with fetal growth restriction (FGR) by examining early and late pregnancy differences in non-targeted urinary metabolites among FGR cases and non-FGR controls. An exploratory case-control study within LIFECODES birth cohort was performed. FGR cases (N = 30), defined as birthweight below the 10th percentile, were matched with controls (N = 30) based on maternal age, race, pre-pregnancy body mass index, and gestational age at delivery. Gas chromatography/electron-ionization mass spectrometry was performed on urine samples collected at 10 and 26 weeks of gestation. Differences in urinary metabolite levels in cases and controls at each time point and between the two time points were calculated and then changes compared across pregnancy. 137 unique urinary metabolites were annotated, and several identified that were higher in cases compared to controls. For example, urinary concentrations of benzoic acid were higher in cases compared to controls at both study visits (3.01-fold higher in cases at visit 1, p < 0.01; 3.10-fold higher in cases at visit 3, p = 0.05). However, these findings from our exploratory analysis were not robust to false-discovery-rate adjustment. In conclusion, using a high-resolution, non-targeted approach, we found specific urinary organic acids differed over pregnancy by FGR case status. [ABSTRACT FROM AUTHOR]

Psychosocial stress during pregnancy has been associated with adverse pregnancy outcomes including preterm birth (PTB). This has not been studied in Puerto Rico, an area with high PTB rates. Our objective was to develop a conceptual model describing the interrelationships between measures of psychosocial stress and depression, a result of stress, among pregnant women in Puerto Rico and to examine their associations with PTB. We used data from the Puerto Rico Testsite for Exploring Contamination Threats pregnancy cohort (PROTECT, N = 1,047) to examine associations among depression and different continuous measures of psychosocial stress using path analysis. Psychosocial stress during pregnancy was assessed using validated measures of perceived stress, negative life experiences, neighborhood perceptions and social support. Logistic regression was used to examine associations between psychosocial stress measures in tertiles and PTB. Perceived stress, negative life experiences, and neighborhood perceptions influenced depression through multiple pathways. Our model indicated that perceived stress had the strongest direct effect on depression, where one standard deviation (SD) increase in perceived stress was associated with a 57% SD increase in depression. Negative life experiences were directly but also indirectly, through perceived stress, associated with depression. Finally, neighborhood perceptions directly influenced negative life experiences and perceived stress and consequently had an indirect effect on depression. Psychosocial stress was not associated with PTB across any of the measures examined. Our study examined interrelationships between multiple measures of psychosocial stress and depression among a pregnant Puerto Rican population and identified negative neighborhood perceptions as important upstream factors leading to depression. Our findings highlight the complex relationship between psychosocial stress measures and indicate that psychosocial stress and depression, assessed using 5 different scales, were not associated with PTB. Future research should investigate other environmental and behavioral risk factors contributing to higher rates of PTB in this population. [ABSTRACT FROM AUTHOR]

BACKGROUND: Perturbations in fetal growth may have adverse consequences for childhood and later life health. Organophosphate pesticide (OP) exposure has been associated with reduced birth weight at delivery but results are not consistent. We investigated this question by utilizing ultrasound measures of size in utero in combination with measures from delivery. METHODS: Within Generation R, a population-based prospective cohort conducted between 2002 and 2006 in Rotterdam, Netherlands, we measured dialkyl phosphates (DAPs), OP metabolites, in urine samples from early, middle, and late pregnancy and created a subject-specific average to estimate OP exposure (n=784). Ultrasound measures of head circumference, femur length, and estimated fetal weight from middle and late pregnancy and delivery measures were converted to standard deviation scores (SDS). Associations with DAP average were examined in linear mixed effects models that included an interaction term between gestational age at measurement and DAP average to investigate whether the relationship differed over time. Windows of vulnerability to exposure were assessed by modeling urinary DAPs from each visit in relation to growth measurements. RESULTS: A 10-fold increase in average DAPs was associated with a −0:53 SDS decrease in fetal length (95% CI = −0:83, −0:23) and a −0:32 SDS decrease in estimated fetal weight (95% CI = −0:59, −0:04) at 20 weeks of gestation. These differences corresponded to 5% and 6% decreases relative to the mean. Effect estimates were greatest in magnitude for DAP concentrations measured early in pregnancy. Associations between average DAPs and growth measures at delivery were positive but not significant for head circumference and length and were null for weight. CONCLUSIONS: Maternal urinary DAPs were associated with decreased fetal weight and length measured during mid-pregnancy, but not at delivery. [ABSTRACT FROM AUTHOR]

Preterm birth is a major public health problem, especially in Puerto Rico where the rates are among the highest observed worldwide, reaching 18% in 2011. The Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) study is an ongoing investigation of environmental factors that contribute to this condition. In the present analysis, we sought to examine common risk factors for preterm birth and other adverse birth outcomes which have not been characterized previously in this unique population. Pregnant women from the PROTECT cohort are recruited from the heavily contaminated Northern coast of the island of Puerto Rico and are free of pre-existing conditions like diabetes. We examined associations between basic demographic, behavioral (e.g., tobacco and alcohol use), and pregnancy (e.g., season and year of delivery) characteristics as well as municipality of residence in relation to preterm birth (<37 weeks gestation), postterm birth (≥41 weeks gestation), and small and large for gestational age in univariate and multivariate logistic regression models. Between 2011 and 2017, 1028 live singleton births were delivered as part of the PROTECT cohort. Of these, 107 (10%) were preterm. Preterm birth rates were higher among women with low socioeconomic status, as indicated by education level and income, and among women with high pre-pregnancy body mass index (BMI). Odds ratios of small for gestational age delivery were higher for women who reported tobacco use in pregnancy and lower for women who delivered in the hurricane and dengue season (July-October). Overall, in pregnant women residing in Puerto Rico, socioeconomic status was associated with preterm birth but few other factors were associated with this or other adverse outcomes of pregnancy. Research to understand environmental factors that could be contributing to the preterm birth epidemic in Puerto Rico is necessary. [ABSTRACT FROM AUTHOR]

