Standardization of TSH and FT4 to gestational age in early pregnancy and associations with clinical outcomes

Joris A.J. Osinga; Layal Chaker; Sjoerd van Den Berg; Vincent W.V. Jaddoe; Eric A.P. Steegers; Henning Tiemeier; Robin P. Peeters; Tim Korevaar

doi:10.1530/ETJ-24-0344

Standardization of TSH and FT4 to gestational age in early pregnancy and associations with clinical outcomes

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Abstract

Background:

To account for pregnancy-specific changes in thyroid physiology, international guidelines recommend the use of trimester-specific reference intervals. However, the pragmatic division in trimesters does not necessarily align with the changes in thyroid physiology. While the goal of treating gestational thyroid dysfunction is to prevent thyroid hormone-mediated adverse events, it remains unclear which method of standardizing to gestational age, if any, is most effective in identifying individuals at higher risk of adverse pregnancy events.

Methods:

We included 5,675 women participating in a population-based prospective cohort with data on thyroid-stimulating hormone (TSH), free thyroxine (FT4) and thyroperoxidase antibodies (TPOAbs) during early pregnancy (median: 13.2 weeks, 95% range: 9.8–17.6). We studied the association of TSH and FT4 with pre-eclampsia, premature delivery, birth weight and offspring IQ with or without full gestational age standardization of TSH and FT4 using multivariable regression models.

Results:

There was a positive association of gestational age at blood sampling with TSH (difference in mean TSH: +9.6%; P < 0.001) and a negative association with FT4 (difference in mean FT4: −20.2%; P < 0.001). Standardizing TSH to gestational age led to reclassification of 36 women as having normal TSH (9.9%) and 27 as having abnormal TSH (0.5%). For FT4, 62 women were reclassified as having normal FT4 (20.3%) and 57 as having abnormal FT4 (1.1%). Standardization of TSH and FT4 concentrations led to an attenuation of the associations with any outcome of up to 71% as compared to non-standardized TSH or FT4.

Conclusions:

Full standardization of TSH and FT4 to gestational age either does not affect or weakens their associations with clinical outcomes, suggesting that accounting for gestational age offers no benefit with regard to identifying high-risk thyroid dysfunction during early pregnancy.

Original language	English
Article number	e240344
Journal	European Thyroid Journal
Volume	14
Issue number	4
Early online date	22 Jul 2025
DOIs	https://doi.org/10.1530/ETJ-24-0344
Publication status	Published - Aug 2025

Bibliographical note

Publisher Copyright:
© 2025 the author(s). Published by Bioscientifica Ltd. This work is licensed under a Creative Commons Attribution 4.0 International License. https://creativecommons.org/licenses/by/4.0/

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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Standardization of TSH and FT4 to gestational age in early pregnancy and associations with clinical outcomesFinal published version, 921 KBLicence: CC BY

Cite this

@article{ee8112847bb44f07b8c756555e113e89,

title = "Standardization of TSH and FT4 to gestational age in early pregnancy and associations with clinical outcomes",

abstract = "Background:To account for pregnancy-specific changes in thyroid physiology, international guidelines recommend the use of trimester-specific reference intervals. However, the pragmatic division in trimesters does not necessarily align with the changes in thyroid physiology. While the goal of treating gestational thyroid dysfunction is to prevent thyroid hormone-mediated adverse events, it remains unclear which method of standardizing to gestational age, if any, is most effective in identifying individuals at higher risk of adverse pregnancy events. Methods: We included 5,675 women participating in a population-based prospective cohort with data on thyroid-stimulating hormone (TSH), free thyroxine (FT4) and thyroperoxidase antibodies (TPOAbs) during early pregnancy (median: 13.2 weeks, 95\% range: 9.8–17.6). We studied the association of TSH and FT4 with pre-eclampsia, premature delivery, birth weight and offspring IQ with or without full gestational age standardization of TSH and FT4 using multivariable regression models. Results: There was a positive association of gestational age at blood sampling with TSH (difference in mean TSH: +9.6\%; P < 0.001) and a negative association with FT4 (difference in mean FT4: −20.2\%; P < 0.001). Standardizing TSH to gestational age led to reclassification of 36 women as having normal TSH (9.9\%) and 27 as having abnormal TSH (0.5\%). For FT4, 62 women were reclassified as having normal FT4 (20.3\%) and 57 as having abnormal FT4 (1.1\%). Standardization of TSH and FT4 concentrations led to an attenuation of the associations with any outcome of up to 71\% as compared to non-standardized TSH or FT4.Conclusions: Full standardization of TSH and FT4 to gestational age either does not affect or weakens their associations with clinical outcomes, suggesting that accounting for gestational age offers no benefit with regard to identifying high-risk thyroid dysfunction during early pregnancy.",

author = "Osinga, \{Joris A.J.\} and Layal Chaker and \{van Den Berg\}, Sjoerd and Jaddoe, \{Vincent W.V.\} and Steegers, \{Eric A.P.\} and Henning Tiemeier and Peeters, \{Robin P.\} and Tim Korevaar",

note = "Publisher Copyright: {\textcopyright} 2025 the author(s). Published by Bioscientifica Ltd. This work is licensed under a Creative Commons Attribution 4.0 International License. https://creativecommons.org/licenses/by/4.0/",

year = "2025",

month = aug,

doi = "10.1530/ETJ-24-0344",

language = "English",

volume = "14",

journal = "European Thyroid Journal",

issn = "2235-0640",

publisher = "Bioscientifica Ltd",

number = "4",

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TY - JOUR

T1 - Standardization of TSH and FT4 to gestational age in early pregnancy and associations with clinical outcomes

AU - Osinga, Joris A.J.

