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

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 Data sets from published and unpublished prospective cohort studies with data on thyroid function tests (thyrotropin [often referred to as thyroid-stimulating hormone or TSH] and free thyroxine [FT4]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 After the addition of 5 unpublished data sets, a total of 19 cohorts were included.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

Figure 1.. Flowchart of the Study and Participant Selections

Figure 2.. Association of Thyroid Function Test Abnormalities With Preterm Birth

All analyses were adjusted for maternal age, body mass index, ethnicity, smoking, parity, gestational age at blood sampling, and fetal sex. Euthyroid was defined as the 2.5th-97.5th cohort-specific percentile for thyrotropin (often referred to as thyroid-stimulating hormone or TSH) and free thyroxine (FT₄) concentrations; subclinical hypothyroidism, increased thyrotropin concentration with a normal FT₄ concentration; subclinical hyperthyroidism, decreased thyrotropin concentration with a normal FT₄ concentration; overt hyperthyroidism, decreased thyrotropin concentration with an increased FT₄ concentration; and isolated hypothyroxinemia, a normal thyrotropin concentration with a decreased FT₄ concentration. These clinical entities were calculated for cohorts that had thyrotropin concentration, FT₄ concentration, and thyroid peroxidase antibody data available. Absolute differences and corresponding 95% CIs were back-calculated from the results of multivariable models and adjusted for baseline risk imprecision. ^aThere were too few samples to conduct a reliable analysis.

Figure 3.. Association of Thyrotropin and Free Thyroxine (FT₄) Concentrations With Preterm Birth

Preterm birth was defined as less than 37 weeks’ gestational age and very preterm birth was defined as less than 32 weeks’ gestational age. The thyrotropin and FT₄ concentrations for all cohorts were log transformed and then standardized to population-specific standard deviation scores after removal of outliers (±4 SD from the mean) to enable comparison between different cohorts and assays. All analyses were adjusted for maternal age, body mass index, ethnicity, smoking, parity, gestational age at blood sampling, and fetal sex. OR indicates odds ratio.

Figure 4.. Association of Thyroid Peroxidase (TPO) Antibody Positivity With Preterm Birth

All analyses were adjusted for maternal age, body mass index, ethnicity, smoking, parity, gestational age at blood sampling, and fetal sex. Absolute differences and corresponding 95% CIs were back-calculated from the results of multivariable models and adjusted for baseline risk imprecision. ^aThyroid peroxidase antibody–positive women and thyrotropin (often referred to as thyroid-stimulating hormone) concentrations within the normal range or higher than 2.5 mIU/L and 4 mIU/L were compared with TPO antibody–negative women regardless of their thyrotropin concentration. ^bThere were too few samples to conduct a reliable analysis.