Background: Higher birth weight is an important adverse outcome associated with hyperglycemia in pregnancy. Recent studies suggest that phthalate exposure is associated with elevated glucose levels in pregnant women, with implications for higher birth weight in the offspring. No study to date has investigated the association between prenatal phthalate exposure on infant high birth weight accounting for the range of pregnancy glucose levels.Methods: A total of 350 women participating in an ongoing pregnancy cohort had data available on urinary phthalate metabolite concentrations at up to four time points across pregnancy. Urinary phthalate metabolites were averaged across pregnancy and log-transformed, specific gravity-adjusted and analyzed in quartiles. Birth weight was examined continuously (in grams), as well as dichotomized as large for gestational age (>90th percentile). Glucose levels were assessed based on Results from 50-g glucose challenge tests as a part of screening for gestational diabetes conducted at 24-28 weeks gestation, and grouped into 3 categories <120 mg/dL, 120-<140 mg/dL and ≥140 mg/dL. Multivariable linear regression was performed, adjusting for potential confounders in the overall population and stratified by pregnancy glucose levels.Results: Approximately 20% of infants born to women with glucose levels ≥140 mg/dL were large for gestational age. Average mono-ethyl phthalate (MEP) concentrations were higher among women who had glucose levels ≥140 mg/dL (geometric mean 140.9 μg/L; 95% CI: 91.6-216.8); however, higher MEP concentrations were not associated with higher birth weight. When stratified by maternal glucose levels, there was a suggestive association between higher concentrations of mono-(3-carboxypropyl) phthalate (MCPP) and higher birth weight among women with glucose levels ≥140 mg/dL (adj. birth weight: 569.2 g; 95% CI: 14.1, 1178.2).Conclusions: Higher urinary phthalate metabolite concentrations were not significantly associated with higher birth weight. Counter to our hypothesis, women with higher glucose levels and higher urinary phthalate metabolites did not deliver babies with higher birth weight. [ABSTRACT FROM AUTHOR]

Abstract Background Phthalates are common plasticizer chemicals that have been linked to glucose intolerance in the general population, but there is only limited research on their association with gestational diabetes (GDM). Objective We evaluated the association between 11 urinary phthalate metabolites and GDM, impaired glucose tolerance (IGT), and continuous blood glucose concentration during pregnancy in The Infant Development and Environment Study (TIDES). Based on prior study results, our primary analyses focused on monoethyl phthalate (MEP) in relation to our outcomes of interest. Study design We used multi-variable logistic regression to examine the odds of GDM and IGT in relation to an interquartile-range (IQR) increase in natural log (ln)-transformed, specific gravity (SG)-adjusted first trimester (T1) and average of T1 and third trimester (T3) ("T1T3avg") phthalate metabolite concentrations. We fit linear regression models to examine the percent change in blood glucose per IQR increase in ln-transformed, SG-adjusted T1 and T1T3avg phthalates. In sensitivity analyses, we examined interactions between exposure and race. We adjusted for maternal age, maternal body mass index, study center, race/ethnicity, parity, and gestational age at glucose testing. Results In our sample of 705 pregnant women, we observed 60 cases of GDM, 90 cases of IGT, and an average GLT blood glucose of 113.6 ± 27.7 mg/dL. In our primary analysis, T1T3avg MEP was positively associated with GDM ([OR (95% CI) per IQR increase] T1T3avg MEP: 1.61 (1.10, 2.36)). In secondary analyses, most other phthalates were not found to be related to study outcomes, though some associations were noted. Sensitivity analyses indicated possible strong race-specific associations in Asians, though these results are based on a small sample size (n = 35). Conclusion In alignment with our a priori selection, we documented an association between T1T3avg MEP and GDM. Additional phthalate metabolites were also found to be linked to glucose intolerance, with possible stronger associations in certain racial/ethnic subgroups. Given the prevalence of phthalate exposures and the growing evidence of associations with metabolic outcomes, future studies should continue to examine this question in diverse cohorts of pregnant women, particularly in those who may be at higher risk for GDM and IGT. Highlights • Limited studies have suggested a possible link between phthalates and impaired glucose tolerance during pregnancy • In agreement with prior studies, we observed an association between mono-ethyl phthalate (MEP) and gestational diabetes • Secondary analyses link other phthalates to glucose intolerance, with possible stronger associations in certain subgroups [ABSTRACT FROM AUTHOR]

