Personal care product use patterns in association with phthalate and replacement biomarkers across pregnancy.

BACKGROUND: Humans are exposed to phthalates, a class of non-persistent chemicals, through multiple products, including personal care and cosmetics. Associations between specific phthalates and product use have been inconsistent. However, determining these connections could provide avenues for exposure reduction. OBJECTIVE: Examine the association between patterns of personal care product use and associations with phthalate and replacement biomarkers. METHODS: In the Human Placenta and Phthalates Study, 303 women were enrolled in early pregnancy and followed for up to 8 visits across gestation. At each visit, women completed a questionnaire about product use in the prior 24 hours and contributed urine samples, subsequently analyzed for 18 phthalate and replacement metabolites. At early, mid-, and late pregnancy, questionnaire responses were condensed and repeated metabolite concentrations were averaged. Latent class analysis (LCA) was used to determine groups of women with similar use patterns, and weighted associations between group membership and biomarker concentrations were assessed. RESULTS: LCA sorted women into groups which largely corresponded to: (1) low fragranced product use (16-23% of women); (2) fragranced product and low body wash use (22-26%); 3) fragranced product and low bar soap use (26-51%); and (4) low product use (7-34%). Monoethyl phthalate (MEP) urinary concentrations were 7-10% lower and concentrations of summed di(2-ethylhexyl) terephthalate metabolites were 15-21% lower among women in the "low fragranced product use" group compared to the population mean. Few other consistent associations between group and biomarker concentrations were noted. IMPACT STATEMENT: Personal care products and cosmetics are a known exposure source for phthalates and potentially represent one of the most accessible intervention targets for exposure reduction. However, in this analysis accounting for concurrent use and fragranced status of products, we did not find any use patterns that corresponded to universally lower levels.

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.

Can Weight of Evidence, Quantitative Bias, and Bounding Methods Evaluate Robustness of Real-world Evidence for Regulator and Health Technology Assessment Decisions on Medical Interventions?

PURPOSE: High-quality evidence is crucial for health care intervention decision-making. These decisions frequently use nonrandomized data, which can be more vulnerable to biases than randomized trials. Accordingly, methods to quantify biases and weigh available evidence could elucidate the robustness of findings, giving regulators more confidence in making approval and reimbursement decisions. METHODS: We conducted an integrative literature review to identify methods for determining probability of causation, evaluating weight of evidence, and conducting quantitative bias analysis as related to health care interventions. Eligible studies were published from 2012 to 2021, applicable to pharmacoepidemiology, and presented a method that met our objective. FINDINGS: Twenty-two eligible studies were classified into 4 categories: (1) quantitative bias analysis; (2) weight of evidence methods; (3) Bayesian networks; and (4) miscellaneous. All of the methods have strengths, limitations, and situations in which they are more well suited than others. Some methods seem to lend themselves more to applications of health care evidence on medical interventions than others. IMPLICATIONS: To provide robust evidence for and improve confidence in regulatory or reimbursement decisions, we recommend applying multiple methods to triangulate associations of medical interventions, accounting for biases in different ways. This approach could lead to well-defined robustness assessments of study findings and appropriate science-driven decisions by regulators and payers for public health.

Variability and Longitudinal Trajectories of Phthalate and Replacement Biomarkers across Pregnancy in the Human Placenta and Phthalates Study.

Human exposure to phthalates is widespread, but assessment of variability across pregnancy has been hampered by short half-lives of phthalate biomarkers and a few repeated measures in prior studies. We aimed to characterize the variability and longitudinal profiles of phthalate and replacement biomarkers across pregnancy. Within the Human Placenta and Phthalates Study, 303 pregnant women provided urine samples at up to 8 visits across gestation. Concentrations of 14 metabolites of phthalates and 4 metabolites of replacements were quantified in each sample, and subject-specific averages within each trimester were calculated. We examined variability in individual biomarker concentrations across the 8 visits, within trimesters, and across trimester-specific averages using intraclass correlation coefficients (ICCs). To explore longitudinal exposure biomarker profiles, we applied group-based trajectory modeling to trimester-specific averages over pregnancy. Pooling multiple visits into trimester-specific averages improved the ICCs for all biomarkers. Most biomarkers generally showed stable concentrations across gestation, i.e., high-, medium-, and low-concentration profiles, with small proportions of participants falling into the "high"-exposure groups. Variability over pregnancy is likely attributable to random fluctuations around a baseline exposure rather than true changes in concentrations over time.

