Sofie Bliddal1, Arash Derakhshan2,3, Yi Xiao4, Liang-Miao Chen5, Tuija Männistö6, Ghalia Ashoor7, Fangbiao Tao8,9, Suzanne J Brown10, Marina Vafeiadi11, Sachiko Itoh12, Elena Nikolaevna Grineva13, Peter Taylor14, Farkhanda Ghafoor15, Bijay Vaidya16, Andrew Hattersley17, Lorena Mosso18, Emily Oken19, Reiko Kishi12, Erik K Alexander20, Spyridoula Maraka21,22,23, Kun Huang8, Layal Chaker2,3, Judit Bassols24, Amna Pirzada25, Abel López-Bermejo26, Laura Boucai27, Robin P Peeters2,3, Elizabeth N Pearce28, Scott McGill Nelson29, Leda Chatzi11, Tanja G Vrijkotte30, Polina V Popova13,31,32, John P Walsh10,33, Kypros H Nicolaides34, Eila Suvanto35, Xuemian Lu5, Victor J M Pop36, Julie Lyng Forman4, Tim I M Korevaar2,3, Ulla Feldt-Rasmussen1,37. 1. Department of Medical Endocrinology and Metabolism, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. 2. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands. 3. Academic Center for Thyroid Diseases, Erasmus University Medical Center, Rotterdam, the Netherlands. 4. Section of Biostatistics, Department of Public Health, Copenhagen University, Copenhagen, Denmark. 5. Department of Endocrinology and Rui'an Center of the Chinese-American Research Institute for Diabetic Complications, Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. 6. Northern Finland Laboratory Center Nordlab and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland. 7. Harris Birthright Research Center for Fetal Medicine, King's College Hospital, London, United Kingdom. 8. Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, Hefei, China. 9. Anhui Provincial Key Laboratory of Population Health & Aristogenics, Hefei, China. 10. Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Australia. 11. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. 12. Center for Environmental and Health Sciences, Hokkaido University, Sapporo, Japan. 13. Institute of Endocrinology, Almazov National Medical Research Centre, St. Petersburg, Russia. 14. Thyroid Research Group, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff, United Kingdom. 15. Research & Innovation, Shalamar Institute of Health Sciences, Lahore, Pakistan. 16. Department of Endocrinology, Royal Devon and Exeter Hospital NHS Foundation Trust, University of Exeter Medical School, Exeter, United Kingdom. 17. University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, United Kingdom. 18. Endocrinology Department and Center of Translational Endocrinology (CETREN), Department of Endocrinology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile. 19. Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Hypertension and Diabetes, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 20. Division of Endocrinology, Hypertension and Diabetes, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 21. Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA. 22. Knowledge and Evaluation Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA. 23. Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA. 24. Maternal-Fetal Metabolic Research Group, Girona Biomedical Research Institute (IDIBGI), Dr. Josep Trueta Hospital, Girona, Spain. 25. Shifa Institute of Medical Technology, Shifa International Hospital, Islamabad, Pakistan. 26. Pediatric Endocrinology Research Group, Girona Biomedical Research Institute (IDIBGI), Dr. Josep Trueta Hospital, Girona, Spain. 27. Division of Endocrinology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell University, New York, New York, USA. 28. Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, Massachusetts, USA. 29. School of Medicine, University of Glasgow, Glasgow, United Kingdom. 30. Department of Public Health, Amsterdam UMC, University of Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands. 31. Department of Internal Diseases and Endocrinology, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia. 32. World-Class Research Center for Personalized Medicine, Almazov National Medical Research Centre, St. Petersburg, Russia. 33. Medical School, University of Western Australia, Crawley, Australia. 34. Department of Women and Children's Health, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom. 35. Department of Obstetrics and Gynecology and Medical Research Center Oulu, University of Oulu, Oulu, Finland. 36. Department of Medical and Clinical Psychology, Tilburg University, Tilburg, the Netherlands. 37. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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.
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.
Authors: Joris A J Osinga; Arash Derakhshan; Glenn E Palomaki; Ghalia Ashoor; Tuija Männistö; Spyridoula Maraka; Liangmiao Chen; Sofie Bliddal; Xuemian Lu; Peter N Taylor; Tanja G M Vrijkotte; Fang-Biao Tao; Suzanne J Brown; Farkhanda Ghafoor; Kris Poppe; Flora Veltri; Lida Chatzi; Bijay Vaidya; Maarten A C Broeren; Beverley M Shields; Sachiko Itoh; Lorena Mosso; Polina V Popova; Anna D Anopova; Reiko Kishi; Ashraf Aminorroaya; Maryam Kianpour; Abel López-Bermejo; Emily Oken; Amna Pirzada; Marina Vafeiadi; Wichor M Bramer; Eila Suvanto; Jun Yoshinaga; Kun Huang; Judit Bassols; Laura Boucai; Ulla Feldt-Rasmussen; Elena N Grineva; Elizabeth N Pearce; Erik K Alexander; Victor J M Pop; Scott M Nelson; John P Walsh; Robin P Peeters; Layal Chaker; Kypros H Nicolaides; Mary E D'Alton; Tim I M Korevaar Journal: J Clin Endocrinol Metab Date: 2022-09-28 Impact factor: 6.134