Abstract Introduction Preterm birth continues to be a significant public heath concern and is a leading cause of perinatal and infant mortality. Environmental exposures to phenols and parabens are suspected to potentially contribute to the pathology of preterm birth, yet limited human studies have characterized the extent to which these toxicants are associated with birth outcomes. Methods We examined the associations between phenols, parabens, and preterm birth, within pregnant women who were recruited early in gestation into the LIFECODES cohort at Brigham and Women's Hospital in Boston, Massachusetts. Urine samples were collected at up to 4 time points in pregnancy and analyzed for phenols and parabens. We selected 130 cases of preterm birth (defined as delivery before 37 weeks gestation), and 350 random controls. We categorized preterm birth subtypes based on clinical presentation and identified 75 cases of spontaneous preterm birth (characterized by spontaneous preterm labor and/or preterm premature rupture of membranes), and 37 cases of placental preterm birth (characterized by preeclampsia and/or intrauterine growth restriction). We used multivariate logistic regression with visit specific and geometric averages of phenols and parabens to determine associations with preterm birth. Results We observed moderate variability in urinary phenol and paraben concentrations over pregnancy with intraclass correlation coefficients ranging between 0.45 and 0.68. Regression analyses indicated mostly null associations. We observed inverse associations, notably between 2,5-dichlorophenol and overall preterm birth (adjusted odds ratio [95% confidence interval, CI]: 0.79 [0.67 – 0.94]), and this relationship was consistent by study visit. Conversely, ethyl paraben was associated with increased risk for placental preterm birth (adjusted odds ratio [95% CI]: 1.47 [1.14 – 1.91]). Bisphenol-S detection at visit 4 was associated with overall preterm birth (adjusted odds ratio [95% CI]: 2.05 [1.09, 3.89]). Conclusions While the findings from this study largely indicate null associations, we observed some relationships between select phenols, parabens and preterm birth, which warrants further investigation of these toxicants and birth outcomes. Highlights • We measured ten unique phenol compounds in this case-control study of preterm birth. • Ethyl paraben was associated with increased risk for placental preterm birth. • 2,5-Dichlorophenol was associated with decreased risk for overall preterm birth. • A majority of the phenols were not associated with birth outcomes. [ABSTRACT FROM AUTHOR]

Phthalate exposure has been shown to be associated with adverse pregnancy outcomes. However, human studies informing relevant mechanistic pathways are lacking. Experimental studies have reported that matrix metalloproteinases (MMPs), which are responsible for extracellular protein degradation, may be upregulated in response to phthalate exposure. In this exploratory study we measured urinary phthalate metabolite concentrations, plasma MMP levels, and relevant covariates among 134 pregnant women. There were statistically significant or suggestive positive relationships between several phthalates, particularly between metabolites of di-(2-ethylhexyl) phthalate, with MMP-1 and MMP-9 levels. Further research is needed to confirm these results and how they may inform the mechanisms involved between phthalate exposure and adverse pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Pregnant women and their fetuses represent susceptible populations to environmental contaminants. Exposure to polycyclic aromatic hydrocarbons (PAHs) among pregnant women may contribute to adverse birth outcomes such as preterm birth. Multiple previous studies have assessed airborne sources of PAHs among pregnant women but few have measured urinary PAH metabolites which can capture total exposure through multiple routes. The aim of this study was to bridge this knowledge gap by assessing longitudinal urinary PAH metabolite concentrations over two time points in pregnancy cohorts in Boston (N = 200) and Puerto Rico (N = 50) to better understand exposure distributions throughout pregnancy and how they relate to demographic factors. Urine samples were analyzed for 1-NAP, 2-NAP, 2-FLU, 1-PHE, 2,3-PHE, 4-PHE, 9-PHE, and 1-PYR. Concentrations of 2-NAP, 1-PYR, and 4-PHE were higher in Puerto Rico, while all other metabolites were present in higher concentrations in Boston. In Puerto Rico, intraclass correlation coefficients (ICC) were weak to moderate, ranging from 0.06 to 0.42. PAH metabolite concentrations were significantly higher among younger, heavier (except 1-NAP and 9-PHE), and less educated individuals in Boston only. Consistent significant associations between PAH concentrations and measured covariates were not found in Puerto Rico. Our results suggest that potentially important differences in PAH exposure exist between these two populations. Additionally, our results indicate that multiple urinary measurements are required to accurately assess PAH exposure throughout pregnancy. [ABSTRACT FROM AUTHOR]

BACKGROUND: In addition to its well-established role in maintaining skeletal health, vitamin D has essential regulatory functions in female reproductive and pregnancy outcomes. Phthalates and bisphenol A (BPA) are endocrine disruptors, and previous research has suggested that these chemical agents may disrupt circulating levels of total 25(OH)D in adults. OBJECTIVES: We investigated the relationships between repeated measures of urinary phthalate metabolites and BPA and circulating total 25(OH)D in a prospective cohort of pregnant women. METHODS: The present study population includes participants (n=477) in a nested case-control study of preterm birth drawn from a prospective birth cohort of pregnant women at Brigham and Women's Hospital in Boston, Massachusetts. Urine and blood samples were collected for biomarker measurements at median 10 wk and 26 wk of gestation. RESULTS: In repeated measures analysis, we observed that an interquartile range (IQR) increase in urinary mono-3-carboxypropyl phthalate (MCPP) was associated with a 4.48% decrease [95% confidence interval (CI): -7:37, -1:58] in total 25(OH)D. We also detected inverse associations for metabolites of di(2-ethylhexyl) phthalate (DEHP) [percent difference (%Δ)= -2:83 to -2:16]. For BPA, we observed a nonsignificant inverse association with total 25(OH)D in the overall population. Our sensitivity analysis revealed that the associations for some metabolites (e.g., MEHP) varied by race/ethnicity, which may reflect potential differences in susceptibility. In agreement with findings from repeated measures analysis, we reported that DEHP metabolites and BPA were significantly associated with an approximate 20% increase in the odds of vitamin D deficiency (≤20 ng=mL) [odds ratio (95%CI): 1:19 (1.06, 1.35) for molar sum of DEHP metabolites and 1.22 (1.01, 1.47) for BPA] at median 10 wk and 26 wk, respectively. CONCLUSIONS: Our results provide suggestive evidence of the potential for environmental exposure to phthalates and/or BPA to disrupt circulating vitamin D levels in pregnancy. [ABSTRACT FROM AUTHOR]

