Association of Thyroid Peroxidase Antibodies and Thyroglobulin Antibodies with Thyroid Function in Pregnancy: An Individual Participant Data Meta-Analysis

Sofie Bliddal; Arash Derakhshan; Yi Xiao; Liang Miao Chen; Tuija Männistö; Ghalia Ashoor; Fangbiao Tao; Suzanne J. Brown; Marina Vafeiadi; Sachiko Itoh; Elena Nikolaevna Grineva; Peter Taylor; Farkhanda Ghafoor; Bijay Vaidya; Andrew Hattersley; Lorena Mosso; Emily Oken; Reiko Kishi; Erik K. Alexander; Spyridoula Maraka; Kun Huang; Layal Chaker; Judit Bassols; Amna Pirzada; Abel López-Bermejo; Laura Boucai; Robin P. Peeters; Elizabeth N. Pearce; Scott Mc Gill Nelson; Leda Chatzi; Tanja G. Vrijkotte; Polina V. Popova; John P. Walsh; Kypros H. Nicolaides; Eila Suvanto; Xuemian Lu; Victor J.M. Pop; Julie Lyng Forman; Tim I.M. Korevaar; Ulla Feldt-Rasmussen

doi:10.1089/thy.2022.0083

Association of Thyroid Peroxidase Antibodies and Thyroglobulin Antibodies with Thyroid Function in Pregnancy: An Individual Participant Data Meta-Analysis

Sofie Bliddal, Arash Derakhshan, Yi Xiao, Liang Miao Chen, Tuija Männistö, Ghalia Ashoor, Fangbiao Tao, Suzanne J. Brown, Marina Vafeiadi, Sachiko Itoh, Elena Nikolaevna Grineva, Peter Taylor, Farkhanda Ghafoor, Bijay Vaidya, Andrew Hattersley, Lorena Mosso, Emily Oken, Reiko Kishi, Erik K. Alexander, Spyridoula MarakaKun Huang, Layal Chaker, Judit Bassols, Amna Pirzada, Abel López-Bermejo, Laura Boucai, Robin P. Peeters, Elizabeth N. Pearce, Scott Mc Gill Nelson, Leda Chatzi, Tanja G. Vrijkotte, Polina V. Popova, John P. Walsh, Kypros H. Nicolaides, Eila Suvanto, Xuemian Lu, Victor J.M. Pop, Julie Lyng Forman, Tim I.M. Korevaar, Ulla Feldt-Rasmussen^*