AU - Chaker, Layal

AU - van Den Berg, Sjoerd

AU - Jaddoe, Vincent W.V.

AU - Steegers, Eric A.P.

AU - Tiemeier, Henning

AU - Peeters, Robin P.

AU - Korevaar, Tim

N1 - Publisher Copyright: © 2025 the author(s). Published by Bioscientifica Ltd. This work is licensed under a Creative Commons Attribution 4.0 International License. https://creativecommons.org/licenses/by/4.0/

PY - 2025/8

Y1 - 2025/8

N2 - Background:To account for pregnancy-specific changes in thyroid physiology, international guidelines recommend the use of trimester-specific reference intervals. However, the pragmatic division in trimesters does not necessarily align with the changes in thyroid physiology. While the goal of treating gestational thyroid dysfunction is to prevent thyroid hormone-mediated adverse events, it remains unclear which method of standardizing to gestational age, if any, is most effective in identifying individuals at higher risk of adverse pregnancy events. Methods: We included 5,675 women participating in a population-based prospective cohort with data on thyroid-stimulating hormone (TSH), free thyroxine (FT4) and thyroperoxidase antibodies (TPOAbs) during early pregnancy (median: 13.2 weeks, 95% range: 9.8–17.6). We studied the association of TSH and FT4 with pre-eclampsia, premature delivery, birth weight and offspring IQ with or without full gestational age standardization of TSH and FT4 using multivariable regression models. Results: There was a positive association of gestational age at blood sampling with TSH (difference in mean TSH: +9.6%; P < 0.001) and a negative association with FT4 (difference in mean FT4: −20.2%; P < 0.001). Standardizing TSH to gestational age led to reclassification of 36 women as having normal TSH (9.9%) and 27 as having abnormal TSH (0.5%). For FT4, 62 women were reclassified as having normal FT4 (20.3%) and 57 as having abnormal FT4 (1.1%). Standardization of TSH and FT4 concentrations led to an attenuation of the associations with any outcome of up to 71% as compared to non-standardized TSH or FT4.Conclusions: Full standardization of TSH and FT4 to gestational age either does not affect or weakens their associations with clinical outcomes, suggesting that accounting for gestational age offers no benefit with regard to identifying high-risk thyroid dysfunction during early pregnancy.

AB - Background:To account for pregnancy-specific changes in thyroid physiology, international guidelines recommend the use of trimester-specific reference intervals. However, the pragmatic division in trimesters does not necessarily align with the changes in thyroid physiology. While the goal of treating gestational thyroid dysfunction is to prevent thyroid hormone-mediated adverse events, it remains unclear which method of standardizing to gestational age, if any, is most effective in identifying individuals at higher risk of adverse pregnancy events. Methods: We included 5,675 women participating in a population-based prospective cohort with data on thyroid-stimulating hormone (TSH), free thyroxine (FT4) and thyroperoxidase antibodies (TPOAbs) during early pregnancy (median: 13.2 weeks, 95% range: 9.8–17.6). We studied the association of TSH and FT4 with pre-eclampsia, premature delivery, birth weight and offspring IQ with or without full gestational age standardization of TSH and FT4 using multivariable regression models. Results: There was a positive association of gestational age at blood sampling with TSH (difference in mean TSH: +9.6%; P < 0.001) and a negative association with FT4 (difference in mean FT4: −20.2%; P < 0.001). Standardizing TSH to gestational age led to reclassification of 36 women as having normal TSH (9.9%) and 27 as having abnormal TSH (0.5%). For FT4, 62 women were reclassified as having normal FT4 (20.3%) and 57 as having abnormal FT4 (1.1%). Standardization of TSH and FT4 concentrations led to an attenuation of the associations with any outcome of up to 71% as compared to non-standardized TSH or FT4.Conclusions: Full standardization of TSH and FT4 to gestational age either does not affect or weakens their associations with clinical outcomes, suggesting that accounting for gestational age offers no benefit with regard to identifying high-risk thyroid dysfunction during early pregnancy.

UR - https://www.scopus.com/pages/publications/105032785258

U2 - 10.1530/ETJ-24-0344

DO - 10.1530/ETJ-24-0344

M3 - Article

C2 - 40663466

AN - SCOPUS:105032785258

SN - 2235-0640

VL - 14

JO - European Thyroid Journal

JF - European Thyroid Journal

IS - 4

M1 - e240344

ER -

Standardization of TSH and FT4 to gestational age in early pregnancy and associations with clinical outcomes

Abstract

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