Home Development of a pregnancy-specific reference material for thyroid biomarkers, vitamin D, and nutritional trace elements in serum
Article
Licensed
Unlicensed Requires Authentication

Development of a pregnancy-specific reference material for thyroid biomarkers, vitamin D, and nutritional trace elements in serum

  • Ashley S. P. Boggs ORCID logo EMAIL logo , Lisa E. Kilpatrick , Carolyn Q. Burdette , Denise S. Tevis , Zachary A. Fultz , Michael A. Nelson , Jeffery M. Jarrett , Jennifer V. Kemp , Ravinder J. Singh , Stefan K. G. Grebe , Stephen A. Wise , Brittany L. Kassim and Stephen E. Long
Published/Copyright: October 26, 2020
Become an author with De Gruyter Brill
Submit Manuscript Author Information
Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 59 Issue 4

Abstract

Objectives

Matrix differences among serum samples from non-pregnant and pregnant patients could bias measurements. Standard Reference Material 1949, Frozen Human Prenatal Serum, was developed to provide a quality assurance material for the measurement of hormones and nutritional elements throughout pregnancy.

Methods

Serum from non-pregnant women and women in each trimester were bottled into four levels based on pregnancy status and trimester. Liquid chromatography tandem mass spectrometry (LC-MS/MS) methods were developed and applied to the measurement of thyroid hormones, vitamin D metabolites, and vitamin D-binding protein (VDBP). Copper, selenium, and zinc measurements were conducted by inductively coupled plasma dynamic reaction cell MS. Thyroid stimulating hormone (TSH), thyroglobulin (Tg), and thyroglobulin antibody concentrations were analyzed using immunoassays and LC-MS/MS (Tg only).

Results

Certified values for thyroxine and triiodothyronine, reference values for vitamin D metabolites, VDBP, selenium, copper, and zinc, and information values for reverse triiodothyronine, TSH, Tg, and Tg antibodies were assigned. Significant differences in serum concentrations were evident for all analytes across the four levels (p≤0.003).

TSH measurements were significantly different (p<0.0001) among research-only immunoassays. Tg concentrations were elevated in research-only immunoassays vs. Federal Drug Administration-approved automated immunoassay and LC-MS/MS. Presence of Tg antibodies increased differences between automated immunoassay and LC-MS/MS.

Conclusions

The analyte concentrations’ changes consistent with the literature and the demonstration of matrix interferences in immunoassay Tg measurements indicate the functionality of this material by providing a relevant matrix-matched reference material for the different stages of pregnancy.

Keywords: mass spectrometry; pregnancy; standard reference material; thyroid; trace elements; vitamin D
Corresponding author: Ashley S. P. Boggs, PhD, Research Biologist, National Institute of Standards and Technology, 331 Fort Johnson Rd, Charleston, SC 29412, USA, Phone: 843 460 9789, Fax: 843 998 6940, E-mail:

Funding source: National Institute of Standards and Technology

Funding source: Office of Dietary Supplements

Acknowledgments

We thank the National Institute of Health and the Office of Dietary Supplements for funding and support of the development of this material.

  1. Research funding: National Institute of Health and the Office of Dietary Supplements and the National Institute of Standards and Technology.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: The authors declare that they have no competing interests in the publication of this manuscript.

  4. Disclaimer: Commercial equipment, instruments, or materials are identified to specify adequately the experimental procedure. Such identification does not imply recommendation or endorsement by NIST nor the CDC, nor does it imply that the materials or equipment identified are necessarily the best available for the purpose. According to NIST’s Order 1801.00, “NIST does not evaluate commercial products unless such an evaluation is part of a formal agreement, usually with the manufacturer of the product.” “NIST does not endorse commercial products or services; commercial products shall be neither promoted nor disparaged by NIST.” Therefore, manufacturer names of commercially available ELISA kits were redacted to comply with federal regulations. This analysis was conducted not to assess manufacturer’s products, but to assess the measurement technique compared to other techniques.

  5. Ethical approval: Research involving human subjects complied with all relevant national regulations, institutional policies and was approved by the Institutional Review Board and NIST Human Subjects Protection Office (MML-17-0013).

