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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.


  1. Benjamin S, Masai E, Kamimura N, Takahashi K, Anderson RC, Faisal PA. Phthalates impact human health: epidemiological evidences and plausible mechanism of action. J Hazard Mater. 2017;340:360–83.

    Article  CAS  PubMed  Google Scholar 

  2. Frederiksen H, Skakkebaek NE, Andersson AM. Metabolism of phthalates in humans. Mol Nutr Food Res. 2007;51:899–911.

    Article  CAS  PubMed  Google Scholar 

  3. Benjamin S, Pradeep S, Josh MS, Kumar S, Masai E. A monograph on the remediation of hazardous phthalates. J Hazard Mater. 2015;298:58–72.

    Article  CAS  PubMed  Google Scholar 

  4. Huang S, Qi Z, Ma S, Li G, Long C, Yu Y. A critical review on human internal exposure of phthalate metabolites and the associated health risks. Environ Pollut. 2021;279:116941.

    Article  CAS  PubMed  Google Scholar 

  5. Radke EG, Glenn BS, Braun JM, Cooper GS. Phthalate exposure and female reproductive and developmental outcomes: a systematic review of the human epidemiological evidence. Environ Int. 2019;130:104580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Koch HM, Ruther M, Schutze A, Conrad A, Palmke C, Apel P, et al. Phthalate metabolites in 24-h urine samples of the German Environmental Specimen Bank (ESB) from 1988 to 2015 and a comparison with US NHANES data from 1999 to 2012. Int J Hyg Environ Health 2017;220(2 Pt A):130–41.

    Article  CAS  PubMed  Google Scholar 

  7. Environmental Protection Agency (EPA). Biomonitoring: Phthalates. 2022.

  8. Dostalova P, Zatecka E, Ded L, Elzeinova F, Valaskova E, Kubatova A, et al. Gestational and pubertal exposure to low dose of di-(2-ethylhexyl) phthalate impairs sperm quality in adult mice. Reprod Toxicol. 2020;96:175–84.

    Article  CAS  PubMed  Google Scholar 

  9. Leng J, Li H, Niu Y, Chen K, Yuan X, Chen H, et al. Low-dose mono(2-ethylhexyl) phthalate promotes ovarian cancer development through PPARalpha-dependent PI3K/Akt/NF-kappaB pathway. Sci Total Environ. 2021;790:147990.

    Article  CAS  PubMed  Google Scholar 

  10. Niermann S, Rattan S, Brehm E, Flaws JA. Prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP) affects reproductive outcomes in female mice. Reprod Toxicol. 2015;53:23–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Richardson KA, Hannon PR, Johnson-Walker YJ, Myint MS, Flaws JA, Nowak RA. Di (2-ethylhexyl) phthalate (DEHP) alters proliferation and uterine gland numbers in the uteri of adult exposed mice. Reprod Toxicol. 2018;77:70–79.

    Article  CAS  PubMed  Google Scholar 

  12. Kolte AM, Bernardi LA, Christiansen OB, Quenby S, Farquharson RG, Goddijn M, et al. Terminology for pregnancy loss prior to viability: a consensus statement from the ESHRE early pregnancy special interest group. Hum Reprod. 2015;30:495–8.

    Article  CAS  PubMed  Google Scholar 

  13. Quenby S, Gallos ID, Dhillon-Smith RK, Podesek M, Stephenson MD, Fisher J, et al. Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet 2021;397:1658–67.

    Article  CAS  PubMed  Google Scholar 

  14. Wang X, Chen C, Wang L, Chen D, Guang W, French J. Conception, early pregnancy loss, and time to clinical pregnancy: a population-based prospective study. Fertil Steril. 2003;79:577–84.

