Environmental Phthalate Exposure, Oxidative Stress, and Preterm Birth.

Abstract

Preterm birth affects over 1 in 10 pregnancies in the US, is a leading contributor of neonatal mortality and morbidities, and has been linked to a number of adverse health outcomes later in life. Despite the severity of the problem, mechanisms of preterm birth are poorly understood, identified causes are few, and preventions are minimally effective. Environmental contributors to preterm birth are understudied but potentially important. Phthalates are a class of chemicals used commonly as plasticizers and solvents in various consumer products. Exposure in the US and elsewhere is ubiquitous. This dissertation provides evidence that maternal exposure to phthalates during pregnancy is associated with preterm birth and that phthalate-induced oxidative stress may play a partial role in mediating this relationship. The nested case-control population examined herein is drawn from a large prospective birth cohort of women recruited early in pregnancy and followed until delivery. Subjects provided urine samples at up to four visits across gestation, which were used for measurement of phthalate metabolites and oxidative stress biomarkers. At delivery, detailed birth outcome data was recorded, including information on preterm etiology. Based on these designations, cases were divided into two groups for the majority of the analysis, including spontaneous preterm births following spontaneous preterm labor and/or preterm premature rupture of the membranes and placental preterm births resulting from preeclampsia and/or intrauterine growth restriction. The results indicated strong associations between maternal phthalate exposure during pregnancy and increased risk of preterm birth, and relationships were strongest in the spontaneous preterm subset. When patterns of urinary phthalate metabolite levels were examined longitudinally across gestation, it became clear that levels measured toward the end of pregnancy were most predictive of prematurity. Oxidative stress biomarkers measured in this study were strongly associated with phthalate metabolites as well as preterm birth. Mediation analysis demonstrated that oxidative stress accounted for 25-50 percent of the association between phthalate exposure and spontaneous preterm birth. These results provide evidence for not only association but causality in the relationship between urinary phthalate metabolites and prematurity. They suggest that women should take steps to decrease exposure levels during pregnancy.