^*Corresponding author for this work

Women & Children's Health

Research output: Contribution to journal › Article › peer-review

21 Citations (Scopus)

Abstract

Objectives: Thyroid autoimmunity is common in pregnant women and associated with thyroid dysfunction and adverse obstetric outcomes. Most studies focus on thyroid peroxidase antibodies (TPOAbs) assessed by a negative-positive dichotomy and rarely take into account thyroglobulin antibodies (TgAbs). This study aimed at determining the association of TPOAbs and TgAbs, respectively, and interdependently, with maternal thyroid function. Methods: This was a meta-Analysis of individual participant cross-sectional data from 20 cohorts in the Consortium on Thyroid and Pregnancy. Women with multiple pregnancy, pregnancy by assisted reproductive technology, history of thyroid disease, or use of thyroid interfering medication were excluded. Associations of (log2) TPOAbs and TgAbs (with/without mutual adjustment) with cohort-specific z-scores of (log2) thyrotropin (TSH), free triiodothyronine (fT3), total triiodothyronine (TT3), free thyroxine (fT4), total thyroxine (TT4), or triiodothyronine:thyroxine (T3:T4) ratio were evaluated in a linear mixed model. Results: In total, 51,138 women participated (51,094 had TPOAb-data and 27,874 had TgAb-data). Isolated TPOAb positivity was present in 4.1% [95% confidence interval, CI: 3.0 to 5.2], isolated TgAb positivity in 4.8% [CI: 2.9 to 6.6], and positivity for both antibodies in 4.7% [CI: 3.1 to 6.3]. Compared with antibody-negative women, TSH was higher in women with isolated TPOAb positivity (z-score increment 0.40, CI: 0.16 to 0.64) and TgAb positivity (0.21, CI: 0.10 to 0.32), but highest in those positive for both antibodies (0.54, CI: 0.36 to 0.71). There was a dose-response effect of higher TPOAb and TgAb concentrations with higher TSH (TSH z-score increment for TPOAbs 0.12, CI: 0.09 to 0.15, TgAbs 0.08, CI: 0.02 to 0.15). When adjusting analyses for the other antibody, only the association of TPOAbs remained statistically significant. A higher TPOAb concentration was associated with lower fT4 (p < 0.001) and higher T3:T4 ratio (0.09, CI: 0.03 to 0.14), however, the association with fT4 was not significant when adjusting for TgAbs (p = 0.16). Conclusions: This individual participant data meta-Analysis demonstrated an increase in TSH with isolated TPOAb positivity and TgAb positivity, respectively, which was amplified for individuals positive for both antibodies. There was a dose-dependent association of TPOAbs, but not TgAbs, with TSH when adjusting for the other antibody. This supports current practice of using TPOAbs in initial laboratory testing of pregnant women suspected of autoimmune thyroid disease. However, studies on the differences between TPOAb-And TgAb-positive women are needed to fully understand the spectrum of phenotypes.

Original language	English
Pages (from-to)	828-840
Number of pages	13
Journal	Thyroid
Volume	32
Issue number	7
DOIs	https://doi.org/10.1089/thy.2022.0083
Publication status	Published - 1 Jul 2022

Keywords

meta-Analysis
pregnancy
thyroglobulin antibodies
thyroid
thyroid autoimmunity
thyroid peroxidase antibodies

UN SDGs

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

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10.1089/thy.2022.0083

Cite this

Bliddal, S., Derakhshan, A., Xiao, Y., Chen, L. M., Männistö, T., Ashoor, G., Tao, F., Brown, S. J., Vafeiadi, M., Itoh, S., Grineva, E. N., Taylor, P., Ghafoor, F., Vaidya, B., Hattersley, A., Mosso, L., Oken, E., Kishi, R., Alexander, E. K., ... Feldt-Rasmussen, U. (2022). Association of Thyroid Peroxidase Antibodies and Thyroglobulin Antibodies with Thyroid Function in Pregnancy: An Individual Participant Data Meta-Analysis. Thyroid, 32(7), 828-840. https://doi.org/10.1089/thy.2022.0083

@article{10d36f2b323c4f11a000fd56a33921b9,

title = "Association of Thyroid Peroxidase Antibodies and Thyroglobulin Antibodies with Thyroid Function in Pregnancy: An Individual Participant Data Meta-Analysis",