    Article  PubMed  Google Scholar 

  15. Messerlian C, Wylie BJ, Minguez-Alarcon L, Williams PL, Ford JB, Souter IC, et al. Urinary concentrations of phthalate metabolites and pregnancy loss among women conceiving with medically assisted reproduction. Epidemiology. 2016;27:879–88.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Deng T, Du Y, Wang Y, Teng X, Hua X, Yuan X, et al. The associations of urinary phthalate metabolites with the intermediate and pregnancy outcomes of women receiving IVF/ICSI treatments: A prospective single-center study. Ecotoxicol Environ Saf. 2020;188:109884.

    Article  CAS  PubMed  Google Scholar 

  17. Peng F, Ji W, Zhu F, Peng D, Yang M, Liu R, et al. A study on phthalate metabolites, bisphenol A and nonylphenol in the urine of Chinese women with unexplained recurrent spontaneous abortion. Environ Res. 2016;150:622–8.

    Article  CAS  PubMed  Google Scholar 

  18. Chang WH, Chou WC, Waits A, Liao KW, Kuo PL, Huang PC. Cumulative risk assessment of phthalates exposure for recurrent pregnancy loss in reproductive-aged women population using multiple hazard indices approaches. Environ Int. 2021;154:106657.

    Article  CAS  PubMed  Google Scholar 

  19. Liao KW, Kuo PL, Huang HB, Chang JW, Chiang HC, Huang PC. Increased risk of phthalates exposure for recurrent pregnancy loss in reproductive-aged women. Environ Pollut. 2018;241:969–77.

    Article  CAS  PubMed  Google Scholar 

  20. Gnoth C, Godehardt E, Frank-Herrmann P, Friol K, Tigges J, Freundl G. Definition and prevalence of subfertility and infertility. Hum Reprod. 2005;20:1144–7.

    Article  CAS  PubMed  Google Scholar 

  21. He J, Chang K, Liu S, Ji J, Liu L, Feng Y, et al. Phthalate levels in urine of pregnant women and their associated missed abortion risk. Reprod Biol. 2021;21:100476.

    Article  CAS  PubMed  Google Scholar 

  22. Gao H, Zhang YW, Huang K, Yan SQ, Mao LJ, Ge X, et al. Urinary concentrations of phthalate metabolites in early pregnancy associated with clinical pregnancy loss in Chinese women. Sci Rep. 2017;7:6800.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Mu D, Gao F, Fan Z, Shen H, Peng H, Hu J. Levels of phthalate metabolites in urine of pregnant women and risk of clinical pregnancy loss. Environ Sci Technol. 2015;49:10651–7.

    Article  CAS  PubMed  Google Scholar 

  24. Toft G, Jonsson BA, Lindh CH, Jensen TK, Hjollund NH, Vested A, et al. Association between pregnancy loss and urinary phthalate levels around the time of conception. Environ Health Perspect. 2012;120:458–63.

    Article  CAS  PubMed  Google Scholar 

  25. Jukic AM, Calafat AM, McConnaughey DR, Longnecker MP, Hoppin JA, Weinberg CR, et al. Urinary concentrations of phthalate metabolites and bisphenol a and associations with follicular-phase length, luteal-phase length, fecundability, and early pregnancy loss. Environ Health Perspect. 2016;124:321–8.

    Article  CAS  PubMed  Google Scholar 

  26. Jurkovic D, Overton C, Bender-Atik R. Diagnosis and management of first trimester miscarriage. BMJ 2013;346:f3676.

    Article  PubMed  Google Scholar 

  27. Yang P, Wang J, Hong AB, Huang LL, Xie QT, Wang YX, et al. Exposure profiles and predictors of a cocktail of environmental chemicals in Chinese men of reproductive age. Chemosphere. 2022;299:134337.

    Article  CAS  PubMed  Google Scholar 

  28. Bobb JF, Claus HB, Valeri L, Coull BA. Statistical software for analyzing the health effects of multiple concurrent exposures via Bayesian kernel machine regression. Environ Health. 2018;17:67.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Lathi RB, Liebert CA, Brookfield KF, Taylor JA, Vom SF, Fujimoto VY, et al. Conjugated bisphenol A in maternal serum in relation to miscarriage risk. Fertil Steril. 2014;102:123–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Aimuzi R, Huang S, Luo K, Ma S, Huo X, Li G, et al. Levels and health risks of urinary phthalate metabolites and the association between phthalate exposure and unexplained recurrent spontaneous abortion: a large case-control study from China. Environ Res. 2022;212(Pt C):113393.

