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Individual and joint effects of phthalates exposure on the risk of early miscarriage



The exposure levels of phthalates in humans have dropped dramatically. Little is known about the individual and joint effects of phthalates exposure at low levels on the risk of early miscarriage.


To examine the association between exposure to phthalates individually or as a mixture and early miscarriage.


A case-control study was conducted in Shanghai, China during 2019–2020. A total of 291 women seeking medical services due to miscarriage (cases) and 308 women planning to terminate an unintended pregnancy (controls) within 12 gestational weeks were recruited. Urinary concentrations of eight phthalate metabolites were determined by ultra-performance liquid chromatography. We included 534 women in the main analysis who had available data on both phthalates exposure and complete information on potential confounders. We used logistic regression and Bayesian kernel machine regression (BKMR) to examine the associations of concentrations of phthalates with miscarriage.


Among the phthalate metabolites, mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) had the highest concentration (8.10 ng/mL), followed by mono(2-ethyl-5-oxohexyl) phthalate (MEOHP, 2.68 ng/mL) and monobutyl phthalate (MBP, 2.24 ng/mL). Higher concentrations of MBP, mono(2-ethylhexyl) phthalate (MEHP), MEHHP, MEOHP and the molar sum of di(2-ethylhexyl) phthalate (DEHP) metabolites (∑DEHPm) were associated with an increased risk of miscarriage exhibiting a dose-response relationship. The most evident association of miscarriage was found with ∑DEHPm, with adjusted odds ratio (95% confidence interval) of 1.94 (1.14, 3.31) for the second quartile, 2.83 (1.67, 4.79) for the third quartile and 4.28 (2.49, 7.37) for the fourth quartile compared to the first quartile. Consistently, the phthalate mixture was positively associated with the risk of miscarriage and DEHP was the predominant contributor to the joint effect in BKMR model.


Phthalates are a family of synthetic chemicals mainly used as plasticizers, solvents and additives in a large variety of industrial and consumer products, including food packing materials, toys, gloves, medical devices and personal care products. Although exposure levels of phthalates of pregnant women have declined sharply over the past few decades, phthalates exposure was still associated with an increased risk of early miscarriage. Our findings suggest that future researchers and policy makers might need to take low-dose effects of phthalates into account regarding the reproductive toxicity of phthalates exposure in humans.


Our findings contribute to the awareness of the reproductive toxic potential of phthalates at low levels in humans and support the ongoing efforts to further reduce exposure to phthalates.

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Fig. 1: The effects of phthalate mixture on miscarriage.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.


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The authors gratefully acknowledge all of the women who participated in this study. This work was supported by the National Key Research and Development Program of China (2021YFC2701003), Science and Technology Commission of Shanghai Municipality (20ZR1448000), Shanghai Municipal Health Commission (20204Y0275, 202140333), Innovation-oriented Science and Technology Grant from NHC Key Lab of Reproduction Regulation (CX2022-04).

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Authors and Affiliations



HJ, ZW, WS, and HL conceived and designed the study. HJ analyzed data and drafted the manuscript. ZW was responsible for the data collection. DC provided expertise in the measurement of phthalates. MM and WY provided critical input to the analyses, interpreted the data, and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Wen Shuai or Hong Liang.

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The authors declare no competing interests.

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This study was approved by the ethics committee board of Shanghai Institute for Biomedical and Pharmaceutical Technologies (PJ2018-18). Women in the study gave written consent to participate.

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Ji, H., Wu, Z., Chen, D. et al. Individual and joint effects of phthalates exposure on the risk of early miscarriage. J Expo Sci Environ Epidemiol (2023).

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