abstract = "Objectives: Thyroid autoimmunity is common in pregnant women and associated with thyroid dysfunction and adverse obstetric outcomes. Most studies focus on thyroid peroxidase antibodies (TPOAbs) assessed by a negative-positive dichotomy and rarely take into account thyroglobulin antibodies (TgAbs). This study aimed at determining the association of TPOAbs and TgAbs, respectively, and interdependently, with maternal thyroid function. Methods: This was a meta-Analysis of individual participant cross-sectional data from 20 cohorts in the Consortium on Thyroid and Pregnancy. Women with multiple pregnancy, pregnancy by assisted reproductive technology, history of thyroid disease, or use of thyroid interfering medication were excluded. Associations of (log2) TPOAbs and TgAbs (with/without mutual adjustment) with cohort-specific z-scores of (log2) thyrotropin (TSH), free triiodothyronine (fT3), total triiodothyronine (TT3), free thyroxine (fT4), total thyroxine (TT4), or triiodothyronine:thyroxine (T3:T4) ratio were evaluated in a linear mixed model. Results: In total, 51,138 women participated (51,094 had TPOAb-data and 27,874 had TgAb-data). Isolated TPOAb positivity was present in 4.1% [95% confidence interval, CI: 3.0 to 5.2], isolated TgAb positivity in 4.8% [CI: 2.9 to 6.6], and positivity for both antibodies in 4.7% [CI: 3.1 to 6.3]. Compared with antibody-negative women, TSH was higher in women with isolated TPOAb positivity (z-score increment 0.40, CI: 0.16 to 0.64) and TgAb positivity (0.21, CI: 0.10 to 0.32), but highest in those positive for both antibodies (0.54, CI: 0.36 to 0.71). There was a dose-response effect of higher TPOAb and TgAb concentrations with higher TSH (TSH z-score increment for TPOAbs 0.12, CI: 0.09 to 0.15, TgAbs 0.08, CI: 0.02 to 0.15). When adjusting analyses for the other antibody, only the association of TPOAbs remained statistically significant. A higher TPOAb concentration was associated with lower fT4 (p < 0.001) and higher T3:T4 ratio (0.09, CI: 0.03 to 0.14), however, the association with fT4 was not significant when adjusting for TgAbs (p = 0.16). Conclusions: This individual participant data meta-Analysis demonstrated an increase in TSH with isolated TPOAb positivity and TgAb positivity, respectively, which was amplified for individuals positive for both antibodies. There was a dose-dependent association of TPOAbs, but not TgAbs, with TSH when adjusting for the other antibody. This supports current practice of using TPOAbs in initial laboratory testing of pregnant women suspected of autoimmune thyroid disease. However, studies on the differences between TPOAb-And TgAb-positive women are needed to fully understand the spectrum of phenotypes.",

keywords = "meta-Analysis, pregnancy, thyroglobulin antibodies, thyroid, thyroid autoimmunity, thyroid peroxidase antibodies",

author = "Sofie Bliddal and Arash Derakhshan and Yi Xiao and Chen, {Liang Miao} and Tuija M{\"a}nnist{\"o} and Ghalia Ashoor and Fangbiao Tao and Brown, {Suzanne J.} and Marina Vafeiadi and Sachiko Itoh and Grineva, {Elena Nikolaevna} and Peter Taylor and Farkhanda Ghafoor and Bijay Vaidya and Andrew Hattersley and Lorena Mosso and Emily Oken and Reiko Kishi and Alexander, {Erik K.} and Spyridoula Maraka and Kun Huang and Layal Chaker and Judit Bassols and Amna Pirzada and Abel L{\'o}pez-Bermejo and Laura Boucai and Peeters, {Robin P.} and Pearce, {Elizabeth N.} and Nelson, {Scott Mc Gill} and Leda Chatzi and Vrijkotte, {Tanja G.} and Popova, {Polina V.} and Walsh, {John P.} and Nicolaides, {Kypros H.} and Eila Suvanto and Xuemian Lu and Pop, {Victor J.M.} and Forman, {Julie Lyng} and Korevaar, {Tim I.M.} and Ulla Feldt-Rasmussen",

note = "Funding Information: S.M.N. has received support from Roche Diagnostics, Access Fertility, Modern Fertility, Ferring Pharmaceuticals, TFP, and Merck. P.V.P.{\textquoteright}s work is supported by the Ministry of Health Care of Russian Federation: Governmental funding research number 121031100288-5. Part of S.J.B.{\textquoteright}s salary was subsidized by Sonic Health (Douglass Hanly Moir Pathology in Sydney). All other authors have nothing to disclose. Funding Information: The present study was kindly supported by Kirsten and Freddy Johansen{\textquoteright}s Foundation, Beckett{\textquoteright}s Foundation, and Rigshospitalet{\textquoteright}s Research Foundation, and the Netherlands Organization for Scientific Research (grant 401.16.020). Information on funding for the original cohort studies is included in Supplementary File S1. The funding sources had no influence on the study design, interpretation of the findings, or on the preparation of this article. Funding Information: The following authors have disclosures not related to or influencing this research project: S.B.{\textquoteright}s research salary was funded by Rigshospitalet{\textquoteright}s Research Foundation and Syge-sikring Danmark. U.F.-R.{\textquoteright}s research salary was funded by Kirsten and Freddy Johansen{\textquoteright}s Foundation. E.K.A. is a consultant for Veracyte, Inc., and Roche Diagnostics. S.M. was supported by the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000, and by the US Department of Veterans Affairs Health Services Research & Development Service of the VA Office of Research and Development, under Merit review award number 1I21HX003268-01A1 (the content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Veterans Affairs or the US Government). Publisher Copyright: {\textcopyright} Copyright 2022, Mary Ann Liebert, Inc., publishers 2022.",

