Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity With Preterm Birth: A Systematic Review and Meta-analysis
Open accessAbstract
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 Data sets from published and unpublished prospective cohort studies with data on thyroid function tests (thyrotropin [often referred to as thyroid-stimulating hormone or TSH] and free thyroxine [FT4]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 After the addition of 5 unpublished data sets, a total of 19 cohorts were included.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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In young fertile women, undertreatment with levothyroxine is associated with compromised neurocognitive development.
“In young fertile women, the consequences of undertreatment with LT4 are subnormal fertility, recurrent pregnancy loss, compromised fetal growth, and neurocognitive development.”
From Risks of suboptimal and excessive thyroid hormone replacement across ages (2023) · cites this paper as [23]
In young fertile women, undertreatment with levothyroxine is associated with compromised fetal growth.
“In young fertile women, the consequences of undertreatment with LT4 are subnormal fertility, recurrent pregnancy loss, compromised fetal growth, and neurocognitive development.”
From Risks of suboptimal and excessive thyroid hormone replacement across ages (2023) · cites this paper as [23]
In young fertile women, undertreatment with levothyroxine is associated with recurrent pregnancy loss.
“In young fertile women, the consequences of undertreatment with LT4 are subnormal fertility, recurrent pregnancy loss, compromised fetal growth, and neurocognitive development.”
From Risks of suboptimal and excessive thyroid hormone replacement across ages (2023) · cites this paper as [23]
In pregnancy, levothyroxine treatment is important to secure sufficient placental transfer of T4, needed for fetal development and to reduce adverse pregnancy outcomes such as pregnancy loss and preterm birth.
“Specifically in pregnancy, the LT4 treatment is not only important to the woman, but also to secure a sufficient placental transfer of T4, which is needed for fetal development and to reduce adverse pregnancy outcomes such as pregnancy loss and preterm birth [23, 24].”
From Risks of suboptimal and excessive thyroid hormone replacement across ages (2023) · cites this paper as [23]
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- Authors
- The Consortium on Thyroid and Pregnancy—Study Group on Preterm Birth, Korevaar, T. I. M., Derakhshan, A., Taylor, P. N., Meima, M., Chen, L., Bliddal, S., Carty, D. M., Meems, M., Vaidya, B., Shields, B., Ghafoor, F., Popova, P. V., Mosso, L., Oken, E., Suvanto, E., Hisada, A., Yoshinaga, J., Brown, S. J., Bassols, J., Auvinen, J., Bramer, W. M., López-Bermejo, A., Dayan, C., Boucai, L., Vafeiadi, M., Grineva, E. N., Tkachuck, A. S., Pop, V. J. M., Vrijkotte, T. G., Guxens, M., Chatzi, L., Sunyer, J., Jiménez-Zabala, A., Riaño, I., Murcia, M., Lu, X., Mukhtar, S., Delles, C., Feldt-Rasmussen, U., Nelson, S. M., Alexander, E. K., Chaker, L., Männistö, T., Walsh, J. P., Pearce, E. N., Steegers, E. A. P., & Peeters, R. P.
- Affiliations
- Erasmus MC (NL)
- Cardiff University (GB)
- Ruian People's Hospital (CN)
- Copenhagen University Hospital (DK)
- Glasgow Royal Infirmary (GB)
- Tilburg University (NL)
- University of Exeter (GB)
- National Health Research Complex, Shaikh Zayed Medical Complex, Lahore, Pakistan
- First Pavlov State Medical University of St. Petersburg (RU)
- Pontificia Universidad Católica de Chile (CL)
- Harvard University (US)
- University of Oulu (FI)
- Chiba University (JP)
- Toyo University (JP)
- Sir Charles Gairdner Hospital (AU)
- Institut d'Investigació Biomèdica de Girona (ES)
- Oulu University Hospital (FI)
- Pediatric Endocrinology Research Group, Girona Biomedical Research Institute, Dr Josep Trueta Hospital, Girona, Spain
- Memorial Sloan Kettering Cancer Center (US)
- University of Crete (GR)
- Almazov National Medical Research Centre, St Petersburg, Russia
- Amsterdam Public Health (NL)
- Universitat Pompeu Fabra (ES)
- University of Southern California (US)
- Basque Government (ES)
- Spanish Consortium for Research on Epidemiology and Public Health, Instituto de Salud Carlos III, Madrid, Spain
- Universitat Jaume I (ES)
- Shaikh Zayed Hospital (PK)
- University of Glasgow (GB)
- Department of Medical Endocrinology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- National Institute for Health and Care Research (GB)
- Brigham and Women's Hospital (US)
- The University of Western Australia (AU)
- Boston University (US)
- Corresponding author
- Korevaar, Tim I. M.