Early pregnancy phthalates and replacements in relation to fetal growth: The human placenta and phthalates study.

BACKGROUND: Pregnant persons are exposed ubiquitously to phthalates and increasingly to chemicals introduced to replace phthalates. In early pregnancy, exposure to these chemicals may disrupt fetal formation and development, manifesting adverse fetal growth. Previous studies examining the consequences of early pregnancy exposure relied on single spot urine measures and did not investigate replacement chemicals. OBJECTIVE: Characterize associations between urinary phthalate and replacement biomarkers in early pregnancy and fetal growth outcomes. METHODS: Analyses were conducted among 254 pregnancies in the Human Placenta and Phthalates Study, a prospective cohort with recruitment 2017-2020. Exposures were geometric mean concentrations of phthalate and replacement biomarkers quantified in two spot urine samples collected around 12- and 14-weeks of gestation. Outcomes were fetal ultrasound biometry (head and abdominal circumferences, femur length, estimated fetal weight) collected in each trimester and converted to z-scores. Adjusted linear mixed effects (single-pollutant) and quantile g-computation (mixture) models with participant-specific random effects estimated the difference, on average, in longitudinal fetal growth for a one-interquartile range (IQR) increase in individual (single-pollutant) or all (mixture) early pregnancy phthalate and replacement biomarkers. RESULTS: Mono carboxyisononyl phthalate and the sums of metabolites of di-n-butyl, di-iso-butyl, and di-2-ethylhexyl phthalate were inversely associated with fetal head and abdominal circumference z-scores. A one-IQR increase in the phthalate and replacement biomarker mixture was inversely associated with fetal head circumference (ß: -0.36 [95% confidence interval: -0.56, -0.15]) and abdominal circumference (-0.31 [-0.49, -0.12]) z-scores. This association was mainly driven by phthalate biomarkers. CONCLUSIONS: Urine concentrations of phthalate biomarkers, but not replacement biomarkers, in early pregnancy were associated with reductions in fetal growth. Though the clinical implications of these differences are unclear, reduced fetal growth contributes to excess morbidity and mortality across the lifecourse. Given widespread global exposure to phthalates, findings suggest a substantial population health burden resulting from early pregnancy phthalate exposure.

Drinking Water-Associated PFAS and Fluoroethers and Lipid Outcomes in the GenX Exposure Study.

BACKGROUND: Residents of Wilmington, North, Carolina, were exposed to drinking water contaminated by fluoroethers and legacy per- and polyfluoroalkyl substances (PFAS), such as perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), with fluoroether exposure occurring from 1980 to 2017. PFOA and PFOS have previously been associated with metabolic dysfunction; however, few prior studies have examined associations between other PFAS and lipid levels. OBJECTIVES: We measured the association between serum fluoroether and legacy PFAS levels and various cholesterol outcomes. METHODS: Participants in the GenX Exposure Study contributed nonfasting blood samples in November 2017 and May 2018 that were analyzed for 20 PFAS (10 legacy, 10 fluoroethers) and serum lipids [total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides] and calculated non-HDL cholesterol. We estimated covariate-adjusted associations between quartiles of exposure to each of the PFAS measures (as well as the summed concentrations of legacy PFAS, fluoroethers, and all 10 targeted PFAS) and lipid outcomes by fitting inverse probability of treatment weighted linear regressions. RESULTS: In this cross-sectional study of 326 participants (age range 6-86 y), eight PFAS were detected in >50% of the population. For PFOS and perfluorononanoic acid (PFNA), non-HDL cholesterol was approximately 5mg/dL higher per exposure quartile increase: [PFOS: 4.89; 95% confidence interval (CI): 0.10, 9.68 and PFNA: 5.25 (95% CI: 0.39, 10.1)], whereas total cholesterol was approximately 6mg/dL higher per quartile [PFOS: 5.71 (95% CI: 0.38, 11.0), PFNA: 5.92 (95% CI: 0.19, 11.7)]. In age-stratified analyses, associations were strongest among the oldest participants. Two fluoroethers were associated with higher HDL, whereas other fluoroether compounds were not associated with serum lipid levels. DISCUSSION: PFNA and PFOS were associated with higher levels of total and non-HDL cholesterol, with associations larger in magnitude among older adults. In the presence of these legacy PFAS, fluoroethers appeared to be associated with HDL but not non-HDL lipid measures. https://doi.org/10.1289/EHP11033.

