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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.

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.

Preterm birth is a leading cause of neonatal mortality. Preterm birth is a public health burden, particularly in the United States, where approximately 10% of deliveries are preterm. Although the underlying cause of most preterm births is unknown, environmental chemical exposures (such as phthalates) possibly contribute. Phthalates are common in consumer products, and exposure can occur through diet, personal care products, and even household dust. Consequently, exposure is ubiquitous for pregnant individuals. Prenatal phthalate exposure has been associated with adverse neurodevelopment in children and disordered development of the male reproductive tract. This study reviewed 16 prospective studies conducted within the United States to pool individual-level data to examine prenatal urinary biomarkers of phthalate exposure and preterm birth. In addition, potential influence of exposure to overall phthalate mixture was assessed to determine the potential impact of reduced exposure on preterm birth.Results of the study indicated that of 6045 pregnant women, 539 (9%) delivered preterm. Overall, of the entire included cohort, 802 individuals were Black (13.3%), 2576 were White (42.6%), 2323 were Latina (38.4%), and 328 had other race identity (including Native Hawaiian, Alaskan Native, or American Indian). Characteristics of participants were similar between those who delivered preterm versus term. Some 96% of urine samples displayed detectable concentrations of urinary phthalate metabolites. As demonstrated by regression analyses, higher concentrations of most phthalate metabolites bore an association of slightly higher odds (12%–16% higher) for preterm birth. In addition, the study estimated that reducing the mixture of phthalate metabolite concentrations by 10%, 30%, or 50%, respectively, could prevent 1.8, 5.9, and 11.1 preterm births per 1000 live births.The study found a relationship between higher maternal pregnancy concentrations of urinary phthalate metabolites and preterm birth. The findings of this study identify a potential benefit of phthalate exposure reduction among pregnant individuals via either regulations or behavioral interventions. Because phthalate exposure can occur through many environments and sources, the US Consumer Product Safety Commission has attempted to pinpoint major sources of phthalate exposure and has determined that the predominate exposures appear to occur through food and medications, although uncertainty in the primary source of exposure remains. Phthalate exposure also widely varies in the United States based on several factors such as whether a person is at a disadvantaged socioeconomic status, is pregnant, or is of a marginalized race or ethnicity. Targeted interventions, such as altering personal care products, is made challenging as consumers are not readily able to access accurate ingredients lists. In the United States, for example, fragrance ingredient lists are not required to list phthalates when they are included in the product.Diet interventions intending to reduce phthalate exposure have had mixed results. Although federally mandated restrictions have limited the use of phthalates in products for children, few such restrictions exist for products intended for pregnant individuals. As 28 phthalates are currently allowed as food additives or in food contact materials, they are difficult to avoid. Mitigation of population-level health effects from phthalates through regulatory means would be most effective when considering phthalates not as individual chemicals, but rather as a class.This study found that higher concentrations of several urinary phthalate metabolites in pregnancy were associated with preterm birth, a consistent finding across 16 prospective US studies. Such findings emphasize the importance of the development of policy measures and public health around phthalate exposure reduction, especially among pregnant individuals.

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.

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-PGF2αalso originates from enzymatic sources linked to inflammation. Therefore, associations between phthalates and 8-iso-PGF2αcould have been misinterpreted. To clarify this, the 8-iso-PGF2α/prostaglandin F2αratio approach was used to quantitatively distinguish between inflammation or oxidative stress derived 8-iso-PGF2αand 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-PGF2αconcentration (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.