Exposure to phthalates and replacements during pregnancy in association with gestational blood pressure and hypertensive disorders of pregnancy

Exposure to endocrine-disrupting chemicals such as phthalates may increase risk of hypertensive disorders of pregnancy (HDP). Prior studies lack investigation of chemical mixtures, phthalate replacements, or key periods of susceptibility including early pregnancy. In the present study, we used a longitudinal approach to evaluate gestational exposure to phthalates and replacements, as both single-pollutants and mixtures, in association with blood pressure and diagnosis of preeclampsia or any HDP. The Human Placenta and Phthalates prospective pregnancy cohort includes 291 participants recruited from two U.S. clinics. Urinary metabolites of ten phthalates and replacements were quantified at up to 8 time points per individual and averaged to create early (12-15 weeks) and overall (12-38 weeks) pregnancy exposure biomarkers. We collected data on gestational blood pressure (mean = 6.2 measures per participant) and diagnosis of preeclampsia (n = 26 cases) or any HDP (n = 44 cases). Linear mixed effects models estimated associations between exposure biomarkers and repeated blood pressure measures. We estimated exposure biomarker associations with preeclampsia and HDP using Cox proportional hazards or logistic regression models, respectively. Quantile g-computation was used to estimate joint effects of a phthalate or replacement mixture with each outcome. Early pregnancy exposure biomarkers demonstrated greater associations with adverse outcomes compared to overall pregnancy. A one-interquartile range increase in early pregnancy di-isononyl phthalate metabolites (Sigma DiNP) was associated with a 1.13 mmHg (95 % confidence interval [CI]: 0.25, 2.37) and 0.90 mmHg (CI: 0.16, 1.65) increase in systolic and diastolic blood pressure, respectively. We also found positive but nonsignificant associations of early pregnancy mono-3-carboxypropyl phthalate, di-2-ethylhexyl terephthalate metabolites, and the high molecular weight phthalate mixture with blood pressure. Early pregnancy Sigma DiNP was furthermore associated with increased odds of HDP (odds ratio: 1.37, CI: 1.03, 1.82), but not preeclampsia. In sum, early gestational exposure to DiNP and other high molecular weight phthalates may contribute to HDP.