References

1. Weeke, J, Dybkjaer, L, Granlie, K, Eskjaer Jensen, S, Kjaerulff, E, Laurberg, P, et al. A longitudinal study of serum TSH, and total and free iodothyronines during normal pregnancy. Acta Endocrinol 1982;101:531–7. https://doi.org/10.1530/acta.0.1010531.Search in Google Scholar

2. American College of Obstetricians and Gynecologists. Practice bulletin no. 148: thyroid disease in pregnancy. Obstet Gynecol 2015;125:996–1005. https://doi.org/10.1097/01.AOG.0000462945.27539.93.Search in Google Scholar

3. Alexander, EK, Pearce, EN, Brent, GA, Brown, RS, Chen, H, Dosiou, C, et al. Guidelines of the American thyroid association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid 2017;27:315. https://doi.org/10.1089/thy.2016.0457.Search in Google Scholar

4. Jansen, TA, Korevaar, TIM, Mulder, TA, White, T, Muetzel, RL, Peeters, RP, et al. Maternal thyroid function during pregnancy and child brain morphology: a time window-specific analysis of a prospective cohort. Lancet Diabetes Endocrinol 2019;7:629–37. https://doi.org/10.1016/s2213-8587(19)30153-6.Search in Google Scholar

5. Specker, BL. Does vitamin D during pregnancy impact offspring growth and bone? Proc Nutr Soc 2011;71:38–45. https://doi.org/10.1017/s0029665111003053.Search in Google Scholar

6. American College of Obstetricians and Gynecologists. Opinion no. 495: vitamin D: screening and supplementation during pregnancy. Obstet Gynecol 2011;118:197–8. https://doi.org/10.1097/AOG.0b013e318227f06b.Search in Google Scholar PubMed

7. Bedwal, RS, Bahuguna, A. Zinc, copper and selenium in reproduction. Experientia 1994;50:626–40. https://doi.org/10.1007/bf01952862.Search in Google Scholar PubMed

8. Joseph, JC, Baker, C, Sprang, ML, Bermes, EW. Changes in plasma proteins during pregnancy. Ann Clin Lab Sci 1978;8:130–41. http://www.annclinlabsci.org/content/8/2/130.full.pdf.Search in Google Scholar

9. Ward, CD, Williams, RJ, Mullenix, K, Syhapanha, K, Jones, RL, Caldwell, K. Trace metals screening process of devices used for the collection, analysis, and storage of biological specimens. At Spectrosc 2018;39:219–28. https://doi.org/10.46770/as.2018.06.001.Search in Google Scholar

10. Nelson, MA, Waters, JF, Toman, B, Lang, BE, Rück, A, Breitruck, K, et al. A new realization of SI for organic chemical measurement: NIST PS1 primary standard for quantitative NMR (benzoic acid). Anal Chem 2018;90:10510–7. https://doi.org/10.1021/acs.analchem.8b02575.Search in Google Scholar PubMed

11. Tai, SSC, Bunk, DM, White, EV, Welch, MJ. Development and evaluation of a reference measurement procedure for the determination of total 3,3′,5-trilodothyronine in human serum using isotope-dilution liquid chromatography-tandem mass spectrometry. Anal Chem 2004;76:5092–6. https://doi.org/10.1021/ac049516h.Search in Google Scholar PubMed

12. Tai, SSC, Sniegoski, LT, Welch, MJ. Candidate reference method for total thyroxine in human serum: use of isotope-dilution liquid chromatography-mass spectrometry with electrospray ionization. Clin Chem 2002;48:637–42. https://doi.org/10.1093/clinchem/48.4.637.Search in Google Scholar

13. Tai, SS, Bedner, M, Phinney, KW. Development of a candidate reference measurement procedure for the determination of 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2 in human serum using isotope-dilution liquid chromatography-tandem mass spectrometry. Anal Chem 2010;82:1942–8. https://doi.org/10.1021/ac9026862.Search in Google Scholar PubMed PubMed Central

14. Kilpatrick, LE, Phinney, KW. Quantification of total vitamin-D-binding protein and the glycosylated isoforms by liquid chromatography–isotope dilution mass spectrometry. J Proteome Res 2017;16:4185–95. https://doi.org/10.1021/acs.jproteome.7b00560.Search in Google Scholar PubMed

15. Kilpatrick, LE, Boggs, ASP, Davis, WC, Long, SE, Yen, JH, Phinney, KW. Assessing a method and reference material for quantification of vitamin D binding protein during pregnancy. Clin Mass Spec 2020;16:11–7. https://doi.org/10.1016/j.clinms.2020.01.002.Search in Google Scholar PubMed PubMed Central

16. Centers for Disease Control and Prevention. Laboratory procedure manual for zinc, copper, and selenium. Available from https://wwwn.cdc.gov/nchs/data/nhanes/2015-2016/labmethods/CUSEZN_I_MET.PDF.Search in Google Scholar