    Article  CAS  PubMed  Google Scholar 

  31. Zhang YJ, Guo JL, Xue JC, Bai CL, Guo Y. Phthalate metabolites: characterization, toxicities, global distribution, and exposure assessment. Environ Pollut. 2021;291:118106.

    Article  CAS  PubMed  Google Scholar 

  32. Hsieh CJ, Chang YH, Hu A, Chen ML, Sun CW, Situmorang RF, et al. Personal care products use and phthalate exposure levels among pregnant women. Sci Total Environ. 2019;648:135–43.

    Article  CAS  PubMed  Google Scholar 

  33. Takeuchi S, Iida M, Kobayashi S, Jin K, Matsuda T, Kojima H. Differential effects of phthalate esters on transcriptional activities via human estrogen receptors alpha and beta, and androgen receptor. Toxicology. 2005;210:223–33.

    Article  CAS  PubMed  Google Scholar 

  34. Shanle EK, Xu W. Endocrine disrupting chemicals targeting estrogen receptor signaling: identification and mechanisms of action. Chem Res Toxicol. 2011;24:6–19.

    Article  CAS  PubMed  Google Scholar 

  35. Lovekamp-Swan T, Davis BJ. Mechanisms of phthalate ester toxicity in the female reproductive system. Environ Health Perspect. 2003;111:139–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Schindler AE. First trimester endocrinology: consequences for diagnosis and treatment of pregnancy failure. Gynecol Endocrinol. 2004;18:51–57.

    Article  CAS  PubMed  Google Scholar 

  37. Martinez-Razo LD, Martinez-Ibarra A, Vazquez-Martinez ER, Cerbon M. The impact of Di-(2-ethylhexyl) phthalate and mono(2-ethylhexyl) phthalate in placental development, function, and pathophysiology. Environ Int. 2021;146:106228.

    Article  CAS  PubMed  Google Scholar 

  38. Shoaito H, Petit J, Chissey A, Auzeil N, Guibourdenche J, Gil S, et al. The role of peroxisome proliferator-activated receptor gamma (PPARgamma) in mono(2-ethylhexyl) phthalate (MEHP)-mediated cytotrophoblast differentiation. Environ Health Perspect. 2019;127:27003.

    Article  CAS  PubMed  Google Scholar 

  39. Thomsen AM, Riis AH, Olsen J, Jonsson BA, Lindh CH, Hjollund NH, et al. Female exposure to phthalates and time to pregnancy: a first pregnancy planner study. Hum Reprod. 2017;32:232–8.

    CAS  PubMed  Google Scholar 

  40. Sapra KJ, McLain AC, Maisog JM, Sundaram R, Buck LG. Successive time to pregnancy among women experiencing pregnancy loss. Hum Reprod. 2014;29:2553–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bui TT, Giovanoulis G, Cousins AP, Magner J, Cousins IT, de Wit CA. Human exposure, hazard and risk of alternative plasticizers to phthalate esters. Sci Total Environ. 2016;541:451–67.

    Article  CAS  PubMed  Google Scholar 

  42. Deng M, Han X, Ge J, Liang X, Du B, Li J, et al. Prevalence of phthalate alternatives and monoesters alongside traditional phthalates in indoor dust from a typical e-waste recycling area: Source elucidation and co-exposure risk. J Hazard Mater. 2021;413:125322.

    Article  CAS  PubMed  Google Scholar 

  43. Johns LE, Cooper GS, Galizia A, Meeker JD. Exposure assessment issues in epidemiology studies of phthalates. Environ Int. 2015;85:27–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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.

Corresponding authors

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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  • Phthalates
  • Di(2-ethylhexyl) phthalate
  • Miscarriage
  • Spontaneous abortion
  • Case-control study


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