Associations between mixtures of urinary phthalate metabolites with gestational age at delivery: a time to event analysis using summative phthalate risk scores

Abstract

BackgroundPreterm birth is a significant public health concern and exposure to phthalates has been shown to be associated with an increased odds of preterm birth. Even modest reductions in gestational age at delivery could entail morbid consequences for the neonate and analyzing data with this additional information may be useful. In the present analysis, we consider gestational age at delivery as our outcome of interest and examine associations with multiple phthalates.MethodsWomen 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 four time points during gestation for urinary phthalate metabolite measurement, and birth outcomes were recorded at delivery. From this population, we selected all 130 cases of preterm birth (< 37 weeks of gestation) as well as 352 random controls. We conducted analysis with both geometric average of the exposure concentrations across the first three visits as well as using repeated measures of the exposure. Two different time to event models were used to examine associations between nine urinary phthalate metabolite concentrations and time to delivery. Two different approaches to constructing a summative phthalate risk score were also considered.ResultsThe single-pollutant analysis using a Cox proportional hazards model showed the strongest association with a hazard ratio (HR) of 1.21 (95% confidence interval (CI): 1.09, 1.33) per interquartile range (IQR) change in average log-transformed mono-2-ethyl-5-carboxypentyl phthalate (MECPP) concentration. Using the accelerated failure time model, we observed a 1.19% (95% CI: 0.26, 2.11%) decrease in gestational age in association with an IQR change in average log-transformed MECPP. We next examined associations with an environmental risk score (ERS). The fourth quartile of ERS was significantly associated with a HR of 1.44 (95% CI: 1.19, 1.75) and a reduction of 2.55% (95% CI: 0.76, 4.30%) in time to delivery (in days) compared to the first quartile.ConclusionsOn average, pregnant women with higher urinary metabolite concentrations of individual phthalates have shorter time to delivery. The strength of the observed associations are amplified with the risk scores when compared to individual pollutants.Electronic supplementary materialThe online version of this article (10.1186/s12940-018-0400-3) contains supplementary material, which is available to authorized users.

Application of an analytical framework for multivariate mediation analysis of environmental data

“…Therefore these eicosanoids may be up-regulated in disease states involving cardiovascular irregularities, an important precursor for adverse pregnancy outcomes 14 . Among the environmental exposures, we also showed that phthalates have been associated with increased risk for preterm delivery and reduced gestational age at delivery within the LIFECODES cohort 15,16 . Based on these previous studies, there is circumstantial evidence of potential mediation between prenatal phthalate exposure and pregnancy outcomes through eicosanoids.…”

“…We propose an analytical framework (Fig. 1 ) that integrates our previous methodological contributions in environmental risk score construction 16 , 23 , 24 with the aforementioned multivariate mediation analysis methods 19 , 21 . In this framework, we provide a guided discussion on approaches that include one-at-a-time pairwise mediation, exposure dimension reduction, and mediator shrinkage, dimension reduction, and penalization.…”

Association of Parental Preconception Exposure to Phthalates and Phthalate Substitutes With Preterm Birth

“…This association was more pronounced among male infants than female infants. [51][52][53][54] while others found inconsistent 55,56 or contrasting 49,57 results.…”

Phthalate exposure from drugs during pregnancy and possible risk of preterm birth and small for gestational age

“…Somewhat surprisingly, we found that phthalate polymers from drugs appear to have similar effects. Some studies have addressed the potential association between environmental phthalate exposure (assessed by biomarkers) and PTB or differences in gestational age 3,[25][26][27][28][29][30][31][32] . Studies that focus on gestational age are less conclusive, whereas studies that address the risk of PTB, support an association.…”