17. Wells, EM, Navas-Acien, A, Apelberg, BJ, Herbstman, JB, Jarrett, JM, Lin, YH, et al. Association of selenium and copper with lipids in umbilical cord blood. J Dev Orig Health Dis 2014;5:281–7. https://doi.org/10.1017/s2040174414000233.Search in Google Scholar

18. Wells, EM, Jarrett, JM, Lin, YH, Caldwell, KL, Hibbeln, JR, Apelberg, BJ, et al. Body burdens of mercury, lead, selenium and copper among Baltimore newborns. Environ Res 2011;111:411–7. https://doi.org/10.1016/j.envres.2010.12.009.Search in Google Scholar PubMed PubMed Central

19. Caudill, SP, Schleicher, RL, Pirkle, JL. Multi-rule quality control for the age-related eye disease study. Stat Med 2008;27:4094–106. https://doi.org/10.1002/sim.3222.Search in Google Scholar PubMed

20. Netzel, BC, Grebe, SKG, Carranza Leon, BG, Castro, MR, Clark, PM, Hoofnagle, AN, et al. Thyroglobulin (Tg) testing revisited: Tg assays, TgAb assays, and correlation of results with clinical outcomes. J Clin Endocrinol Metab 2015;100:E1074–E83. https://doi.org/10.1210/jc.2015-1967.Search in Google Scholar PubMed PubMed Central

21. Beauchamp, CR, Camara, JE, Carney, J, Choquette, SJ, Cole, KD, DeRose, PC, et al.. NIST special publication 260-136: metrological tools for the reference materials and reference instruments of the NIST material measurement laboratory. Washington, DC: U.S. Government Printing Office; 2020 https://nvlpubs.nist.gov/nistpubs/SpecialPublications/NIST.SP.260-136-2020.pdf.10.6028/NIST.SP.260-136-2020Search in Google Scholar

22. Soldin, OP, Tractenberg, RE, Hollowell, JG, Jonklaas, J, Janicic, N, Soldin, SJ. Trimester-specific changes in maternal thyroid hormone, thyrotropin, and thyroglobulin concentrations during gestation: trends and associations across trimesters in iodine sufficiency. Thyroid 2004;14:1084–90. https://doi.org/10.1089/thy.2004.14.1084.Search in Google Scholar PubMed PubMed Central

23. Bärebring, L, Bullarbo, M, Glantz, A, Hulthén, L, Ellis, J, Jagner, Å, et al. Trajectory of vitamin D status during pregnancy in relation to neonatal birth size and fetal survival: a prospective cohort study. BMC Pregnancy Childbirth 2018;18:51. https://doi.org/10.1186/s12884-018-1683-7.Search in Google Scholar PubMed PubMed Central

24. Mulligan, ML, Felton, SK, Riek, AE, Bernal-Mizrachi, C. Implications of vitamin D deficiency in pregnancy and lactation. Am J Obstet Gynecol 2010;202:429.e1–9. https://doi.org/10.1016/j.ajog.2009.09.002.Search in Google Scholar PubMed PubMed Central

25. Hollis, BW, Wagner, CL. Assessment of dietary vitamin D requirements during pregnancy and lactation. Am J Clin Nutr 2004;79:717–26. https://doi.org/10.1093/ajcn/79.5.717.Search in Google Scholar PubMed

26. Karras, SN, Koufakis, T, Fakhoury, H, Kotsa, K. Deconvoluting the biological roles of vitamin D-binding protein during pregnancy: a both clinical and theoretical challenge. Front Endocrinol 2018;9:259. https://doi.org/10.3389/fendo.2018.00259.Search in Google Scholar PubMed PubMed Central

27. Collins, JF, Prohaska, JR, Knutson, MD. Metabolic crossroads of iron and copper. Nutr Rev 2010;68:133–47. https://doi.org/10.1111/j.1753-4887.2010.00271.x.Search in Google Scholar PubMed PubMed Central

28. Vukelic, J, Kapamadzija, A, Petrovic, D, Grujic, Z, Novakov-Mikic, A, Kopitovic, V, et al. Variations of serum copper values in pregnancy. Srp Arh Celok Lek 2012;140:42–6. https://doi.org/10.2298/sarh1202042v.Search in Google Scholar

29. Varsi, K, Bolann, B, Torsvik, I, Rosvold Eik, TC, Høl, PJ, Bjørke-Monsen, A-L. Impact of maternal selenium status on infant outcome during the first 6 Months of life. Nutrients 2017;9:486. https://doi.org/10.3390/nu9050486.Search in Google Scholar PubMed PubMed Central