year = "2022",

month = jul,

day = "1",

doi = "10.1089/thy.2022.0083",

language = "English",

volume = "32",

pages = "828--840",

journal = "Thyroid",

issn = "1050-7256",

publisher = "Mary Ann Liebert",

number = "7",

}

Bliddal, S, Derakhshan, A, Xiao, Y, Chen, LM, Männistö, T, Ashoor, G, Tao, F, Brown, SJ, Vafeiadi, M, Itoh, S, Grineva, EN, Taylor, P, Ghafoor, F, Vaidya, B, Hattersley, A, Mosso, L, Oken, E, Kishi, R, Alexander, EK, Maraka, S, Huang, K, Chaker, L, Bassols, J, Pirzada, A, López-Bermejo, A, Boucai, L, Peeters, RP, Pearce, EN, Nelson, SMG, Chatzi, L, Vrijkotte, TG, Popova, PV, Walsh, JP, Nicolaides, KH, Suvanto, E, Lu, X, Pop, VJM, Forman, JL, Korevaar, TIM & Feldt-Rasmussen, U 2022, 'Association of Thyroid Peroxidase Antibodies and Thyroglobulin Antibodies with Thyroid Function in Pregnancy: An Individual Participant Data Meta-Analysis', Thyroid, vol. 32, no. 7, pp. 828-840. https://doi.org/10.1089/thy.2022.0083

TY - JOUR

T1 - Association of Thyroid Peroxidase Antibodies and Thyroglobulin Antibodies with Thyroid Function in Pregnancy

T2 - An Individual Participant Data Meta-Analysis

AU - Bliddal, Sofie

AU - Derakhshan, Arash

AU - Xiao, Yi

AU - Chen, Liang Miao

AU - Männistö, Tuija

AU - Ashoor, Ghalia

AU - Tao, Fangbiao

AU - Brown, Suzanne J.

AU - Vafeiadi, Marina

AU - Itoh, Sachiko

AU - Grineva, Elena Nikolaevna

AU - Taylor, Peter

AU - Ghafoor, Farkhanda

AU - Vaidya, Bijay

AU - Hattersley, Andrew

AU - Mosso, Lorena

AU - Oken, Emily

AU - Kishi, Reiko

AU - Alexander, Erik K.

AU - Maraka, Spyridoula

AU - Huang, Kun

AU - Chaker, Layal

AU - Bassols, Judit

AU - Pirzada, Amna

AU - López-Bermejo, Abel

AU - Boucai, Laura

AU - Peeters, Robin P.

AU - Pearce, Elizabeth N.

AU - Nelson, Scott Mc Gill

AU - Chatzi, Leda

AU - Vrijkotte, Tanja G.

AU - Popova, Polina V.

AU - Walsh, John P.

AU - Nicolaides, Kypros H.

AU - Suvanto, Eila

AU - Lu, Xuemian

AU - Pop, Victor J.M.

AU - Forman, Julie Lyng

AU - Korevaar, Tim I.M.

