Risk Factors for Thyroid Dysfunction in Pregnancy: An Individual Participant Data Meta-Analysis

Abstract

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction.

Keywords: pregnancy; risk factors; screening; thyroid; thyroid function tests.

FIG. 1.

Study flowchart.

FIG. 2.

Association of maternal age and BMI with the risk of thyroid function test abnormalities. A treatment indication and consideration were defined according to the 2017 American Thyroid Association guidelines. BMI, body mass index.

FIG. 3.

Association of parity and maternal smoking status with thyroid function test abnormalities. A treatment indication and consideration were defined according to the 2017 American Thyroid Association guidelines.

FIG. 4.

Association of pregnancy through IVF and twin pregnancy with thyroid function test abnormalities. A treatment indication and consideration were defined according to the 2017 American Thyroid Association guidelines. IVF, in vitro fertilization.

FIG. 5.

Association of thyroid autoimmunity with thyroid function test abnormalities. A treatment indication and consideration were defined according to the 2017 American Thyroid Association guidelines. Analyses with TPOAb and TgAb were performed in a subset with data on both autoantibodies. *Since TPOAb positivity is part of the definition of a treatment indication, treatment indication was alternatively defined as either overt hypothyroidism or TSH >10 mU/L. TgAb, thyroglobulin antibodies; TPOAb, thyroperoxidase antibodies.

FIG. 6.

Receiver operating characteristic curves. Visualization of discriminatory ability of significant explanatory variables; maternal age, BMI, smoking status, parity, and gestational age at blood sampling. TPOAb/TgAb status were not included in the models to be able to assess both the direct predictive effects and indirect predictive effects through thyroid autoimmunity. A treatment indication and consideration are defined according to the 2017 American Thyroid Association guidelines. (A) Overt hypothyroidism; (B) Subclinical hypothyroidism; (C) Treatment indication; (D) Treatment consideration.