BACKGROUND: Mediation analysis is useful for understanding mechanisms and has been used minimally in the study of the environment and disease. OBJECTIVE: We examined mediation of the association between phthalate exposure during pregnancy and preterm birth by oxidative stress. METHODS: This nested case -- control study of preterm birth (n = 130 cases, 352 controls) included women who delivered in Boston, Massachusestts, from 2006 through 2008. Phthalate metabolites and 8-isoprostane, an oxidative stress biomarker, were measured in urine from three visits in pregnancy. We applied four counterfactual mediation methods: method 1, utilizing exposure and mediator averages; method 2, using averages but allowing for an exposure -- mediator interaction; method 3, incorporating longitudinal measurements of the exposure and mediator; and method 4, using longitudinal measurements and allowing for an exposure -- mediator interaction. RESULTS: We observed mediation of the associations between phthalate metabolites and all preterm birth by 8-isoprostane, with the greatest estimated proportion mediated observed for spontaneous preterm births specifically. Fully utilizing repeated measures of the exposure and mediator improved precision of indirect (i.e., mediated) effect estimates, and including an exposure -- mediator interaction increased the estimated proportion mediated. For example, for mono(2-ethyl-carboxy-propyl) phthalate (MECPP), a metabolite of di(2-ethylhexyl) phthalate (DEHP), the percent of the total effect mediated by 8-isoprostane increased from 47% to 60% with inclusion of an exposure-mediator interaction term, in reference to a total adjusted odds ratio of 1.67 or 1.48, respectively. CONCLUSIONS: This demonstrates mediation of the phthalate -- preterm birth relationship by oxidative stress, and the utility of complex regression models in capturing mediated associations when repeated measures of exposure and mediator are available and an exposure -- mediator interaction may exist. CITATION: Ferguson KK, Chen YH, VanderWeele TJ, McElrath TF, Meeker JD, Mukherjee B. 2017. Mediation of the relationship between maternal phthalate exposure and preterm birth by oxidative stress with repeated measurements across pregnancy. Environ Health Perspect 125:488-494; http://dx.doi.org/10.1289/EHP282 [ABSTRACT FROM AUTHOR]

Introduction: Overt thyroid disease in pregnancy is associated with numerous maternal and neonatal complications including preterm birth. Less is known about the contribution of trimester-specific subclinical alterations in individual thyroid hormones, especially in late gestation, on the risk of preterm birth. Herein, we examined the associations between subclinical changes in maternal thyroid hormone concentrations (TSH, total T3, free and total T4), measured at multiple time points in pregnancy, and the odds of preterm birth in pregnant women without clinical thyroid disease. Participants and Methods: Data were obtained from pregnant women participating in a nested case-control study of preterm birth within on ongoing birth cohort study at Brigham and Women’s Hospital in Boston, MA (N = 439; 116 cases and 323 controls). We measured thyroid hormones in plasma collected at up to four time points in pregnancy (median = 10, 18, 26, and 35 weeks). We used multivariate logistic regression models stratified by study visit of sample collection to examine associations. To reveal potential biological pathways, we also explored these relationships by obstetric presentation of preterm birth (e.g., spontaneous preterm delivery) that have been previously hypothesized to share common underlying mechanisms. Results: In samples collected at median 10 and 26 weeks of gestation, we found inverse associations between FT4 and the odds of overall preterm birth (odds ratio [OR] = 0.57, 95% confidence interval (CI) = 0.33, 1.00; and OR = 0.53, 95% CI = 0.34, 0.84, respectively). Positive associations were detected for total T3 at these same time points (OR = 2.52, 95% CI = 1.20, 5.31; and OR = 3.40, 95% CI = 1.56, 7.40, respectively). These effect estimates were stronger for spontaneous preterm birth. Conclusions: Our results suggest that subclinical alterations in individual maternal thyroid hormones may influence the risk of preterm birth, and the strength of these associations vary by gestational age. [ABSTRACT FROM AUTHOR]

BACKGROUND: Maintaining thyroid homeostasis during pregnancy is essential for normal fetal growth and development. Growing evidence suggests that phthalates interfere with normal thyroid function. Few human studies have investigated the degree to which phthalates may affect thyroid hormone levels in particularly susceptible populations such as pregnant women. OBJECTIVES: We examined the associations between repeated measures of urinary phthalate metabolites and plasma thyroid hormone levels in samples collected at up to four time points per subject in pregnancy. Additionally, we investigated the potential windows of susceptibility to thyroid hormone disturbances related to study visit of sample collection. METHODS: Data were obtained from pregnant women (n = 439) participating in a nested case -- control study of preterm birth with 116 cases and 323 controls. We measured 9 phthalate metabolite concentrations in urine samples collected at up to four study visits per subject during pregnancy (median = 10, 18, 26, and 35 weeks of gestation, respectively). We also measured a panel of thyroid function markers in plasma collected at the same four time points per subject during pregnancy. RESULTS: Although our results were generally null, in repeated measures analyses we observed that phthalate metabolites were largely inversely associated with thyrotropin and positively associated with free and total thyroid hormones. Cross-sectional analyses by study visit revealed that the magnitude and/or direction of these relationships varied by timing of exposure during gestation. CONCLUSIONS: These results support previous reports showing the potential for environmental phthalate exposure to alter circulating levels of thyroid hormones in pregnant women. CITATION: Johns LE, Ferguson KK, McElrath TF, Mukherjee B, Meeker JD. 2016. Associations between repeated measures of maternal urinary phthalate metabolites and thyroid hormone parameters during pregnancy. Environ Health Perspect 124:1808-1815; http://dx.doi.org/10.1289/EHP170 [ABSTRACT FROM AUTHOR]

