T I M Korevaar1,2, Arash Derakhshan1,2, Peter N Taylor3, Marcel Meima1,2, Liangmiao Chen4, Sofie Bliddal5, David M Carty6,7, Margreet Meems8, Bijay Vaidya9, Beverley Shields10, Farkhanda Ghafoor11, Polina V Popova12,13, Lorena Mosso14, Emily Oken15,16,17, Eila Suvanto18, Aya Hisada19, Jun Yoshinaga20, Suzanne J Brown21, Judit Bassols22, Juha Auvinen23, Wichor M Bramer24, Abel López-Bermejo25, Colin Dayan26, Laura Boucai27, Marina Vafeiadi28, Elena N Grineva12,13, Alexandra S Tkachuck12,13, Victor J M Pop8, T G Vrijkotte, M Guxens, L Chatzi, J Sunyer, A Jiménez-Zabala, I Riaño, M Murcia, X Lu, S Mukhtar, C Delles, U Feldt-Rasmussen, S M Nelson, E K Alexander, L Chaker, T Männistö, J P Walsh, E N Pearce, E A P Steegers, R P Peeters. 1. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands. 2. Academic Center for Thyroid Diseases, Erasmus University Medical Center, Rotterdam, the Netherlands. 3. Thyroid Research Group, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, England. 4. 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. 5. Department of Medical Endocrinology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. 6. Department of Diabetes, Endocrinology, and Clinical Pharmacology, Glasgow Royal Infirmary, Glasgow, Scotland. 7. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland. 8. Departments of Medical and Clinical Psychology, Tilburg University, Tilburg, the Netherlands. 9. Department of Endocrinology, Royal Devon and Exeter Hospital NHS Foundation Trust, University of Exeter Medical School, Exeter, England. 10. Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, England. 11. National Health Research Complex, Shaikh Zayed Medical Complex, Lahore, Pakistan. 12. Almazov National Medical Research Centre, St Petersburg, Russia. 13. Department of Internal Diseases and Endocrinology, St Petersburg Pavlov State Medical University, St Petersburg, Russia. 14. Department of Endocrinology, Pontificia Universidad Catolica de Chile, Santiago. 15. Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School, Boston, Massachusetts. 16. Harvard Pilgrim Health Care Institute, Boston, Massachusetts. 17. Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. 18. Department of Obstetrics and Gynecology and Medical Research Center Oulu, University of Oulu, Oulu, Finland. 19. Center for Preventive Medical Science, Chiba University, Chiba, Japan. 20. Faculty of Life Sciences, Toyo University, Gunma, Japan. 21. Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Australia. 22. Maternal-Fetal Metabolic Research Group, Girona Biomedical Research Institute, Dr Josep Trueta Hospital, Girona, Spain. 23. Medical Research Center Oulu, Oulu University Hospital, Center for Life Course Health Research, University of Oulu, Oulu, Finland. 24. Medical Library, Erasmus University Medical Center, Rotterdam, the Netherlands. 25. Pediatric Endocrinology Research Group, Girona Biomedical Research Institute, Dr Josep Trueta Hospital, Girona, Spain. 26. Thyroid Research Group, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff, England. 27. Division of Endocrinology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell University, New York, New York. 28. Department of Social Medicine, University of Crete, Heraklion, Greece.
Abstract
Importance: Maternal hypothyroidism and hyperthyroidism are risk factors for preterm birth. Milder thyroid function test abnormalities and thyroid autoimmunity are more prevalent, but it remains controversial if these are associated with preterm birth. Objective: To study if maternal thyroid function test abnormalities and thyroid autoimmunity are risk factors for preterm birth. Data Sources and Study Selection: Studies were identified through a search of the Ovid MEDLINE, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar databases from inception to March 18, 2018, and by publishing open invitations in relevant journals. Data sets from published and unpublished prospective cohort studies with data on thyroid function tests (thyrotropin [often referred to as thyroid-stimulating hormone or TSH] and free thyroxine [FT4] concentrations) or thyroid peroxidase (TPO) antibody measurements and gestational age at birth were screened for eligibility by 2 independent reviewers. Studies in which participants received treatment based on abnormal thyroid function tests were excluded. Data Extraction and Synthesis: The primary authors provided individual participant data that were analyzed using mixed-effects models. Main Outcomes and Measures: The primary outcome was preterm birth (<37 weeks' gestational age). Results: From 2526 published reports, 35 cohorts were invited to participate. After the addition of 5 unpublished data sets, a total of 19 cohorts were included. The study population included 47 045 pregnant women (mean age, 29 years; median gestational age at blood sampling, 