Associations Between Prenatal Urinary Biomarkers of Phthalate Exposure and Preterm Birth: A Pooled Study of 16 US Cohorts.

Importance: Phthalate exposure is widespread among pregnant women and may be a risk factor for preterm birth. Objective: To investigate the prospective association between urinary biomarkers of phthalates in pregnancy and preterm birth among individuals living in the US. Design, Setting, and Participants: Individual-level data were pooled from 16 preconception and pregnancy studies conducted in the US. Pregnant individuals who delivered between 1983 and 2018 and provided 1 or more urine samples during pregnancy were included. Exposures: Urinary phthalate metabolites were quantified as biomarkers of phthalate exposure. Concentrations of 11 phthalate metabolites were standardized for urine dilution and mean repeated measurements across pregnancy were calculated. Main Outcomes and Measures: Logistic regression models were used to examine the association between each phthalate metabolite with the odds of preterm birth, defined as less than 37 weeks of gestation at delivery (n = 539). Models pooled data using fixed effects and adjusted for maternal age, race and ethnicity, education, and prepregnancy body mass index. The association between the overall mixture of phthalate metabolites and preterm birth was also examined with logistic regression. G-computation, which requires certain assumptions to be considered causal, was used to estimate the association with hypothetical interventions to reduce the mixture concentrations on preterm birth. Results: The final analytic sample included 6045 participants (mean [SD] age, 29.1 [6.1] years). Overall, 802 individuals (13.3%) were Black, 2323 (38.4%) were Hispanic/Latina, 2576 (42.6%) were White, and 328 (5.4%) had other race and ethnicity (including American Indian/Alaskan Native, Native Hawaiian, >1 racial identity, or reported as other). Most phthalate metabolites were detected in more than 96% of participants. Higher odds of preterm birth, ranging from 12% to 16%, were observed in association with an interquartile range increase in urinary concentrations of mono-n-butyl phthalate (odds ratio [OR], 1.12 [95% CI, 0.98-1.27]), mono-isobutyl phthalate (OR, 1.16 [95% CI, 1.00-1.34]), mono(2-ethyl-5-carboxypentyl) phthalate (OR, 1.16 [95% CI, 1.00-1.34]), and mono(3-carboxypropyl) phthalate (OR, 1.14 [95% CI, 1.01-1.29]). Among approximately 90 preterm births per 1000 live births in this study population, hypothetical interventions to reduce the mixture of phthalate metabolite levels by 10%, 30%, and 50% were estimated to prevent 1.8 (95% CI, 0.5-3.1), 5.9 (95% CI, 1.7-9.9), and 11.1 (95% CI, 3.6-18.3) preterm births, respectively. Conclusions and Relevance: Results from this large US study population suggest that phthalate exposure during pregnancy may be a preventable risk factor for preterm delivery.

Prenatal Phthalate Exposure and Child Weight and Adiposity from in Utero to 6 Years of Age.

BACKGROUND: Prenatal 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. OBJECTIVE: We assessed associations between maternal phthalate exposures in pregnancy and child weight and adiposity measured prenatally through childhood (3-6 years of age). METHODS: Within 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. RESULTS: For 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). DISCUSSION: We 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.

Is prenatal diet associated with the composition of the vaginal microbiome?

