Mediation of the Relationship between Maternal Phthalate Exposure and Preterm Birth by Oxidative Stress with Repeated Measurements across Pregnancy

Abstract

Background:Mediation analysis is useful for understanding mechanisms and has been used minimally in the study of the environment and disease.Objective:We examined mediation of the association between phthalate exposure during pregnancy and preterm birth by oxidative stress.Methods:This nested case–control study of preterm birth (n = 130 cases, 352 controls) included women who delivered in Boston, Massachusestts, from 2006 through 2008. Phthalate metabolites and 8-isoprostane, an oxidative stress biomarker, were measured in urine from three visits in pregnancy. We applied four counterfactual mediation methods: method 1, utilizing exposure and mediator averages; method 2, using averages but allowing for an exposure–mediator interaction; method 3, incorporating longitudinal measurements of the exposure and mediator; and method 4, using longitudinal measurements and allowing for an exposure–mediator interaction.Results:We observed mediation of the associations between phthalate metabolites and all preterm birth by 8-isoprostane, with the greatest estimated proportion mediated observed for spontaneous preterm births specifically. Fully utilizing repeated measures of the exposure and mediator improved precision of indirect (i.e., mediated) effect estimates, and including an exposure–mediator interaction increased the estimated proportion mediated. For example, for mono(2-ethyl-carboxy-propyl) phthalate (MECPP), a metabolite of di(2-ethylhexyl) phthalate (DEHP), the percent of the total effect mediated by 8-isoprostane increased from 47% to 60% with inclusion of an exposure–mediator interaction term, in reference to a total adjusted odds ratio of 1.67 or 1.48, respectively.Conclusions:This demonstrates mediation of the phthalate–preterm birth relationship by oxidative stress, and the utility of complex regression models in capturing mediated associations when repeated measures of exposure and mediator are available and an exposure–mediator interaction may exist.Citation:Ferguson KK, Chen YH, VanderWeele TJ, McElrath TF, Meeker JD, Mukherjee B. 2017. Mediation of the relationship between maternal phthalate exposure and preterm birth by oxidative stress with repeated measurements across pregnancy. Environ Health Perspect 125:488–494; http://dx.doi.org/10.1289/EHP282

Association between prenatal psychological stress and oxidative stress during pregnancy

“…However, since previous associations between family death, anxiety, depression, and oxidative stress have been observed in non‐pregnant populations, it is unlikely that these results occurred by chance. In addition, TIDES has not yet extracted detailed information on birth outcomes, therefore gestational age was not examined as part of these analyses despite associations between oxidative stress and gestational age in previous studies . As with all observational studies, these results do not provide evidence of causality.…”

“…Despite these limitations, this study has many strengths. The outcome measure 8‐iso‐PGF 2α is one of the best biomarkers of oxidative stress because it is relatively stable, including in human pregnancy, unaffected by dietary lipid intake as some other oxidative stress measures are, and is readily detectable in urine . 8‐iso‐PGF 2α concentration is not significantly affected by differences in dietary lipid intake of participants .…”

“…Oxidative stress as measured through the biomarker 8‐iso‐prostaglandin F 2α (8‐iso‐PGF 2α ) is elevated in a variety of diseases as well as pregnancy related complications . Increased levels of 8‐iso‐PGF 2α in pregnancy have been observed among mothers who later experienced preterm birth and preeclampsia . Studies in animal models show that 8‐iso‐PGF 2α is elevated subsequent to stressful situations .…”

“…9 Increased levels of 8-iso-PGF 2α in pregnancy have been observed among mothers who later experienced preterm birth and preeclampsia. 10,11 Studies in animal models show that 8-iso-PGF 2α is elevated subsequent to stressful situations. 12 Several studies in humans show that psychological stress is associated with increased oxidative stress biomarkers; 13,14 however, to our knowledge, this has not been examined in pregnant women.…”

Urinary phthalate and phthalate alternative metabolites and isoprostane among couples undergoing fertility treatment

“…Additionally, recent evidence suggests strong positive associations between urinary phthalate metabolite concentrations and biomarkers of oxidative stress among pregnant women (Ferguson et al, 2014; Ferguson et al, 2015; Holland et al, 2016), couples who were planning pregnancy (Guo et al, 2014), and the general US population (Ferguson et al, 2012). Most recently, oxidative stress was shown to partially mediate the association of phthalate exposure on preterm birth in Puerto Rico (Ferguson et al, 2016). …”