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

Preterm birth complicates 5% to 15% of births worldwide, and although it is the most important direct cause of morbidity and mortality in children younger than 5 years, no known risk factors can be identified in the majority of cases. However, overt hypothyroidism and hyperthyroidism during pregnancy are well-known risk factors for preterm birth, and as such, the purpose of this study was to assess whether thyroid function test abnormalities and thyroid peroxidase (TPO) antibody positivity were associated with preterm birth. The study conducted a systematic review on the association of thyroid function or autoimmunity with preterm birth published from database inception to March 18, 2018, without language restrictions, using the Ovid MEDLINE, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and Google Scholar databases. Possible studies for inclusion were independently assessed for suitability by 2 of the authors, and study quality and risk of bias were assessed using the Newcastle-Ottawa Scale. Then, authors were contacted to ascertain interest in participating in the individual patient meta-analysis. The primary outcome was preterm birth defined as a gestational age at birth of less than 37 weeks, as assessed using either ultrasound measurements or time after the last menstrual period. Secondary outcomes were very preterm birth (<32 weeks' gestational age) and the gestational age at birth. As a primary analysis of the study, the association of thyroid function test abnormalities in particular thyrotropin and free thyroxine concentrations were studied continuously using generalized linear mixed models with a random intercept for each cohort. As a secondary analysis, a post hoc sensitivity analysis assessed whether the association of TPO antibody positivity with preterm birth and very preterm birth differed for each increase in continuous thyrotropin concentration. Of the 2526 published reports, 133 remained eligible for inclusion based on screening of the title and abstract. Upon reading the full text, 35 cohorts were invited to participate in the study, and 19 cohorts from Europe, the United States, Chile, Australia, Pakistan, and Japan responded to the invitation and were able to participate. Associations between both subclinical hypothyroidism (SCH; adjusted odds ratio, 1.29, 95% confidence interval, 1.01–1.64) and isolated hypothyroxinemia (adjusted odds ratio, 1.46; 95% confidence interval, 1.12–1.90) with preterm birth were demonstrated. Those with TPO positivity only showed an increased risk of preterm birth with isolated hypothyroxinemia, not SCH. Limitations of the study included a lack of statistical power to optimally investigate the risk of very preterm birth in specific clinically relevant subgroups and the fact that only 5 of the 19 studies had data available on thyroglobulin antibodies. Next, pregnancy-related changes in thyroid-binding proteins could interfere with immunoassays. Also, studies published while conducting statistical analyses for the current study could not be included. In addition, because the included studies were observational, residual or unmeasured confounding cannot be excluded. Finally, causality cannot be determined from observational studies. Results of the study concluded that SCH, isolated hypothyroxinemia, and TPO antibody positivity indicated a much higher risk of preterm birth for pregnant women without overt thyroid disease. This study is also the first participant data metaanalysis to demonstrate that isolated hypothyroxinemia is associated with a higher risk of preterm birth and very preterm birth.

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