30. Hotz, C, Peerson, JM, Brown, KH. Suggested lower cutoffs of serum zinc concentrations for assessing zinc status: reanalysis of the second National Health and Nutrition Examination Survey data (1976–1980). Am J Clin Nutr 2003;78:756–64. https://doi.org/10.1093/ajcn/78.4.756.Search in Google Scholar PubMed

31. Glinoer, D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev 1997;18:404–33. https://doi.org/10.1210/edrv.18.3.0300.Search in Google Scholar PubMed

32. Soh, SB, Aw, TC. Laboratory testing in thyroid conditions – pitfalls and clinical utility. Ann Lab Med 2019;39:3–14. https://doi.org/10.3343/alm.2019.39.1.3.Search in Google Scholar PubMed PubMed Central

33. Mazzaferri, EL. Approach to the pregnant patient with thyroid cancer. J Clin Endocrinol Metab 2011;96:265–72. https://doi.org/10.1210/jc.2010-1624.Search in Google Scholar PubMed

Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2020-0977).

Received: 2020-06-24
Accepted: 2020-10-06
Published Online: 2020-10-26
Published in Print: 2021-03-26

© 2020 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Editorials
  3. Perspectives in developments of mass spectrometry for improving diagnosis and monitoring of multiple myeloma and other plasma cell disorders
  4. Cytokine “storm”, cytokine “breeze”, or both in COVID-19?
  5. Review
  6. Clinical relevance of biological variation of cardiac troponins
  7. General Clinical Chemistry and Laboratory Medicine
  8. Development of novel methods for non-canonical myeloma protein analysis with an innovative adaptation of immunofixation electrophoresis, native top-down mass spectrometry, and middle-down de novo sequencing
  9. Falsely markedly elevated 25-hydroxyvitamin D in patients with monoclonal gammopathies
  10. Development of a pregnancy-specific reference material for thyroid biomarkers, vitamin D, and nutritional trace elements in serum
  11. Applying the concept of uncertainty to the sFlt-1/PlGF cut-offs for diagnosis and prognosis of preeclampsia
  12. Reducing sample rejection in Durban, South Africa
  13. Quality benchmarking of smartphone laboratory medicine applications: comparison of laboratory medicine specialists’ and non-laboratory medicine professionals’ evaluation
  14. Urine soluble CD163 (sCD163) as biomarker in glomerulonephritis: stability, reference interval and diagnostic performance
  15. Measurement of urine albumin by liquid chromatography-isotope dilution tandem mass spectrometry and its application to value assignment of external quality assessment samples and certification of reference materials
  16. Choice of faecal immunochemical test matters: comparison of OC-Sensor and HM-JACKarc, in the assessment of patients at high risk of colorectal cancer
  17. Reference Values and Biological Variations
  18. Reference values of trace elements in blood and/or plasma in adults living in Belgium
  19. Cancer Diagnostics
  20. Clinical performance of calcitonin and procalcitonin Elecsys® immunoassays in patients with medullary thyroid carcinoma
  21. Cardiovascular Diseases
  22. Analytical assessment of ortho clinical diagnostics high-sensitivity cardiac troponin I assay
  23. Evaluation of the 0 h/1 h high-sensitivity cardiac troponin T algorithm in diagnosis of non-ST-segment elevation myocardial infarction (NSTEMI) in Han population
  24. Diabetes
  25. Are hemoglobin A1c point-of-care analyzers fit for purpose? The story continues
  26. Infectious Diseases
  27. Diagnostic and prognostic role of presepsin in patients with cirrhosis and bacterial infection
  28. Hemocytometric characteristics of COVID-19 patients with and without cytokine storm syndrome on the sysmex XN-10 hematology analyzer
  29. Letters to the Editor
  30. Letter in reply to the letter to the editor of Geerts N and Schanhorst V with the title “Roche Troponin T hs-STAT meets all expert opinion analytical laboratory practice recommendations for the use of the differential diagnosis of acute coronary syndrome”
  31. Improving measurement uncertainty of plasma electrolytes: a complex but not impossible task
  32. Truncation limits of patient-based real-time quality control: a new model derived from between-subject biological variations
  33. Plasma xanthine oxidoreductase activity change over 12 months independently associated with change in serum uric acid level: MedCity21 health examination registry
  34. Exogenous triglycerides interfere with a point of care CRP assay: a pre-analytical caveat
  35. Monoclonal components in alpha-2 region should not be neglected in capillary electrophoresis
  36. Do not measure an extra high value monoclonal IgM by immunoturbidity: a case report
  37. Reference values for plasma neurofilament light chain (NfL) in healthy Chinese
  38. Diagnosis of vitamin B12 deficiency: combined indicator of B12-status should be interpreted with caution in the case of renal impairment
  39. Could the UKNEQAS program “Manual Differential Blood Count” be performed by the use of an automated digital morphology analyzer (Sysmex DI-60)? A feasibility study
  40. Low-dose oral methotrexate-induced crystalluria
https://doi.org/10.1515/cclm-2020-0977
Keywords for this article
mass spectrometry; pregnancy; standard reference material; thyroid; trace elements; vitamin D

