Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

An assessment of measurement error when using maternal urinary phthalates as proxies for placental tissue levels in the estimation of the association of prenatal phthalates and infant anogenital distance

Journal of Exposure Science & Environmental Epidemiology (2026) Cite this article

Abstract

Background

Direct measurement of in utero phthalate exposure in placental and fetal tissues is generally not possible. Maternal urinary levels serve as proxies and may introduce measurement error, biasing health effect estimates.

Objective

We adjusted for measurement error when using maternal urinary phthalates as proxies for placental–fetal exposure and to evaluate the impact of this correction on the association between prenatal phthalate exposure and anogenital distance (AGD).

Method

We biopsied and analyzed 68 placentas from the TIDES study (San Francisco site: n = 204, 2010–2012). Phthalate metabolite concentrations were measured in three placental tissue types: chorion smooth (CS), chorion frondosum (CF), and basal plate (BP). Phthalate concentrations were standardized to remove pre-processing variation. Regression calibration (RC) and multiple imputation for measurement error (MIME) were used for correction. Associations between phthalates and AGD were estimated by generalized linear models. Bias was quantified by calculating the percent change in the beta coefficient from the gold standard (placental phthalate) to the proxy (urinary phthalate), after correction for measurement error.

Results

Phthalate metabolites were detected in over 70% of placental tissues. Monoethylhexyl (MEHP) phthalate was the most abundant metabolite in CF and in CS. Phthalate concentrations were lowest in BP and varied across placental tissues. Weak associations were found between urinary and placental phthalates. MIME outperformed RC, reducing bias in the average phthalate effect on AGD in the male by 30% for AGD-penis and 69% for AGD-scrotum, and in the female by 32% for AGD-clitoris and 45% for AGD-fourchette.

Significance

Placental phthalate concentrations varied by tissue type and showed poor correlation with maternal urinary levels. MIME outperformed RC in adjusting for measurement error in this setting. Findings suggest maternal and placental exposures are distinct constructs, highlighting the need for direct placental measurement in phthalate toxicity studies. Further research can improve phthalate exposure assessment and knowledge of maternal-placental-fetal transfer.

Impact

This study highlights a key gap in environmental health research, where maternal urinary phthalates are often used as proxies for placental and fetal exposure. Using two correction methods, we found that maternal urinary and placental phthalates represent distinct exposure constructs and are not interchangeable.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Conceptional model of the association of prenatal phthalates and infant anogenital 543 distance (AGD).
The alternative text for this image may have been generated using AI.
Fig. 2: Forest plots of the beta coefficients (95% CI) for the adjusted linear associations of placental and maternal phthalate metabolites and AGD (z score) in male and female infants.
The alternative text for this image may have been generated using AI.
Fig. 3: Percent change in beta coefficients after vs. before correction by MIME in the association of phthalates and AGD in the male fetus using phthalate data in the two placental tissue types (chorion frondosum and villi [CF], chorion smooth membrane [CS], and compared to uinary concentrations in three trimesters.
The alternative text for this image may have been generated using AI.
Fig. 4: Percent change in beta coefficients after vs. before correction by MIME in the association of phthalates and AGD in the female fetus using phthalate data in the two placental tissue types (chorion frondosum and villi [CF], chorion smooth membrane [CS], and compared to urinary concentrations in three trimesters.
The alternative text for this image may have been generated using AI.

Similar content being viewed by others

Data availability

The data are available from the corresponding author on reasonable request.

References

  1. White E. Measurement error in biomarkers: sources, assessment, and impact on studies. IARC Sci Publ. 2011;143–61.

  2. Ratain MJ, Plunkett WK Jr. Principles of Pharmacokinetics. In: Kufe DW, Pollock RE, Weichselbaum RR, Bast RC Jr, Gansler TS, Holland JF, Frei E III, editors. Holland-Frei Cancer Medicine. 6th edn. Hamilton: BC Decker; 2003.

