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Original Investigation
August 20, 2019

Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity With Preterm Birth: A Systematic Review and Meta-analysis

The Consortium on Thyroid and Pregnancy—Study Group on Preterm Birth
JAMA. 2019;322(7):632-641. doi:10.1001/jama.2019.10931
Key Points

Question  Are thyroid function test abnormalities or thyroid autoimmunity a risk factor for preterm birth?

Findings  In this individual participant data meta-analysis of 19 prospective cohort studies including 47 045 women, subclinical hypothyroidism (odds ratio [OR], 1.29), isolated hypothyroxinemia (OR, 1.46), and thyroid peroxidase antibody positivity (OR, 1.33) were each significantly associated with a higher risk of preterm birth.

Meaning  These findings provide evidence that subclinical hypothyroidism, isolated hypothyroxinemia, and thyroid peroxidase antibody positivity in pregnant women are risk factors for preterm birth.

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 Data sets from published and unpublished prospective cohort studies with data on thyroid function tests (thyrotropin [often referred to as thyroid-stimulating hormone or TSH] and free thyroxine [FT4]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 After the addition of 5 unpublished data sets, a total of 19 cohorts were included.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.

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