Articles in the same Issue

  1. Frontmatter
  2. Editorials
  3. Perspectives in developments of mass spectrometry for improving diagnosis and monitoring of multiple myeloma and other plasma cell disorders
  4. Cytokine “storm”, cytokine “breeze”, or both in COVID-19?
  5. Review
  6. Clinical relevance of biological variation of cardiac troponins
  7. General Clinical Chemistry and Laboratory Medicine
  8. Development of novel methods for non-canonical myeloma protein analysis with an innovative adaptation of immunofixation electrophoresis, native top-down mass spectrometry, and middle-down de novo sequencing
  9. Falsely markedly elevated 25-hydroxyvitamin D in patients with monoclonal gammopathies
  10. Development of a pregnancy-specific reference material for thyroid biomarkers, vitamin D, and nutritional trace elements in serum
  11. Applying the concept of uncertainty to the sFlt-1/PlGF cut-offs for diagnosis and prognosis of preeclampsia
  12. Reducing sample rejection in Durban, South Africa
  13. Quality benchmarking of smartphone laboratory medicine applications: comparison of laboratory medicine specialists’ and non-laboratory medicine professionals’ evaluation
  14. Urine soluble CD163 (sCD163) as biomarker in glomerulonephritis: stability, reference interval and diagnostic performance
  15. Measurement of urine albumin by liquid chromatography-isotope dilution tandem mass spectrometry and its application to value assignment of external quality assessment samples and certification of reference materials
  16. Choice of faecal immunochemical test matters: comparison of OC-Sensor and HM-JACKarc, in the assessment of patients at high risk of colorectal cancer
  17. Reference Values and Biological Variations
  18. Reference values of trace elements in blood and/or plasma in adults living in Belgium
  19. Cancer Diagnostics
  20. Clinical performance of calcitonin and procalcitonin Elecsys® immunoassays in patients with medullary thyroid carcinoma
  21. Cardiovascular Diseases
  22. Analytical assessment of ortho clinical diagnostics high-sensitivity cardiac troponin I assay
  23. Evaluation of the 0 h/1 h high-sensitivity cardiac troponin T algorithm in diagnosis of non-ST-segment elevation myocardial infarction (NSTEMI) in Han population
  24. Diabetes
  25. Are hemoglobin A1c point-of-care analyzers fit for purpose? The story continues
  26. Infectious Diseases
  27. Diagnostic and prognostic role of presepsin in patients with cirrhosis and bacterial infection
  28. Hemocytometric characteristics of COVID-19 patients with and without cytokine storm syndrome on the sysmex XN-10 hematology analyzer
  29. Letters to the Editor
  30. Letter in reply to the letter to the editor of Geerts N and Schanhorst V with the title “Roche Troponin T hs-STAT meets all expert opinion analytical laboratory practice recommendations for the use of the differential diagnosis of acute coronary syndrome”
  31. Improving measurement uncertainty of plasma electrolytes: a complex but not impossible task
  32. Truncation limits of patient-based real-time quality control: a new model derived from between-subject biological variations
  33. Plasma xanthine oxidoreductase activity change over 12 months independently associated with change in serum uric acid level: MedCity21 health examination registry
  34. Exogenous triglycerides interfere with a point of care CRP assay: a pre-analytical caveat
  35. Monoclonal components in alpha-2 region should not be neglected in capillary electrophoresis
  36. Do not measure an extra high value monoclonal IgM by immunoturbidity: a case report
  37. Reference values for plasma neurofilament light chain (NfL) in healthy Chinese
  38. Diagnosis of vitamin B12 deficiency: combined indicator of B12-status should be interpreted with caution in the case of renal impairment
  39. Could the UKNEQAS program “Manual Differential Blood Count” be performed by the use of an automated digital morphology analyzer (Sysmex DI-60)? A feasibility study
  40. Low-dose oral methotrexate-induced crystalluria
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 10.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/cclm-2020-0977/html
Scroll to top button