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    TSH and FT4 reference intervals in pregnancy: a systematic review and individual participant data meta-analysis
    (Endocrine Society, 2022-07-21) Osinga, J. A. J.; Derakhshan, A.; Palomaki, G. E.; Ashoor, G.; Männistö, T.; Maraka, S.; Chen, L.; Bliddal, S.; Lu, X.; Taylor, P. N.; Vrijkotte, T. G. M.; Tao, F. B.; Brown, S. J.; Ghafoor, F.; Poppe, K.; Veltri, F.; Chatzi, L.; Vaidya, B.; Broeren, M. A. C.; Shields, B. M.; Itoh, S.; Mosso, L.; Popova, P. V.; Anopova, A. D.; Kishi, R.; Aminorroaya, A.; Kianpour, M.; López-Bermejo, A.; Oken, E.; Pirzada, A.; Vafeiadi, M.; Bramer, W. M.; Suvanto, E.; Yoshinaga, J.; Huang, K.; Bassols, J.; Boucai, L.; Feldt-Rasmussen, U.; Grineva, E. N.; Pearce, E. N.; Alexander, E. K.; Pop, V. J. M.; Nelson, S. M.; Walsh, J. P.; Peeters, R. P.; Chaker, L.; Nicolaides, K. H.; D'Alton, M. E.; Korevaar, T. I. M.
    CONTEXT: Interpretation of thyroid function tests during pregnancy is limited by the generalizability of reference intervals between cohorts due to inconsistent methodology. OBJECTIVE: 1) To provide an overview of published reference intervals for TSH and FT4 in pregnancy, 2) to assess the consequences of common methodological between-study differences by combining raw data from different cohorts. METHODS: 1) Ovid MEDLINE, EMBASE and Web of Science were searched until the 12th of December 2021. Studies were assessed in duplicate. 2) The individual participant data (IPD) meta-analysis was performed in participating cohorts in the Consortium on Thyroid and Pregnancy. RESULTS: 1) Large between-study methodological differences were identified, 11 of 102 included studies were in accordance with current guidelines. 2) 22 cohorts involving 63,198 participants, were included in the meta-analysis. Not excluding TPOAb-positive participants led to a rise of the upper limits of TSH in all cohorts, especially in the first (mean: +17.4%[range +1.6 to +30.3%]) and second trimester (mean: +9.8% [range +0.6 to +32.3%]). The use of the 95th percentile led to considerable changes in upper limits, varying from -10.8% to -21.8% for TSH and -1.2% to -13.2% for FT4. All other additional exclusion criteria changed reference interval cut-offs by a maximum of 3.5%. Applying these findings to the 102 studies included in the systematic review, 48 studies could be used in a clinical setting. CONCLUSIONS: We provide an overview of clinically relevant reference intervals for TSH and FT4 in pregnancy. The results of the meta-analysis indicate that future studies can adopt a simplified study setup without additional exclusion criteria.