- ORCID
- Korevaar, Tim I. M.
- Derakhshan, Arash
- Taylor, Peter N.
- Meima, Marcel
- Chen, Liangmiao
- Bliddal, Sofie
- Carty, David M.
- Meems, Margreet
- Vaidya, Bijay
- Shields, Beverley
- Popova, Polina V.
- Mosso, Lorena
- Oken, Emily
- Hisada, Aya
- Yoshinaga, Jun
- Brown, Suzanne J.
- Bassols, Judit
- Auvinen, Juha
- Bramer, Wichor M.
- Dayan, Colin
- Boucai, Laura
- Vafeiadi, Marina
- Grineva, Elena N.
- Pop, Victor J. M.
- Vrijkotte, Tanja G.
- Guxens, Mònica
- Chatzi, Leda
- Sunyer, Jordi
- Jiménez-Zabala, Ana
- Murcia, Mario
- Lu, Xuemian
- Delles, Christian
- Nelson, Scott M.
- Alexander, Erik K.
- Chaker, Layal
- Männistö, Tuija
- Walsh, John P.
- Pearce, Elizabeth N.
- Steegers, Eric A. P.
- Peeters, Robin P.
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2019-08-20
- Volume
- 322
- Issue
- 7
- Pages
- 632
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC6704759
- OpenAlex
- W2969751565
- Cited by
- 378
- References
- 51
- Citations by year
- 2026: 36 · 2025: 47 · 2024: 68 · 2023: 67 · 2022: 78 · 2021: 33 · 2020: 37 · 2019: 12
- FWCI
- 6.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- UWA Profiles and Research Repository (UWA) (publishedVersion, other-oa)
- Research portal (Tilburg University) (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc-nd)
- University of Birmingham Research Portal (University of Birmingham) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion, cc-by-sa)
- Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion)
- Funders
- Brigham and Women's Hospital
- University of Southern California
- Memorial Sloan-Kettering Cancer Center
- School of Medicine, Boston University
- Medical Research Center Oulu
- Universitat Pompeu Fabra
- National Institute for Health and Care Research
- University of Exeter
- University of Glasgow
- Cardiff University
- Universiteit van Amsterdam
- Eusko Jaurlaritza
- Universitat de València
- University of Crete
- Universitat Jaume I
- Oulun Yliopisto
- Universiteit van Tilburg
- Chiba University
- Toyo University
- Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana
- Weill Cornell Medical College
- Instituto de Salud Carlos III
- Erasmus Universitair Medisch Centrum Rotterdam
- National Cancer Institute (P30CA008748)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD034568)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Health Sciences › Medicine › Epidemiology › Preterm Birth and Chorioamnionitis
- Keywords
- preterm birth, thyroid autoimmunity, subclinical hypothyroidism, isolated hypothyroxinemia, thyroid peroxidase antibodies, thyroid-stimulating hormone, free thyroxine, maternal thyroid disease, pregnancy complications, preterm birth risk factors, individual patient data meta-analysis, pooled odds ratio, risk difference
- MeSH terms
- Adult, Autoantibodies, Autoimmune Diseases, Female, Gestational Age, Humans, Hypothyroidism, Infant, Newborn, Iodide Peroxidase, Pregnancy, Pregnancy Complications, Thyroid Diseases, Thyroid Function Tests, Thyrotropin, Thyroxine, Premature Birth
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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