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Accounting for urinary dilution in peri-implantation samples: implications for creatinine adjustment and specimen pooling

Journal of Exposure Science & Environmental Epidemiology volume 31, pages 356–365 (2021)Cite this article

Abstract

This study examines critical issues in accounting for urinary dilution in peri-implantation samples used to assess environmental exposures. Early pregnancy could impact creatinine excretion, which could bias biomarker measurement and interpretation when creatinine adjustment is used. We compared creatinine levels pre-implantation with levels soon after implantation at 3–6 weeks gestation. Using data and urine specimens from 145 women who conceived, we used linear mixed models to estimate the effect of pregnancy on creatinine concentrations. We also studied whether creatinine adjustment is biased when using pooled, within-person samples rather than averaging individually-adjusted results. For this, we grouped 2655 daily urinary estrogen metabolite and associated creatinine measures into 762 mathematically-constructed sample pools, and compared averaged individual measures with pooled measures using weighted kappa coefficients and t-tests. Urinary creatinine concentration declined an average of 14% (95% CI: −19, −11%) from pre- to post-implantation. While there was strong correlation between results based on the two creatinine adjustment methods, adjustment based on pooled specimens introduced a small 3% (95% CI: 2, 4%) underestimation of the analyte compared with averaging individually-adjusted samples. Postimplantation creatinine declines could introduce errors in biomonitoring results when comparing exposure measures from pre- and post-implantation. Though pooled creatinine adjustment underestimated adjusted analyte concentrations, the bias was small and agreement excellent between pooled and averaged individually-adjusted assessments.

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Fig. 1: Pooled sampling strategy for urine specimens from a theoretical 28-day cycle, and from early pregnancy.

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Acknowledgements

Many thanks to Dr D. Robert McConnaughey for his data management support, and to Drs Kaitlyn Gam and Kelly Ferguson for their comments on an earlier draft of this paper. This research was supported, in part, by the intramural research program of the NIH (project numbers ES103333-01 and ES103086), and by a doctoral fellowship at the Yale School of Public Health.

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Authors and Affiliations

  1. Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA

    Ana K. Rosen Vollmar, Caroline H. Johnson & Nicole C. Deziel

  2. Biostatistics & Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, NC, USA

    Clarice R. Weinberg

  3. Epidemiology Branch, National Institute of Environmental Health Sciences, Durham, NC, USA

    Donna D. Baird, Allen J. Wilcox & Anne Marie Z. Jukic

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  1. Ana K. Rosen Vollmar
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Correspondence to Ana K. Rosen Vollmar.

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Rosen Vollmar, A.K., Johnson, C.H., Weinberg, C.R. et al. Accounting for urinary dilution in peri-implantation samples: implications for creatinine adjustment and specimen pooling. J Expo Sci Environ Epidemiol 31, 356–365 (2021). https://doi.org/10.1038/s41370-020-0227-1

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