BACKGROUND: The vaginal microbiome has been associated with adverse pregnancy outcomes, but information on the impact of diet on microbiome composition is largely unexamined. OBJECTIVE: To estimate the association between prenatal diet and vaginal microbiota composition overall and by race. METHODS: We leveraged a racially diverse prenatal cohort of North Carolina women enrolled between 1995 and 2001 to conduct this analysis using cross-sectional data. Women completed food frequency questionnaires about diet in the previous 3 months and foods were categorised into subgroups: fruits, vegetables, nuts/seeds, whole grains, low-fat dairy, sweetened beverages and red meat. We additionally assessed dietary vitamin D, fibre and yogurt consumption. Stored vaginal swabs collected in mid-pregnancy were sequenced using 16S taxonomic profiling. Women were categorised into three groups based on predominance of species: Lactobacillus iners, Lactobacillus miscellaneous and Bacterial Vaginosis (BV)-associated bacteria. Adjusted Poisson models with robust variance estimators were run to assess the risk of being in a specific vagitype compared to the referent. Race-stratified models (Black/White) were also run. RESULTS: In this study of 634 women, higher consumption of dairy was associated with increased likelihood of membership in the L. crispatus group compared to the L. iners group in a dose-dependent manner (risk ratio quartile 4 vs. 1: 2.01, 95% confidence interval 1.36, 2.95). Increased intake of fruit, vitamin D, fibre and yogurt was also associated with increased likelihood of membership in L. crispatus compared to L. iners, but only among black women. Statistical heterogeneity was only detected for fibre intake. There were no detected associations between any other food groups or risk of membership in the BV group. CONCLUSIONS: Higher consumption of low-fat dairy was associated with increased likelihood of membership in a beneficial vagitype, potentially driven by probiotics.

Omega-3 fatty acid supplement use and oxidative stress levels in 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.

Time to blastulation is superior to individual components of embryo grading for live-birth prediction.

OBJECTIVE: To compare components of the embryo grading system with time for blastocyst formation (i.e., day of embryo transfer) for predicting live-birth rate in frozen embryo transfer cycles. DESIGN: Retrospective cohort study. SETTING: University-affiliated fertility clinic. PATIENTS: From January 2015 to October 2018, 870 frozen embryos transferred in a total of 509 women and 728 cycles at our institution. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Probability of live birth per cycle. RESULTS: In unadjusted analysis of embryo grading components, both inner cell mass (ICM) and trophectoderm grades demonstrated a correlation with live-birth rates. However, this effect was lost in the ICM subgroup analysis by day of embryo transfer and preserved only in declining trophectoderm grades of day-6 transfers. In the adjusted analysis for prediction of live birth, only day of transfer was statistically significant. When assessing the composite score by Society for Assisted Reproductive Technology (SART) embryo grading, good embryos that blastulated on day 6 were statistically significantly less likely than day-5 embryos to result in live birth (risk ratio 0.70; 95% confidence interval, 0.58-0.85). Finally, in a predictive model adjusted for all individual components of embryo grade, the day of blastulation was the only statistically significant contributor. CONCLUSIONS: Time to blastulation is superior to other individual components of embryonic grading for prediction of live birth.

Joint impact of phthalate exposure and stressful life events in pregnancy on preterm birth.

BACKGROUND: Urinary 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. METHODS: We 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. RESULTS: Summed 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). CONCLUSIONS: We 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.

Environmental phthalate exposure and preterm birth in the PROTECT birth cohort.

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.

Phthalates and Phthalate Alternatives Have Diverse Associations with Oxidative Stress and Inflammation in Pregnant Women.

Exposure to environmental chemicals such as phthalates has been linked to numerous adverse pregnancy outcomes, potentially through an oxidative stress mediated mechanism. Most research examined urinary 8-iso-prostaglandin F2α (8-iso-PGF2α) as the oxidative stress biomarker. However, 8-iso-PGF2α also originates from enzymatic sources linked to inflammation. Therefore, associations between phthalates and 8-iso-PGF2α could have been misinterpreted. To clarify this, the 8-iso-PGF2α/prostaglandin F2α ratio approach was used to quantitatively distinguish between inflammation or oxidative stress derived 8-iso-PGF2α and estimate their associations with phthalate metabolites in a cohort of 758 pregnant women from The Infant Development and Environment Study (TIDES). Most urinary phthalate metabolites were associated with a significant increase in 8-iso-PGF2α. For example, a 22.4% higher 8-iso-PGF2α concentration (95% confidence interval = 14.4, 30.9) was observed with an interquartile range increase in mono- n-butyl phthalate. For most metabolites, associations were observed solely with oxidative stress derived 8-iso-PGF2α. In contrast, monocarboxy-isononyl phthalate and monoisononyl phthalate (MNP) were associated with both sources of 8-iso-PGF2α. Metabolites of the phthalate alternative 1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH), were only associated with inflammation-derived 8-iso-PGF2α, which is interesting because DINCH metabolites and MNP have structural similarities.In conclusion, phthalates metabolites are not exclusively associated with oxidative stress derived 8-iso-PGF2α. Depending on the metabolite structure, some are also associated with inflammation derived sources, which provides interesting insights in the toxicology of phthalates.