AU - Feldt-Rasmussen, Ulla

N1 - Funding Information: S.M.N. has received support from Roche Diagnostics, Access Fertility, Modern Fertility, Ferring Pharmaceuticals, TFP, and Merck. P.V.P.’s work is supported by the Ministry of Health Care of Russian Federation: Governmental funding research number 121031100288-5. Part of S.J.B.’s salary was subsidized by Sonic Health (Douglass Hanly Moir Pathology in Sydney). All other authors have nothing to disclose. Funding Information: The present study was kindly supported by Kirsten and Freddy Johansen’s Foundation, Beckett’s Foundation, and Rigshospitalet’s Research Foundation, and the Netherlands Organization for Scientific Research (grant 401.16.020). Information on funding for the original cohort studies is included in Supplementary File S1. The funding sources had no influence on the study design, interpretation of the findings, or on the preparation of this article. Funding Information: The following authors have disclosures not related to or influencing this research project: S.B.’s research salary was funded by Rigshospitalet’s Research Foundation and Syge-sikring Danmark. U.F.-R.’s research salary was funded by Kirsten and Freddy Johansen’s Foundation. E.K.A. is a consultant for Veracyte, Inc., and Roche Diagnostics. S.M. was supported by the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000, and by the US Department of Veterans Affairs Health Services Research & Development Service of the VA Office of Research and Development, under Merit review award number 1I21HX003268-01A1 (the content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Veterans Affairs or the US Government). Publisher Copyright: © Copyright 2022, Mary Ann Liebert, Inc., publishers 2022.

PY - 2022/7/1

Y1 - 2022/7/1

N2 - Objectives: Thyroid autoimmunity is common in pregnant women and associated with thyroid dysfunction and adverse obstetric outcomes. Most studies focus on thyroid peroxidase antibodies (TPOAbs) assessed by a negative-positive dichotomy and rarely take into account thyroglobulin antibodies (TgAbs). This study aimed at determining the association of TPOAbs and TgAbs, respectively, and interdependently, with maternal thyroid function. Methods: This was a meta-Analysis of individual participant cross-sectional data from 20 cohorts in the Consortium on Thyroid and Pregnancy. Women with multiple pregnancy, pregnancy by assisted reproductive technology, history of thyroid disease, or use of thyroid interfering medication were excluded. Associations of (log2) TPOAbs and TgAbs (with/without mutual adjustment) with cohort-specific z-scores of (log2) thyrotropin (TSH), free triiodothyronine (fT3), total triiodothyronine (TT3), free thyroxine (fT4), total thyroxine (TT4), or triiodothyronine:thyroxine (T3:T4) ratio were evaluated in a linear mixed model. Results: In total, 51,138 women participated (51,094 had TPOAb-data and 27,874 had TgAb-data). Isolated TPOAb positivity was present in 4.1% [95% confidence interval, CI: 3.0 to 5.2], isolated TgAb positivity in 4.8% [CI: 2.9 to 6.6], and positivity for both antibodies in 4.7% [CI: 3.1 to 6.3]. Compared with antibody-negative women, TSH was higher in women with isolated TPOAb positivity (z-score increment 0.40, CI: 0.16 to 0.64) and TgAb positivity (0.21, CI: 0.10 to 0.32), but highest in those positive for both antibodies (0.54, CI: 0.36 to 0.71). There was a dose-response effect of higher TPOAb and TgAb concentrations with higher TSH (TSH z-score increment for TPOAbs 0.12, CI: 0.09 to 0.15, TgAbs 0.08, CI: 0.02 to 0.15). When adjusting analyses for the other antibody, only the association of TPOAbs remained statistically significant. A higher TPOAb concentration was associated with lower fT4 (p < 0.001) and higher T3:T4 ratio (0.09, CI: 0.03 to 0.14), however, the association with fT4 was not significant when adjusting for TgAbs (p = 0.16). Conclusions: This individual participant data meta-Analysis demonstrated an increase in TSH with isolated TPOAb positivity and TgAb positivity, respectively, which was amplified for individuals positive for both antibodies. There was a dose-dependent association of TPOAbs, but not TgAbs, with TSH when adjusting for the other antibody. This supports current practice of using TPOAbs in initial laboratory testing of pregnant women suspected of autoimmune thyroid disease. However, studies on the differences between TPOAb-And TgAb-positive women are needed to fully understand the spectrum of phenotypes.