  3. Koch HM, Calafat AM. Human body burdens of chemicals used in plastic manufacture. Philos Trans R Soc Lond B Biol Sci. 2009;364:2063–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhang Y, Lin L, Cao Y, Chen B, Zheng L, Ge RS. Phthalate levels and low birth weight: a nested case-control study of Chinese newborns. J Pediatr. 2009;155:500–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wittassek M, Angerer J, Kolossa-Gehring M, Schäfer SD, Klockenbusch W, Dobler L, et al. Fetal exposure to phthalates: a pilot study. Int J Hyg Environ Health. 2009;212:492–8.

    Article  CAS  PubMed  Google Scholar 

  6. Huang PC, Kuo PL, Chou YY, Lin SJ, Lee CC. Association between prenatal exposure to phthalates and the health of newborns. Environ Int. 2009;35:14–20.

    Article  PubMed  Google Scholar 

  7. Mose T, Knudsen LE, Hedegaard M, Mortensen GK. Transplacental transfer of monomethyl phthalate and mono(2-ethylhexyl) phthalate in a human placenta perfusion system. Int J Toxicol. 2007;26:221–9.

    Article  CAS  PubMed  Google Scholar 

  8. Liang HW, Snyder N, Wang J, Xun X, Yin Q, LeWinn K, et al. A study on the association of placental and maternal urinary phthalate metabolites. J Expo Sci Environ Epidemiol. 2023;33:264–72.

    Article  CAS  PubMed  Google Scholar 

  9. Mathew L, Snyder NW, Lyall K, Lee BK, McClure LA, Elliott AJ, et al. Prenatal phthalate exposure measurement: A comparison of metabolites quantified in prenatal maternal urine and newborn’s meconium. Sci Total Environ. 2021;796:148898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Adibi JJ, Lee MK, Naimi AI, Barrett E, Nguyen RH, Sathyanarayana S, et al. Human chorionic gonadotropin partially mediates phthalate association with male and female anogenital distance. J Clin Endocrinol Metab. 2015;100:E1216–24.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Adibi JJ, Zhao Y, Koistinen H, Mitchell RT, Barrett ES, Miller R, et al. Molecular pathways in placental-fetal development and disruption. Mol Cell Endocrinol. 2024;581:112075.

    Article  CAS  PubMed  Google Scholar 

  12. Xun X, Qin X, Layden AJ, Yin Q, Swan SH, Barrett ES, et al. Application of 4-way decomposition to the analysis of placental-fetal biomarkers as intermediary variables between maternal body mass index and birthweight. Front Reprod Health. 2022;4:994436.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Adibi JJ, Layden AJ, Birru RL, Miragaia A, Xun X, Smith MC, et al. First-trimester mechanisms of gestational sac placental and foetal teratogenicity: a framework for birth cohort studies. Hum Reprod Update. 2021;27:747–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nelson W, Liu DY, Yang Y, Zhong ZH, Wang YX, Ding YB. In utero exposure to persistent and nonpersistent endocrine-disrupting chemicals and anogenital distance. A systematic review of epidemiological studies. Biol Reprod. 2020;102:276–91.

    Article  PubMed  Google Scholar 

  15. Innes GK, Bhondoekhan F, Lau B, Gross AL, Ng DK, Abraham AG. The measurement error elephant in the room: challenges and solutions to measurement error in epidemiology. Epidemiol Rev. 2022;43:94–105.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Swan SH, Sathyanarayana S, Barrett ES, Janssen S, Liu F, Nguyen RHN, et al. First-trimester phthalate exposure and anogenital distance in newborns. Hum Reprod. 2015;30:963–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kuiper JR, O’Brien KM, Ferguson KK, Buckley JP. Urinary specific gravity measures in the U.S. population: implications for the adjustment of non-persistent chemical urinary biomarker data. Environ Int. 2021;156:106656.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mortamais M, Chevrier C, Philippat C, Petit C, Calafat AM, Ye X, et al. Correcting for the influence of sampling conditions on biomarkers of exposure to phenols and phthalates: a 2-step standardization method based on regression residuals. Environ Health. 2012;11:29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nab L, van Smeden M, Keogh RH, Groenwold RH. Mecor: an R package for measurement error correction in linear regression models with a continuous outcome. Comput Methods Prog Biomed. 2021;208:106238.