Urinary oxidative stress biomarkers and accelerated time to spontaneous delivery.

BACKGROUND: Oxidative 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. METHODS: Our 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. RESULTS: The 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. CONCLUSIONS: Our 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.

Environmental contaminants and preeclampsia: a systematic literature review.

Preeclampsia is a medical condition specific to pregnancy characterized by high blood pressure and protein in the woman's urine, indicating kidney damage. It is one of the most serious reproductive conditions, posing substantial risks to the baby and potentially fatal for the mother. The causes of preeclampsia are largely unknown and environmental contaminants merit further investigation. The aim of this review was to determine the association between environmental chemical exposures and preeclampsia. PubMed was searched for articles examining a priori chemical exposures and preeclampsia through April 2018. Studies were included in our review if they included at least 10 cases, evaluated preeclampsia independent of gestational hypertension, and used either measured or modeled exposure assessments. Our review contained 28 investigations examining persistent organic pollutants (POP) (6 studies), drinking water contaminants (1 study), atmospheric pollutants (11 studies), metals and metalloids (6 studies), and other environmental contaminants (4 studies). There were an insufficient number of investigations on most chemicals to draw definitive conclusions, but strong evidence existed for an association between preeclampsia and cadmium (Cd). There is suggestive evidence for associations between nitrogen dioxide (NO2), particulate matter (PM)2.5, and traffic exposure with preeclampsia. There is evidence for an association between preeclampsia and Cd but insufficient literature to evaluate many other environmental chemicals. Additional studies using repeated measures, appropriate biological matrices, and mixtures methods are needed to expand this area of research and address the limitations of previous studies.

Maternal Plasma Concentrations of Per- and polyfluoroalkyl Substances and Breastfeeding Duration in the Norwegian Mother and Child Cohort.

BACKGROUND: Per- and polyfluoroalkyl substances (PFASs) have been widely produced, many of them persist in the environment, and have been associated with various health effects. Previous studies have identified inverse associations between perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS) and breastfeeding duration, but have been limited in investigation of other PFASs. METHODS: We measured the associations between plasma concentrations of 9 different PFASs and cessation of breastfeeding before 3 and 6 complete months using women from the Norwegian Mother and Child Cohort Study (MoBa). The study population includes 1716 primarily nulliparous women from two previous studies of MoBa participants, enrolled from 2003-2007. The association was measured using Cox proportional hazards model. Mixtures analyses were performed using Elastic net regularization to identify interactive effects and control for co-pollutant confounding. RESULTS: Concentrations of PFASs in this population were lower than concentrations in the previous studies on this topic. We found associations between increasing concentrations of perfluorononanoic acid (PFNA), perfluorodecaconic acid (PFDA), perfluoroundecanoic acid (PFUnDA) and decreased breastfeeding cessation (increased duration). The strongest associations were seen between PFDA and PFUnDA and cessation before 3 months: (both hazard ratios = 0.73, 95% confidence intervals: 0.62, 0.86). In our population, the other PFASs appeared to be unassociated with breastfeeding cessation. The mixtures analyses identified meaningful interactions between PFUnDA:PFDA, perfluorohexane sulfonate (PFHXS):PFOA and PFOA:PFOS. CONCLUSIONS: The identification of associations between previously unexamined PFASs concentrations and increased breastfeeding duration is novel and may be explained by differences in transplacental transfer rates.