AB - Objectives: Thyroid autoimmunity is common in pregnant women and associated with thyroid dysfunction and adverse obstetric outcomes. Most studies focus on thyroid peroxidase antibodies (TPOAbs) assessed by a negative-positive dichotomy and rarely take into account thyroglobulin antibodies (TgAbs). This study aimed at determining the association of TPOAbs and TgAbs, respectively, and interdependently, with maternal thyroid function. Methods: This was a meta-Analysis of individual participant cross-sectional data from 20 cohorts in the Consortium on Thyroid and Pregnancy. Women with multiple pregnancy, pregnancy by assisted reproductive technology, history of thyroid disease, or use of thyroid interfering medication were excluded. Associations of (log2) TPOAbs and TgAbs (with/without mutual adjustment) with cohort-specific z-scores of (log2) thyrotropin (TSH), free triiodothyronine (fT3), total triiodothyronine (TT3), free thyroxine (fT4), total thyroxine (TT4), or triiodothyronine:thyroxine (T3:T4) ratio were evaluated in a linear mixed model. Results: In total, 51,138 women participated (51,094 had TPOAb-data and 27,874 had TgAb-data). Isolated TPOAb positivity was present in 4.1% [95% confidence interval, CI: 3.0 to 5.2], isolated TgAb positivity in 4.8% [CI: 2.9 to 6.6], and positivity for both antibodies in 4.7% [CI: 3.1 to 6.3]. Compared with antibody-negative women, TSH was higher in women with isolated TPOAb positivity (z-score increment 0.40, CI: 0.16 to 0.64) and TgAb positivity (0.21, CI: 0.10 to 0.32), but highest in those positive for both antibodies (0.54, CI: 0.36 to 0.71). There was a dose-response effect of higher TPOAb and TgAb concentrations with higher TSH (TSH z-score increment for TPOAbs 0.12, CI: 0.09 to 0.15, TgAbs 0.08, CI: 0.02 to 0.15). When adjusting analyses for the other antibody, only the association of TPOAbs remained statistically significant. A higher TPOAb concentration was associated with lower fT4 (p < 0.001) and higher T3:T4 ratio (0.09, CI: 0.03 to 0.14), however, the association with fT4 was not significant when adjusting for TgAbs (p = 0.16). Conclusions: This individual participant data meta-Analysis demonstrated an increase in TSH with isolated TPOAb positivity and TgAb positivity, respectively, which was amplified for individuals positive for both antibodies. There was a dose-dependent association of TPOAbs, but not TgAbs, with TSH when adjusting for the other antibody. This supports current practice of using TPOAbs in initial laboratory testing of pregnant women suspected of autoimmune thyroid disease. However, studies on the differences between TPOAb-And TgAb-positive women are needed to fully understand the spectrum of phenotypes.

KW - meta-Analysis

KW - pregnancy

KW - thyroglobulin antibodies

KW - thyroid

KW - thyroid autoimmunity

KW - thyroid peroxidase antibodies

UR - http://www.scopus.com/inward/record.url?scp=85134265107&partnerID=8YFLogxK

U2 - 10.1089/thy.2022.0083

DO - 10.1089/thy.2022.0083

M3 - Article

C2 - 35596568

AN - SCOPUS:85134265107

SN - 1050-7256

VL - 32

SP - 828

EP - 840

JO - Thyroid

JF - Thyroid

IS - 7

ER -

Association of Thyroid Peroxidase Antibodies and Thyroglobulin Antibodies with Thyroid Function in Pregnancy: An Individual Participant Data Meta-Analysis

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