Maternal urine phthalate metabolite exposure and miscarriage risk: A nested case–control study of the Zunyi Birth Cohort

Abstract Phthalates (PAEs) are widespread persistent organic pollutants and endocrine disruptors. Exposure to certain phthalate metabolites can increase miscarriage risk, but the associations between PAE exposure and the risk of miscarriage in humans are unclear. In addition, an insufficient number of studies have evaluated the possible threshold or dose-dependent effects of first-trimester PAE exposure on miscarriage risk. In a nested case–control study of the Zunyi Birth Cohort, we compared 150 pregnancies ending in miscarriage and 150 pregnancies with live births as controls. The levels of mono-methyl phthalate (MMP), mono-ethyl phthalate, mono-isobutyl phthalate, MiBP mono-butyl phthalate (MBP), mono-octyl phthalate, mono-benzyl phthalate, mono(2-ethylhexyl) phthalate, mono(2-ethyl-5-oxohexyl) phthalate, and mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) in maternal urine collected in early gestation were measured. We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) for miscarriage and each PAE as a continuous variable or quartile. Sensitivity analysis and multiple adjustments were performed on the results. A restrictive cubic spline was used to assess dose-dependent effects after controlling for maternal characteristics (e.g., age, educational level). This study identified monotonically increasing dose-dependent effects of MEHHP and MMP on the risk of miscarriage. The largest effect estimates were approximately 3–4-fold higher for the highest MBP (OR = 2.57; 95% CI = 1.32–5.01) or MMP quartile (OR = 3.57; 95% CI = 1.82–7.00) and 2-fold higher for the highest MEHHP quartile (OR = 2.12; 95% CI = 1.10–4.11. Our research preliminarily obtained possible thresholds, for the risk of miscarriage, and the corresponding concentrations of MBP, MEHHP, and MMP were approximately 18.07, 2.38, and 0.80 µg/g Cr, respectively. First-trimester exposure to MBP, MEHHP, and MMP exceeding certain thresholds increases the risk of miscarriage. Thus, strong caution is needed, and preventative and control strategies are required to reduce the risk of PAE exposure.