Supplementation with antioxidant micronutrients in pregnant women with obesity: a randomized controlled trial.

BACKGROUND/OBJECTIVE: Obesity increases maternal morbidity and adversely affects child health. Maternal inflammation may play a role in adverse outcomes. The objective of this study was to determine whether providing a higher dose of antioxidant micronutrients to pregnant women with obesity would raise concentrations of key antioxidant vitamins and impact inflammation and oxidative stress during pregnancy. SUBJECTS/METHODS: This was a double-blind, randomized controlled trial. We recruited pregnant women with a body mass index (BMI) ≥ 30 kg/m2 at their initial prenatal visit ( < 13 weeks gestation) and collected blood and urine samples at baseline, 24-28 weeks, and 32-36 weeks to measure micronutrient concentrations (vitamin C, E, B6 and folate), markers of inflammation (C-reactive protein, interleukin-6, 8, and 1ß) and oxidative stress (8-epi-PGF2α and malondialdehyde). We collected maternal and infant health data from enrollment to delivery as secondary outcomes. We enrolled 128 participants (64 in each arm), and 98 (49 in each arm) completed follow-up through delivery. INTERVENTION: Both groups received a standard prenatal vitamin containing the recommended daily allowance of micronutrients in pregnancy. In addition, the intervention group received a supplement with 90 mg vitamin C, 30 αTU vitamin E, 18 mg vitamin B6, and 800 µg folic acid, and the control group received a placebo. RESULTS: The intervention group had higher vit B6 (log transformed (ln), ß 24-28 weeks: 0.76 nmol/L (95% CI: 0.40, 1.12); ß 32-36 weeks: 0.52 nmol/L (95% CI: 0.17, 0.88)) than the control group. Vitamins C, E, erythrocyte RBC folate concentrations did not differ by randomization group. The intervention did not impact biomarkers of inflammation or oxidative stress. There were no differences in maternal or neonatal clinical outcomes by randomization group. CONCLUSIONS: Higher concentrations of antioxidant vitamins during pregnancy increased specific micronutrients and did not impact maternal inflammation and oxidative stress, which may be related to dosing or type of supplementation provided. CLINICAL TRIAL REGISTRATION: Clinical Trial Identification Number: NCT02802566; URL of the Registration Site: www. CLINICALTRIALS: gov .

Associations of urinary polycyclic aromatic hydrocarbon (PAH) metabolites and their mixture with thyroid hormone concentration during pregnancy in the LIFECODES cohort: A repeated measures study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Prenatal per- and polyfluoroalkyl substances (PFAS) and maternal oxidative stress: Evidence from the LIFECODES study.

BACKGROUND: 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. OBJECTIVE: We examined associations between early pregnancy PFAS exposure and OS biomarkers, exploring potential effect modifications by fetal sex and maternal race. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Prenatal exposure to environmental phenols and fetal growth across pregnancy in the LIFECODES fetal growth study.

INTRODUCTION: Environmental phenols are endocrine disrupting chemicals hypothesized to affect early life development. Previous research examining the effects of phenols on fetal growth has focused primarily on associations with measures of size at delivery. Few have included ultrasound measures to examine growth across pregnancy. OBJECTIVE: Investigate associations between prenatal exposure to phenols and ultrasound and delivery measures of fetal growth. METHODS: Using the LIFECODES Fetal Growth Study (n = 900), a case-cohort including 248 small-for-gestational-age, 240 large-for-gestational age, and 412 appropriate-for-gestational-age births, we estimated prenatal exposure to 12 phenols using three urine samples collected during pregnancy (median 10, 24, and 35 weeks gestation). We abstracted ultrasound and delivery measures of fetal growth from medical records. We estimated associations between pregnancy-average phenol biomarker concentrations and repeated ultrasound measures of fetal growth using linear mixed effects models and associations with birthweight using linear regression models. We also used logistic regression models to estimate associations with having a small- or large-for-gestational birth. RESULTS: We observed positive associations between 2,4-dichlorophenol, benzophenone-3, and triclosan (TCS) and multiple ultrasound measures of fetal growth. For example, TCS was associated with a 0.09 (95 % CI: 0.01, 0.18) higher estimated fetal weight z-score longitudinally across pregnancy. This effect size corresponds to a 21 g increase in estimated fetal weight at 30 weeks gestation. Associations with delivery measures of growth were attenuated, but TCS remained positively associated with birthweight z-scores (mean difference: 0.13, 95 % CI: 0.02, 0.25). Conversely, methylparaben was associated with higher odds of a small-for-gestational age birth (odds ratio: 1.45, 95 % CI: 1.06, 1.98). DISCUSSION: We observed associations between some biomarkers of phenol exposure and ultrasound measures of fetal growth, though associations at the time of delivery were attenuated. These findings are consistent with hypotheses that phenols have the potential to affect growth during the prenatal period.

