Objective: International guidelines recommend to diagnose gestational thyroid disease according to trimester-specific reference intervals (RIs) for TSH and FT4. Yet, the majority of centers still rely on non-pregnancy RIs in combination with a fixed upper limit for TSH or by a subtraction from this limit, both are based on expert opinion and haven’t been thoroughly investigated. We aim to quantify the rate of over and underdiagnosis when using an alternative method, and to explore other methods which might better simulate the trimester specific approach.

Methods: We performed an individual participant data meta-analysis within the Consortium on Thyroid and Pregnancy. RIs and disease prevalences were calculated according to different methods currently advised in guidelines and with varying TSH and FT4 limits in order to optimize alternative strategies for the diagnosis of (subclinical) hypothyroidism.

Results: The study population comprised 58,815 participants participating in 19 prospective cohorts. The use of non-pregnancy RIs in the first trimester resulted in considerable over and underdiagnosis of overt hypothyroidism (0.1% and 57%) and subclinical hypothyroidism (0.5% and 56.5%). The underdiagnosis was lower for subclinical hypothyroidism with the fixed limit approach (46%) and the subtraction approach (44.8%) although overdiagnosis was higher (0.6 and 1.1%). The use of non-pregnancy RIs with a 0.5mU/L subtraction from the upper limit of TSH and a 1pmol/L subtraction from the lower limit of FT4 resulted in the lowest possible rates of over and underdiagnosis for entities in the first trimester with a current treatment indication or consideration.

Conclusion: Approaches to RI determinations other than calculating hospital specific RIs lead to considerable over and underdiagnosis of gestational thyroid disease. A relative subtraction from the non-pregnancy upper limit of TSH and lower limit of FT4 might improve diagnosis rates of specifically TPOAb positive hypothyroid patients in terms of over and underdiagnosis as compared to the trimester-specific approach.