Prenatal Environmental Exposure to Phthalates and Their Replacements and Fetal Growth

Prenatal exposure to phthalates has been associated with several pregnancy and developmental end points, including birthweight, and may be harmful to fetal growth across pregnancy and not only at birth. Therefore, this study investigates associations between environmental exposure to phthalates and their replacements, individually and as mixtures, with ultrasound and delivery measures of fetal growth. This study leverages data from the LIFECODES Fetal Growth Study, a case-cohort study (N = 900) selected from an ongoing prospective pregnancy cohort at Brigham and Women’s Hospital (BWH). Pregnant women were eligible for inclusion in the parent cohort if they were at least 18 years of age, were recruited prior to 15 weeks gestation, and intended to deliver at BWH. Selection into the case-cohort was restricted to nonanomalous singleton pregnancies that ended in a live birth. Biomarkers of exposure to phthalate and replacement metabolites were quantified in samples from three time points across pregnancy (median 10, 26, and 35 weeks gestation) and examined individually and as mixtures. The main outcomes were small-for-gestational-age (SGA, birthweight <10th percentile) or large-for-gestational-age (LGA, birthweight >90th percentile). Associations with repeated ultrasound measures of fetal growth and birthweight z-scores were also assessed. As a secondary analysis, associations with phenotypes of SGA and LGA births based on patterns of prenatal growth were examined. We report that the LMW phthalate mixture was inversely associated with ultrasound measures of fetal growth as well as birth weight among male fetuses. Conversely, certain HMW phthalates were associated with higher ultrasound measures among female fetuses. Similar patterns of effect were observed for associations with SGA and LGA birth, but confidence intervals crossed the null. When associations with phenotypes of growth were examined, many individual phthalate biomarkers were associated with increased odds of belonging in a group with a phenotype late-pregnancy growth restriction. This study demonstrated that ultrasound measures provided evidence of associations that were absent when using measures at birth. Notably, phthalates were associated with a specific phenotype of SGA birth characterized by late-pregnancy growth restriction. These findings support biological effects of phthalate exposure in utero that may have long-term consequences to the developing fetus.