TSH and FT4 Reference Interval Recommendations and Prevalence of Gestational Thyroid Dysfunction: Quantification of Current Diagnostic Approaches

Abstract

Context: Guidelines recommend use of population- and trimester-specific thyroid-stimulating hormone (TSH) and free thyroxine (FT4) reference intervals (RIs) in pregnancy. Since these are often unavailable, clinicians frequently rely on alternative diagnostic strategies. We sought to quantify the diagnostic consequences of current recommendations.

Methods: We included cohorts participating in the Consortium on Thyroid and Pregnancy. Different approaches were used to define RIs: a TSH fixed upper limit of 4.0 mU/L (fixed limit approach), a fixed subtraction from the upper limit for TSH of 0.5 mU/L (subtraction approach) and using nonpregnancy RIs. Outcome measures were sensitivity and false discovery rate (FDR) of women for whom levothyroxine treatment was indicated and those for whom treatment would be considered according to international guidelines.

Results: The study population comprised 52 496 participants from 18 cohorts. Compared with the use of trimester-specific RIs, alternative approaches had a low sensitivity (0.63-0.82) and high FDR (0.11-0.35) to detect women with a treatment indication or consideration. Sensitivity and FDR to detect a treatment indication in the first trimester were similar between the fixed limit, subtraction, and nonpregnancy approach (0.77-0.11 vs 0.74-0.16 vs 0.60-0.11). The diagnostic performance to detect overt hypothyroidism, isolated hypothyroxinemia, and (sub)clinical hyperthyroidism mainly varied between FT4 RI approaches, while the diagnostic performance to detect subclinical hypothyroidism varied between the applied TSH RI approaches.

Conclusion: Alternative approaches to define RIs for TSH and FT4 in pregnancy result in considerable overdiagnosis and underdiagnosis compared with population- and trimester-specific RIs. Additional strategies need to be explored to optimize identification of thyroid dysfunction during pregnancy.

Keywords: pregnancy; reference values; thyroid function tests; thyroid gland; thyrotropin; thyroxine.

Figure 1.

Inclusion flowchart. TPOAb, thyroid peroxidase antibodies.

Figure 2.

Figure shows participants with a treatment recommendation according to the reference standard (top row, based on trimester-specific reference intervals using 2.5th and 97.5th percentile in TPOAb negative women). Going down the figure shows the proportion of the same group of participants which has a changed treatment recommendation with alternative diagnostic approaches. A treatment indication is defined as overt hypothyroidism, subclinical hypothyroidism with either TSH >10 mU/L or concomitant thyroid peroxidase antibody [TPOAb] positivity). Treatment consideration is defined as TSH between 2.5 mU/L and upper reference limit with positive TPOAb; TSH between RI upper limit and 10 mU/L with negative TPOAb). Fixed limit approach: nonpregnancy reference intervals with a 4.0 mU/L fixed upper limit for TSH. Subtraction approach: nonpregnancy reference intervals with a 0.5 mU/L subtraction from the upper limit of TSH. Nonpregnancy approach: unadjusted nonpregnancy reference intervals as a historical benchmark. All definitions are based on the 2017 American Thyroid Association guidelines.

Figure 3.

Change in diagnosis comparing the trimester-specific reference intervals (left; using 2.5th and 97.5th percentile in TPOAb-negative women) and the fixed limit approach (right; nonpregnancy reference intervals with a 4.0 mU/L fixed upper limit for TSH). Labels indicate proportion of women for that specific thyroid function test abnormality who change to a certain other label. Orange labels and flow indicate a change in treatment recommendation, white labels indicate a change in biochemical diagnosis but with the same treatment recommendation, blue labels indicate proportion with the same biochemical diagnosis between methods.

Figure 4.

Change in diagnosis comparing the trimester-specific reference intervals (left; using 2.5th and 97.5th percentile in TPOAb-negative women) and the subtraction approach (right; nonpregnancy reference intervals subtracting 0.5 mU/L from the upper limit for TSH). Labels indicate proportion of women for that specific thyroid function test abnormality who change to a certain other label. Orange labels and flow indicate a change in treatment recommendation, white labels indicate a change in biochemical diagnosis but with the same treatment recommendation, blue labels indicate proportion with the same biochemical diagnosis between methods.