Objective: TPOAb positivity is an important risk factor for (subclinical) hypothyroidism and is used to define levothyroxine treatment indications during pregnancy. TPOAb positivity is usually defined by manufacturer cutoffs, most of which were derived from the general non-pregnant population. Besides the general lack of uniformity, current TPOAb positivity cutoffs are likely to perform poorly during pregnancy due to immune tolerance (underestimate thyroid autoimmunity). In this study, we explored whether TPOAb concentrations below the clinically used threshold for positivity would be associated with lower maternal thyroid function during pregnancy.

Methods: This study was an individual participant data meta-analysis of prospective cohort studies in the Consortium on Thyroid and Pregnancy. Participants with a multiple pregnancy, pre-existing thyroid diseases, thyroid (interfering) medication usage, or pregnancy by IVF were excluded. The associations of TPOAb percentiles with SD-scores of TSH and FT4, and the risk of TSH higher than 2.5 mU/L and the upper limit of reference ranges were explored.

Results: We finally included 69,713 participants from 24 cohorts. As compared to TPOAb concentrations ≤80^th percentile, the association of TPOAbs with TSH concentration was significant from the 89^th percentile and upwards (effect estimates, range +0.13 SD to +1.04 SD) and the association with FT4 concentration was significant from the 91^st percentile (effect estimates, range -0.08 SD to -0.45 SD). Pregnant women with TPOAb concentrations ≥89th percentile had a higher risk of TSH concentrations from 2.5 mU/L to the upper limit of reference ranges (ORs, range 1.39 to 6.27) and a TSH above the upper limit of normal (ORs, range 1.91 to 39.4). The associations of TPOAbs with TSH and FT4 were more relevant during early pregnancy than late pregnancy (P for interaction <0.001 for TSH and <0.001 for FT4).

Conclusion: This study indicates TPOAb concentrations just below the currently used manufacturer cutoffs may already reflect relevant thyroid autoimmunity during pregnancy.