Predictors of upstream inflammation and oxidative stress pathways during early pregnancy.

BACKGROUND: Inflammation and oxidative stress are critical to pregnancy, but most human study has focused on downstream, non-causal indicators. Oxylipins are lipid mediators of inflammation and oxidative stress that act through many biological pathways. Our aim was to characterize predictors of circulating oxylipin concentrations based on maternal characteristics. METHODS: Our study was conducted among 901 singleton pregnancies in the LIFECODES Fetal Growth Study, a nested case-cohort with recruitment from 2007 to 2018. We measured a targeted panel of oxylipins in early pregnancy plasma and urine samples from several biosynthetic pathways, defined by the polyunsaturated fatty acid (PUFA) precursor and enzyme group. We evaluated levels across predictors, including characteristics of participants' pregnancy, socioeconomic determinants, and obstetric and medical history. RESULTS: Current pregnancy and sociodemographic characteristics were the most important predictors of circulating oxylipins concentrations. Plasma oxylipins were lower and urinary oxylipins higher for participants with a later gestational age at sampling (13-23 weeks), higher prepregnancy BMI (obesity class I, II, or III), Black or Hispanic race and ethnicity, and lower socioeconomic status (younger age, lower education, and uninsured). For example, compared to those with normal or underweight prepregnancy BMI, participants with class III prepregnancy obesity had 45-46% lower plasma epoxy-eicosatrienoic acids, the anti-inflammatory oxylipins produced from arachidonic acid (AA) by cytochrome P450, and had 81% higher urinary 15-series F2-isoprostanes, an indicator of oxidative stress produced from non-enzymatic AA oxidation. Similarly, in urine, Black participants had 92% higher prostaglandin E2 metabolite, a pro-inflammatory oxylipin, and 41% higher 5-series F2-isoprostane, an oxidative stress indicator. CONCLUSIONS: In this large pregnancy study, we found that circulating levels of oxylipins were different for participants of lower socioeconomic status or of a systematically marginalized racial and ethnic groups. Given associations differed along biosynthetic pathways, results provide insight into etiologic links between maternal predictors and inflammation and oxidative stress.

Organophosphate Ester Flame Retardants and Plasticizers in Relation to Fetal Growth in the LIFECODES Fetal Growth Study.