Problem We assess whether inflammatory and oxidative stress markers early in pregnancy are associated with decreasing cervical length in the second trimester. Method of study This is a secondary analysis of a nested case-control study of preterm birth conducted at a tertiary care center from 2006 to 2008. Plasma inflammatory markers included the following: interleukin-6 ( IL-6), interleukin-10 ( IL-10), interleukin-1 beta ( IL-1β), tumor necrosis factor alpha ( TNF-α), and C-reactive protein ( CRP); and urine oxidative stress markers included the following: 8-hydroxydeoxyguanosine (8- OHdG) and 8-isoprostane, measured at two study visits (median 10 and 18 weeks of gestation). The primary outcome was cervical length<10th percentile measured between 16 and 24 weeks of gestation. Logistic regression models were used, adjusting for body mass index, age, race, parity, tobacco use, education, and gestational age at cervical length measurement. Results Among 384 observed women, the 10th percentile cervical length was 3.0 cm. IL-10 levels were significantly higher among women with a cervical length<10th percentile compared to women with a longer cervix (mean IL-10: 95.5 vs 25.8 pg/mL, P<.01). Similarly, IL-6 levels were significantly higher among women with a cervical length<10th percentile (mean IL-6: 25.2 vs 4.3 pg/mL, P<.01). After controlling for potential confounders, an increase in IL-10 was significantly associated with a cervical length<10th percentile at both 10 and 18 weeks (adjusted odd ratio [ AOR]: 1.74; 95% CI: 1.18-2.58; P=.005). At 18 weeks, only IL-6 was also significantly associated with a cervical length<10th percentile ( AOR: 1.54; 95% CI: 1.11-2.13; P=.009). Other inflammatory biomarkers, including CRP, IL-1β, TNF-α, and oxidative stress biomarkers, 8- OHdG and 8-isoprostane, were not associated with cervical length. Conclusion There was a significant association between the cytokines IL-6 and IL-10 early in pregnancy and decreased cervical length, suggesting an imbalance of immune regulation could impact cervical length. [ABSTRACT FROM AUTHOR]

BACKGROUND: Preeclampsia represents a major cause of maternal mortality and morbidity worldwide. Although it is known that the placenta plays a central role in development of preeclampsia, investigation into the contribution of environmental toxicants to the risk of preeclampsia has been sparse. OBJECTIVES: In the present study we examined the relationship between longitudinally measured urinary BPA and phthalate metabolite concentrations during gestation and preeclampsia. METHODS: A nested case -- control study of preterm birth was performed in 2011 from women enrolled in a prospective birth cohort study at Brigham and Women's Hospital in Boston. There were 50 cases of preeclampsia as part of this study. Urine samples were analyzed for concentrations of BPA and nine phthalate metabolites several times during pregnancy. Adjusted Cox proportional hazard models were used to calculate hazard ratios of preeclampsia in association with an interquartile range increase in BPA and phthalate concentrations and were weighted to reflect results generalizable to the base population. RESULTS: Adjusted hazard ratios indicated that an interquartile range increase of urinary concentrations of BPA (1.53; 95% CI: 1.04, 2.25) and MEP (monoethyl phthalate) (1.72; 95% CI: 1.28, 2.30) at 10 weeks gestation was associated with onset of preeclampsia, whereas significantly elevated hazard ratios were found across gestation for all DEHP [di(2-ethylhexyl) phthalate] metabolites. These relationships differed based on infant sex. CONCLUSIONS: Urinary concentrations of BPA and several phthalate metabolites were significantly associated with increased risk of preeclampsia. If validated, these results indicate an environmental contribution of endocrine-disrupting chemicals to preeclampsia and suggest a modifiable means to reduce the mortality and morbidity associated with this condition. CITATION: Cantonwine DE, Meeker JD, Ferguson KK, Mukherjee B, Hauser R, McElrath TF. 2016. Urinary concentrations of bisphenol A and phthalate metabolites measured during pregnancy and risk of preeclampsia. Environ Health Perspect 124:1651-1655; http://dx.doi.org/10.1289/EHP188 [ABSTRACT FROM AUTHOR]

Background: Preterm birth (PTB), a leading cause of infant mortality and morbidity, has a complex etiology with a multitude of interacting causes and risk factors. The role of environmental contaminants, particularly bisphenol A (BPA), is understudied with regard to PTB. Objectives: In the present study we examined the relationship between longitudinally measured BPA exposure during gestation and PTB. Methods: A nested case–control study was performed from women enrolled in a prospective birth cohort study at Brigham and Women's Hospital in Boston, Massachusetts, during 2006-2008. Urine samples were analyzed for BPA concentrations at a minimum of three time points during pregnancy on 130 cases of PTB and 352 randomly assigned controls. Clinical classifications of PTB were defined as “spontaneous,” which was preceded by spontaneous preterm labor or preterm premature rupture of membranes, or “placental,” which was preceded by preeclampsia or intrauterine growth restriction. Results: Geometric mean concentrations of BPA did not differ significantly between cases and controls. In adjusted models, urinary BPA averaged across pregnancy was not significantly associated with PTB. When examining clinical classifications of PTB, urinary BPA late in pregnancy was significantly associated with increased odds of delivering a spontaneous PTB. After stratification on infant's sex, averaged BPA exposure during pregnancy was associated with significantly increased odds of being delivered preterm among females, but not males. Conclusions: These results provide little evidence of a relationship between BPA and prematurity, though further research may be warranted given the generalizability of participant recruitment from a tertiary teaching hospital, limited sample size, and significant associations among females and within the clinical subcategories of PTB. [ABSTRACT FROM AUTHOR]

