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Background:

Humans are exposed to complex mixtures of phthalate chemicals from a range of consumer products. Previous studies have reported significant associations between individual phthalate metabolites and pregnancy outcomes, but mixtures research is limited.

Objectives:

We used the Puerto Rico Testsite for Exploring Contamination Threats longitudinal pregnancy cohort to investigate associations between phthalate metabolite mixtures and pregnancy outcomes.

Methods:

Women ($n=462$ carrying females, $n=540$ carrying males) provided up to three urine samples throughout gestation (median 18, 22, and 26 wk), which were analyzed for 13 phthalate metabolites. Pregnancy outcomes including preterm birth (PTB), spontaneous PTB, small and large for gestational age (SGA, LGA), birth weight z-score, and gestational age at delivery were abstracted from medical records. Environmental risk scores (ERS) were calculated as a weighted linear combination of the phthalates from ridge regression and adaptive elastic net, which are variable selection methods to handle correlated predictors. Birth outcomes were regressed on continuous ERS. We assessed gestational average and visit-specific ERS and stratified all analyses by fetal sex. Finally, we used Bayesian kernel machine regression (BKMR) to explore nonlinear associations and interactions between metabolites.

Results:

Differences in metabolite weights from ridge and elastic net were apparent between birth outcomes and between fetal sexes. An interquartile range increase in gestational average phthalate ERS was associated with increased odds of PTB [male $\text{odds}\text{ratio}\left(\text{OR}\right)=1.56$; 95% confidence interval (CI): 1.08, 2.27; female $\text{OR}=1.91$; 95% CI: 1.23, 2.98], spontaneous PTB (male $\text{OR}=2.32$; 95% CI: 1.46, 3.68; female $\text{OR}=2.00$; 95% CI: 1.04, 3.82), and reduced gestational age at birth (male $\mathrm{\beta }=-0.39$ wk, 95% CI: $-0.62$, $-0.15$; female $\mathrm{\beta }=-0.29$ wk, 95% CI: $-0.52$, $-0.05$). Analyses by study visit suggested that exposure at $\sim 22$ wk (range 20–24 wk) was driving those associations. Bivariate plots from BKMR analysis revealed some nonlinear associations and metabolite interactions that were different between fetal sexes.

Discussion:

These results suggest that exposure to phthalate mixtures was associated with increased risk of early delivery and highlight the need to study mixtures by fetal sex. We also identified various metabolites displaying nonlinear relationships with measures of birth weight. https://doi.org/10.1289/EHP8990