BACKGROUND: Organophosphate esters (OPEs), used ubiquitously as flame retardants and plasticizers in consumer products, are suspected of having developmental toxicity. OBJECTIVES: Our study aimed to estimate associations between prenatal exposure to OPEs and fetal growth, including both ultrasound (head circumference, abdominal circumference, femur length, and estimated fetal weight) and delivery [birth weight z-score, small-for-gestational age (SGA), and large-for-gestational age (LGA)] measures of growth. METHODS: In the LIFECODES Fetal Growth Study (2008-2018), an enriched case-cohort of 900 babies born at the small and large ends of the growth spectrum, we quantified OPE biomarkers in three urine samples per pregnant participant and abstracted ultrasound and delivery measures of fetal growth from medical records. We estimated associations between pregnancy-averaged log-transformed OPE biomarkers and repeated ultrasound measures of fetal growth using linear mixed-effects models, and delivery measures of fetal growth using linear (birth weight) and logistic (SGA and LGA) regression models. RESULTS: Most OPE biomarkers were positively associated with at least one ultrasound measure of fetal growth, but associations with delivery measures were largely null. For example, an interquartile range (IQR; 1.31 ng/mL) increase in bis(2-chloroethyl) phosphate concentration was associated with larger z-scores in head circumference [mean difference (difference): 0.09; 95% confidence interval (CI): 0.01, 0.17], abdominal circumference (difference: 0.10; 95% CI: 0.02, 0.18), femur length (difference: 0.11; 95% CI: 0.03, 0.19), and estimated fetal weight (difference: 0.13; 95% CI: 0.04, 0.22) but not birth weight (difference: 0.04; 95% CI: -0.08, 0.17). At delivery, an IQR (1.00 ng/mL) increase in diphenyl phosphate (DPHP) concentration was associated with an SGA birth (odds ratio: 1.46; 95% CI: 1.10, 1.94). CONCLUSIONS: In a large prospective cohort, gestational OPE exposures were associated with larger fetal size during pregnancy, but associations at delivery were null. DPHP concentrations were associated with heightened risk of an SGA birth. These findings suggest that OPE exposure may affect fetal development. https://doi.org/10.1289/EHP14647.

Cohort profile: the Environmental Reproductive and Glucose Outcomes (ERGO) Study (Boston, Massachusetts, USA) - a prospective pregnancy cohort study of the impacts of environmental exposures on parental cardiometabolic health.

PURPOSE: Pregnancy and the postpartum period are increasingly recognised as sensitive windows for cardiometabolic disease risk. Growing evidence suggests environmental exposures, including endocrine-disrupting chemicals (EDCs), are associated with an increased risk of pregnancy complications that are associated with long-term cardiometabolic risk. However, the impact of perinatal EDC exposure on subsequent cardiometabolic risk post-pregnancy is less understood. The Environmental Reproductive and Glucose Outcomes (ERGO) Study was established to investigate the associations of environmental exposures during the perinatal period with post-pregnancy parental cardiometabolic health. PARTICIPANTS: Pregnant individuals aged ≥18 years without pre-existing diabetes were recruited at <15 weeks of gestation from Boston, Massachusetts area hospitals. Participants completed ≤4 prenatal study visits (median: 12, 19, 26, 36 weeks of gestation) and 1 postpartum visit (median: 9 weeks), during which we collected biospecimens, health histories, demographic and behavioural data, and vitals and anthropometric measurements. Participants completed a postpartum fasting 2-hour 75 g oral glucose tolerance test. Clinical data were abstracted from electronic medical records. Ongoing (as of 2024) extended post-pregnancy follow-up visits occur annually following similar data collection protocols. FINDINGS TO DATE: We enrolled 653 unique pregnancies and retained 633 through delivery. Participants had a mean age of 33 years, 10% (n=61) developed gestational diabetes and 8% (n=50) developed pre-eclampsia. Participant pregnancy and postpartum urinary phthalate metabolite concentrations and postpartum glycaemic biomarkers were quantified. To date, studies within ERGO found higher exposure to phthalates and phthalate mixtures, and separately, higher exposure to radioactive ambient particulate matter, were associated with adverse gestational glycaemic outcomes. Additionally, certain personal care products used in pregnancy, notably hair oils, were associated with higher urinary phthalate metabolite concentrations, earlier gestational age at delivery and lower birth weight. FUTURE PLANS: Future work will leverage the longitudinal data collected on pregnancy and cardiometabolic outcomes, environmental exposures, questionnaires, banked biospecimens and paediatric data within the ERGO Study.

Racial and Ethnic Disparities in Phthalate Exposure and Preterm Birth: A Pooled Study of Sixteen U.S. Cohorts.

BACKGROUND: Phthalate exposures are ubiquitous during pregnancy and may contribute to racial and ethnic disparities in preterm birth. OBJECTIVES: We 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. METHODS: We 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. RESULTS: In 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. CONCLUSIONS: Phthalate 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.