Background: Phthalate exposure occurs readily in the environment and has been associated with an array of health end points, including adverse birth outcomes. Some of these may be mediated by oxidative stress, a proposed mechanism for phthalate action. Objectives: In the present study, we explored the associations between phthalate metabolites and biomarkers of oxidative stress measured in urine samples from multiple time points during pregnancy. Methods: Women were participants in a nested case–control study of preterm birth (n = 130 cases, n = 352 controls). Each was recruited early in pregnancy and followed until delivery, providing urine samples at up to four visits. Nine phthalate metabolites were measured to assess exposure, and 8-hydroxydeoxyguanosine and 8-isoprostane were also measured in urine as markers of oxidative stress. Associations were assessed using linear mixed models to account for intraindividual correlation, with inverse selection probability weightings based on case status to allow for greater generalizability. Results: Interquartile range increases in phthalate metabolites were associated with significantly higher concentrations of both biomarkers. Estimated differences were greater in association with monobenzyl phthalate (MBzP), mono-n-butyl phthalate (MBP), and monoisobutyl phthalate (MiBP), compared with di(2-ethylhexyl) phthalate (DEHP) metabolites. Conclusions: Urinary phthalate metabolites were associated with increased oxidative stress biomarkers in our study population of pregnant women. These relationships may be particularly relevant to the study of birth outcomes linked to phthalate exposure. Although replication is necessary in other populations, these results may also be of great importance for a range of other health outcomes associated with phthalates. [ABSTRACT FROM AUTHOR]

Background Preterm birth is a significant public health problem, affecting over 1 in 10 live births and contributing largely to infant mortality and morbidity. Everyday exposure to environmental chemicals such as phthalates could contribute to prematurity, and may be modifiable. In the present study we examine variability in phthalate exposure across gestation and identify windows of susceptibility for the relationship with preterm birth. Methods Women were recruited early in pregnancy as part of a prospective, longitudinal birth cohort at the Brigham and Women's Hospital in Boston, Massachusetts. Urine samples were collected at up to 4 time points during gestation for phthalate measurement, and birth outcomes were recorded at delivery. From this population we selected all 130 cases of preterm birth, defined as delivery before 37 weeks of completed gestation, as well as 352 random controls. Results Urinary phthalate metabolite levels were moderately variable over pregnancy, but levels measured at multiple time points were associated with increased odds of preterm birth. Adjusted odds ratios (aOR) for spontaneous preterm birth were strongest in association with phthalate metabolite concentrations measured at the beginning of the third trimester (aOR for summed di-2-ethylhexyl phthalate metabolites [∑ DEHP] = 1.33, 95% confidence interval [CI] = 1.02, 1.73). Odds ratios for placental preterm birth, defined as delivery with presentation of preeclampsia or intrauterine growth restriction, were slightly elevated in the first trimester for DEHP metabolites (aOR for ∑ DEHP = 1.33, 95% CI = 0.99, 1.78). Conclusions Pregnant women with exposure to phthalates both early and late in pregnancy are at an increased risk of delivering preterm, but mechanisms may differ based on etiology. [ABSTRACT FROM AUTHOR]

Phthalate exposure during pregnancy has been linked to adverse birth outcomes such as preterm birth, and inflammation and oxidative stress may mediate these relationships. In a prospective cohort study of pregnant women recruited early in gestation in Northern Puerto Rico, we investigated the associations between urinary phthalate metabolites and biomarkers of inflammation, including C- reactive protein, IL-1μ, IL-6, IL-10, and TNF-α, and oxidative stress, including 8-hydroxydeoxyguanosine (OHdG) and 8-isoprostane. Inflammation biomarkers were measured in plasma twice during pregnancy (N = 215 measurements, N = 120 subjects), and oxidative stress biomarkers in urine were measured three times (N = 148 measurements, N = 54 subjects) per woman. In adjusted linear mixed models, metabolites of di-2-ethylhexyl phthalate (DEHP) were associated with increased IL-6 and IL-10 but relationships were generally not statistically significant All phthalates were associated with increases in oxidative stress markers. Relationships with OHdG were significant for DEHP metabolites as well as mono-n-butyl phthalate (MBP) and monoiso-butyl phthalate (MiBP). For 8-isoprostane, associations with nearly all phthalates were statistically significant and the largest effect estimates were observed for MBP and MiBP (49-50% increase in 8-isoprostane with an interquartile range increase in metabolite concentration). These relationships suggest a possible mechanism for phthalate action that may be relevant to a number of adverse health outcomes. [ABSTRACT FROM AUTHOR]