12.9 weeks), of whom 1234 (3.1%) had subclinical hypothyroidism (increased thyrotropin concentration with normal FT4 concentration), 904 (2.2%) had isolated hypothyroxinemia (decreased FT4 concentration with normal thyrotropin concentration), and 3043 (7.5%) were TPO antibody positive; 2357 (5.0%) had a preterm birth. The risk of preterm birth was higher for women with subclinical hypothyroidism than euthyroid women (6.1% vs 5.0%, respectively; absolute risk difference, 1.4% [95% CI, 0%-3.2%]; odds ratio [OR], 1.29 [95% CI, 1.01-1.64]). Among women with isolated hypothyroxinemia, the risk of preterm birth was 7.1% vs 5.0% in euthyroid women (absolute risk difference, 2.3% [95% CI, 0.6%-4.5%]; OR, 1.46 [95% CI, 1.12-1.90]). In continuous analyses, each 1-SD higher maternal thyrotropin concentration was associated with a higher risk of preterm birth (absolute risk difference, 0.2% [95% CI, 0%-0.4%] per 1 SD; OR, 1.04 [95% CI, 1.00-1.09] per 1 SD). Thyroid peroxidase antibody-positive women had a higher risk of preterm birth vs TPO antibody-negative women (6.6% vs 4.9%, respectively; absolute risk difference, 1.6% [95% CI, 0.7%-2.8%]; OR, 1.33 [95% CI, 1.15-1.56]). Conclusions and Relevance: Among pregnant women without overt thyroid disease, subclinical hypothyroidism, isolated hypothyroxinemia, and TPO antibody positivity were significantly associated with higher risk of preterm birth. These results provide insights toward optimizing clinical decision-making strategies that should consider the potential harms and benefits of screening programs and levothyroxine treatment during pregnancy.
Importance: Maternal hypothyroidism and hyperthyroidism are risk factors for preterm birth. Milder thyroid function test abnormalities and thyroid autoimmunity are more prevalent, but it remains controversial if these are associated with preterm birth. Objective: To study if maternal thyroid function test abnormalities and thyroid autoimmunity are risk factors for preterm birth. Data Sources and Study Selection: Studies were identified through a search of the Ovid MEDLINE, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar databases from inception to March 18, 2018, and by publishing open invitations in relevant journals. Data sets from published and unpublished prospective cohort studies with data on thyroid function tests (thyrotropin [often referred to as thyroid-stimulating hormone or TSH] and free thyroxine [FT4] concentrations) or thyroid peroxidase (TPO) antibody measurements and gestational age at birth were screened for eligibility by 2 independent reviewers. Studies in which participants received treatment based on abnormal thyroid function tests were excluded. Data Extraction and Synthesis: The primary authors provided individual participant data that were analyzed using mixed-effects models. Main Outcomes and Measures: The primary outcome was preterm birth (<37 weeks' gestational age). Results: From 2526 published reports, 35 cohorts were invited to participate. After the addition of 5 unpublished data sets, a total of 19 cohorts were included. The study population included 47 045 pregnant women (mean age, 29 years; median gestational age at blood sampling, 12.9 weeks), of whom 1234 (3.1%) had subclinical hypothyroidism (increased thyrotropin concentration with normal FT4 concentration), 904 (2.2%) had isolated hypothyroxinemia (decreased FT4 concentration with normal thyrotropin concentration), and 3043 (7.5%) were TPO antibody positive; 2357 (5.0%) had a preterm birth. The risk of preterm birth was higher for women with subclinical hypothyroidism than euthyroid women (6.1% vs 5.0%, respectively; absolute risk difference, 1.4% [95% CI, 0%-3.2%]; odds ratio [OR], 1.29 [95% CI, 1.01-1.64]). Among women with isolated hypothyroxinemia, the risk of preterm birth was 7.1% vs 5.0% in euthyroid women (absolute risk difference, 2.3% [95% CI, 0.6%-4.5%]; OR, 1.46 [95% CI, 1.12-1.90]). In continuous analyses, each 1-SD higher maternal thyrotropin concentration was associated with a higher risk of preterm birth (absolute risk difference, 0.2% [95% CI, 0%-0.4%] per 1 SD; OR, 1.04 [95% CI, 1.00-1.09] per 1 SD). Thyroid peroxidase antibody-positive women had a higher risk of preterm birth vs TPO antibody-negative women (6.6% vs 4.9%, respectively; absolute risk difference, 1.6% [95% CI, 0.7%-2.8%]; OR, 1.33 [95% CI, 1.15-1.56]). Conclusions and Relevance: Among pregnant women without overt thyroid disease, subclinical hypothyroidism, isolated hypothyroxinemia, and TPO antibody positivity were significantly associated with higher risk of preterm birth. These results provide insights toward optimizing clinical decision-making strategies that should consider the potential harms and benefits of screening programs and levothyroxine treatment during pregnancy.
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