    Article  Google Scholar 

  20. van Buuren S, Groothuis-Oudshoorn K. mice: multivariate Imputation by Chained Equations in R. J Stat Softw. 2011;45:1–67.

    Article  Google Scholar 

  21. Martino-Andrade AJ, Liu F, Sathyanarayana S, Barrett ES, Redmon JB, Nguyen RHN, et al. Timing of prenatal phthalate exposure in relation to genital endpoints in male newborns. Andrology. 2016;4:585–93.

    Article  CAS  PubMed  Google Scholar 

  22. Marsh B, Zhou Y, Kapidzic M, Fisher S, Blelloch R. Regionally distinct trophoblasts regulate barrier function and invasion in the human placenta. Elife. 2022;11:e70027.

    Article  Google Scholar 

  23. Menon R, Richardson LS, Lappas M. Fetal membrane architecture, aging and inflammation in pregnancy and parturition. Placenta. 2019;79:40–5.

    Article  CAS  PubMed  Google Scholar 

  24. Genbacev O, Donne M, Kapidzic M, Gormley M, Lamb J, Gilmore J, et al. Establishment of human trophoblast progenitor cell lines from the chorion. Stem Cells. 2011;29:1427–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Welsh M, Saunders PT, Fisken M, Scott HM, Hutchison GR, Smith LB, et al. Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Investig. 2008;118:1479–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by NIH grants K99/R00ES017780, R01ES016863, and R01ES025169.

Author information

Authors and Affiliations

  1. Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA

    Hai-Wei Liang & Jennifer J. Adibi

  2. Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA

    Nathaniel Snyder

  3. Department of Biostatistics and Health Data Science, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA

    Jiebiao Wang

  4. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA

    Janet Catov, Rahel Birru & Jennifer J. Adibi

  5. Department of Biostatistics and Epidemiology, Rutgers School of Public Health; Environmental and Occupational Health Sciences Institute; Rutgers University, Piscataway, NJ, USA

    Emily S. Barrett

  6. Department of Pediatrics; Department of Environmental and Occupational Health Sciences/Epidemiology, University of Washington; Seattle Children’s Research Institute, Seattle, WA, USA

    Sheela Sathyanarayana

  7. Wadsworth Center, New York State Department of Health, Albany, NY, USA

    Kurunthachalam Kannan

  8. Department of Environmental Health Sciences, State University of New York at Albany, Albany, NY, USA

    Kurunthachalam Kannan

Authors
  1. Hai-Wei Liang
    View author publications

    Search author on:PubMed Google Scholar

  2. Nathaniel Snyder
    View author publications

    Search author on:PubMed Google Scholar

  3. Jiebiao Wang
    View author publications

    Search author on:PubMed Google Scholar

  4. Janet Catov
    View author publications

    Search author on:PubMed Google Scholar

  5. Rahel Birru
    View author publications

    Search author on:PubMed Google Scholar

  6. Emily S. Barrett
    View author publications

    Search author on:PubMed Google Scholar

  7. Sheela Sathyanarayana
    View author publications

    Search author on:PubMed Google Scholar

  8. Kurunthachalam Kannan
    View author publications

    Search author on:PubMed Google Scholar

  9. Jennifer J. Adibi
    View author publications

    Search author on:PubMed Google Scholar

Contributions

HWL drafted the manuscript and performed the statistical analysis. NS conducted the phthalate analysis. JW provided statistical consultation. RB handled sample preprocessing. JC, KK, ESB, SS, and JJA reviewed and provided feedback on the manuscript.

Corresponding author

Correspondence to Hai-Wei Liang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval

Approval for this research was obtained from the UCSF Human Subjects Committee, at the Icahn School of Medicine at Mount Sinai, which served as the TIDES Coordinating Center after 2011, and the University of Pittsburgh Institutional Review Board.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liang, HW., Snyder, N., Wang, J. et al. An assessment of measurement error when using maternal urinary phthalates as proxies for placental tissue levels in the estimation of the association of prenatal phthalates and infant anogenital distance. J Expo Sci Environ Epidemiol (2026). https://doi.org/10.1038/s41370-026-00886-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41370-026-00886-3

Keywords

Search

Advanced search

Quick links