Background: Epidemiologic studies suggest phthalate metabolite concentrations are associated with type 2 diabetes. GDM is a strong risk factor for type 2 diabetes. Little is known about phthalates and GDM risk factors (i.e. 1st trimester body mass index (BMI), gestational weight gain (GWG), and 2nd trimester glucose levels). Methods: A total of 350 women participating in Lifecodes pregnancy cohort (Boston, MA), delivered at term and had pregnancy urinary phthalate metabolite concentrations. Nine specific gravity-adjusted urinary phthalate metabolites were evaluated. General linear regression was used to assess associations between quartiles of phthalate metabolites and continuous 1st trimester BMI and late 2nd trimester blood glucose. Linear mixed models were used for total GWG. Multivariable logistic regression was used for phthalate concentrations and categorized GWG and impaired glucose tolerance defined as glucose≥140 mg/dL based on a 50-gram glucose load test. Models were adjusted for potential confounders. Results: There were no associations between 1st trimester urinary phthalate metabolite concentrations and 1st trimester BMI. Mono-ethyl phthalate concentrations averaged across pregnancy were associated with a 2.17 increased odds of excessive GWG (95% CI: 0.98, 4.79). Second trimester mono-ethyl phthalate was associated with increased odds of impaired glucose tolerance (adj. OR: 7.18; 95% CI: 1.97, 26.15). A summary measure of di-2- ethylhexyl phthalate metabolite concentrations were inversely associated with impaired glucose tolerance (adj. OR: 0.25; adj. 95% CI: 0.08, 0.85). Conclusions: Higher exposure to mono-ethyl phthalate, a metabolite of the parent compound of di-ethyl phthalate, may be associated with excessive GWG and impaired glucose tolerance; higher di-2 ethylhexyl phthalate was associated with reduced odds of impaired glucose tolerance.

Higher concentrations of certain phthalate metabolites are associated with adverse reproductive and pregnancy outcomes, as well as poor infant/child health outcomes. In non-pregnant populations, phthalate metabolite concentrations vary by race/ethnicity. Few studies have documented racial/ethnic differences between phthalate metabolite concentrations at multiple time points across the full-course of pregnancy. The objective of the study was to characterize the change in phthalate metabolite concentrations by race/ethnicity across multiple pregnancy time points. Women were participants in a prospectively collected pregnancy cohort who delivered at term (≥37 weeks) and had available urinary phthalate metabolite concentrations for ≥ 3 time points across full-term pregnancies (n = 350 women). We assessed urinary concentrations of eight phthalate metabolites that were log-transformed and specific gravity-adjusted. We evaluated the potential racial/ethnic differences in phthalate metabolite concentrations at baseline (median 10 weeks gestation) using ANOVA and across pregnancy using linear mixed models to calculate the percent change and 95% confidence intervals adjusted for sociodemographic and lifestyle factors. Almost 30% of the population were non-Hispanic black or Hispanic. With the exception of mono-(3 carboxypropyl) (MCPP) and di-ethylhexyl phthalate (DEHP) metabolites, baseline levels of phthalate metabolites were significantly higher in non-whites (Po0.05). When evaluating patterns by race/ethnicity, mono-ethyl phthalate (MEP) and MCPP had significant percent changes across pregnancy. MEP was higher in Hispanics at baseline and decreased in mid-pregnancy but increased in late pregnancy for non-Hispanic blacks. MCPP was substantially higher in non-Hispanic blacks at baseline but decreased later in pregnancy. Across pregnancy, non-Hispanic black and Hispanic women had higher concentrations of certain phthalate metabolites. These differences may have implications for racial/ethnic differences in adverse pregnancy and child health outcomes.

Polycyclic aromatic hydrocarbons (PAHs) are endocrine disruptors resulting from incomplete combustion. Pregnancy represents a particularly vulnerable period to such exposures, given the significant influence of hormone physiology on fetal growth and pregnancy outcomes. Maternal thyroid hormones play crucial roles in fetal development and pregnancy outcomes. However, limited studies have examined gestational PAH exposure and maternal thyroid hormones during pregnancy. Our study included 439 women enrolled in the LIFECODES birth cohort in Boston, aiming to explore the relationship between urinary PAH metabolites and thyroid hormones throughout pregnancy. Urine samples for PAH metabolite analysis and plasma samples for thyroid hormone were measured up to four visits throughout gestation. Single pollutant analyses employed linear mixed effect models to investigate individual associations between each PAH metabolite and thyroid hormone concentration. Sensitivity analyses were conducted to assess potential susceptibility windows and fetal-sex-specific effects of PAH exposure. Mixture analyses utilized quantile g-computation to evaluate the collective impact of eight PAH metabolites on thyroid hormone concentrations. Additionally, Bayesian kernel machine regression (BKMR) was employed to explore potential non-linear associations and interactions between PAH metabolites. Subject-specific random intercepts were incorporated to address intra-individual correlation of serial measurements over time in both single pollutant and mixture analyses. Our findings revealed positive trends in associations between PAH metabolites and thyroid hormones, both individually and collectively as a mixture. Sensitivity analyses indicated that these associations were influenced by the study visit and fetal sex. Mixture analyses suggested non-linear relationships and interactions between different PAH exposures. This comprehensive investigation underscores the critical importance of understanding the impact of PAH exposures on thyroid hormone physiology during pregnancy. The findings highlight the intricate interplay between environmental pollutants and human pregnancy physiology, emphasizing the need for targeted interventions and public health policies to mitigate adverse outcomes associated with prenatal PAH exposure. • Polycyclic aromatic hydrocarbons (PAHs) exposure and thyroid hormone levels were assessed up to four times during pregnancy. • Gestational exposure to PAHs was associated with thyroid hormone concentration during pregnancy. • Associations between PAHs and thyroid hormone concentration varied based on study visit and fetal sex. • Certain PAHs exhibited non-linear associations with thyroid hormones and interacted with other PAHs. [ABSTRACT FROM AUTHOR]

Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals linked to adverse pregnancy outcomes. Although their underlying biological mechanisms are not fully understood, evidence suggests PFAS may disrupt endocrine functions and contribute to oxidative stress (OS) and inflammation. We examined associations between early pregnancy PFAS exposure and OS biomarkers, exploring potential effect modifications by fetal sex and maternal race. We used data from 469 LIFECODES participants with measured plasma PFAS (median 10 weeks gestation) and repeated measures (median 10, 18, 26, and 35 weeks gestation) of urinary OS biomarkers [8-iso-prostaglandin-F2α (8-isoprostane) and 8-hydroxydeoxyguanosine (8-OHdG)]. Protein damage biomarkers (chlorotyrosine, dityrosine, and nitrotyrosine) were additionally measured in plasma from a subset (N = 167) during the third visit. Associations between each PFAS and OS biomarkers were examined using linear mixed-effects models and multivariable linear regressions, adjusting for potential confounders, including maternal age, race, education level, pre-pregnancy BMI, insurance status, and parity. Effect modifications were evaluated by including an interaction term between each PFAS and fetal sex or maternal race in the models. We observed significant positive associations between PFOS and 8-isoprostane, with a 9.68% increase in 8-isoprostane levels (95% CI: 0.10%, 20.18%) per interquartile range increase in PFOS. In contrast, PFUA was negatively associated [9.32% (95% CI: −17.68%, −0.11%)], while there were suggestive positive associations for MPAH and PFOA with 8-isoprostane. The associations of several PFAS with 8-OHdG varied by fetal sex, showing generally positive trends in women who delivered females, but negative or null in those who delivered males. No significant effect modification by maternal race was observed. This study provides evidence linking PFAS exposure to OS during pregnancy, with potential sex-specific effects of certain PFAS on 8-OHdG. Further research should explore additional OS/inflammatory biomarkers and assess the modifying effects of dietary and behavioral patterns across diverse populations. [Display omitted] • PFOS significantly linked with increase in 8-isoprostane levels. • MPAH and PFOA marginally linked with increase in 8-isoprostane levels. • Fetal sex-specific effects of several PFAS on 8-OHdG levels. [ABSTRACT FROM AUTHOR]

Maternal exposure to environmental phenols is common in pregnancy and has been linked to preterm birth, preeclampsia, and reduced fetal growth. One potential mechanism may be through increased maternal oxidative stress. We examined the associations between a panel of 10 urinary phenols, including dichlorophenols, benzophenone-3, parabens, triclosan and triclocarban, and bisphenol-S, and two urinary oxidative stress biomarkers, 8-hydroxydeoxyguanosine (8-OHdG) and 8-isoprostane. All exposure and outcome biomarkers were measured at 4 time points in pregnancy. We used repeated measures models to examine the association between repeated exposure and outcome biomarkers. Additionally, we used adaptive elastic net (AENET) to identify non-null associations accounting for the correlation structure of exposures, both for phenols and urinary phthalate metabolites that were previously associated with the oxidative stress biomarkers in our study population. In adjusted repeated measures models, we observed that dichlorophenols, benzophenone-3, triclosan, and some parabens were associated with increases in both oxidative stress biomarkers. The greatest effect estimates were observed for 2,5-dichlorophenol; an interquartile range (IQR) increase in this compound was associated with a 15.2% (95% confidence interval [CI] = 11.0, 19.6) increase in 8-OHdG and a 16.7% (95% CI = 9.66, 24.2) increase in 8-isoprostane. Bisphenol-S detection was associated with a clear increase in 8-isoprostane (18.5%, 95% CI = 7.68, 30.5) but a more modest increase in 8-OHdG (6.18%, 95% CI = −0.27, 13.1). However, AENET models did not consistently select any of the phenols as predictors of 8-OHdG or 8-isoprostane when phthalate metabolites were included in the model. Overall, urinary phenols were associated with increases in biomarkers of oxidative stress in pregnancy but either to a lesser extent, or due to correlation with, urinary phthalate metabolites. • We examined the association between urinary phenols and oxidative stress biomarkers. • Urinary exposure and outcome biomarkers were measured at 4 study visits in pregnancy. • Phenols were associated with modest increases in both oxidative stress biomarkers. • AENET selected the drivers of associations from the mixture of phenols and phthalates. • Mixture results suggested phthalates were driving phenol-oxidative stress associations. [ABSTRACT FROM AUTHOR]

Background: Non-persistent chemicals, such as phthalates, environmental phenols, organophosphate pesticides, and others, are challenging to study because of their ubiquity in the environment, diverse exposure routes, and high temporal variability of biomarkers. Nonetheless, there is interest in understanding how gestational exposure to these chemicals may affect fetal growth, as perturbations to normal fetal growth are related to a plethora of adverse health outcomes in childhood and adulthood.Methods: The purpose of this review is to describe the state of the science on this topic. We searched PubMed for studies that included both 1) biomarkers of non-persistent chemicals collected during pregnancy and 2) fetal growth outcomes measured at birth (e.g., birth weight) or by ultrasound in utero (e.g., estimated fetal weight).Results: The bulk of the literature we found uses biomarkers measured at a single time point in pregnancy and birth weight as the primary measure of fetal growth. There is a small, but growing, body of research that uses ultrasound measures to assess fetal growth during pregnancy. In addition to summarizing the findings of the publications we identified, we describe inconsistencies in methodology, areas for improvement, and gaps in existing knowledge that can be targeted for improvement in future work. This literature is characterized by variability in methodology, likely contributing to the inconsistency of results reported. We further discuss maternal, placental, and fetal pathways by which these classes of chemicals may affect fetal growth.Conclusions: To improve understanding of how everyday chemical exposures affect fetal growth, and ultimately lifelong health outcomes, mechanisms of toxicant action should be considered alongside improved study designs for future hypothesis-driven research. [ABSTRACT FROM AUTHOR]