TSH and FT4 Reference Intervals in Pregnancy: A Systematic Review and Individual Participant Data Meta-Analysis

Joris A. J. Osinga, Arash Derakhshan, Glenn E. Palomaki, Ghalia Ashoor, Tuija Mannisto, Spyridoula Maraka, Liangmiao Chen, Sofie Bliddal, Xuemian Lu, Peter N. Taylor, Tanja G. M. Vrijkotte, Fang-Biao Tao, Suzanne J. Brown, Farkhanda Ghafoor, Kris Poppe, Flora Veltri, Lida Chatzi, Bijay Vaidya, Maarten A. C. Broeren, Beverley M. ShieldsSachiko Itoh, Lorena Mosso, Polina Popova, Anna D. Anopova, Reiko Kishi, Ashraf Aminorroaya, Maryam Kianpour, Abel Lopez-Bermejo, Emily Oken, Amna Pirzada, Marina Vafeiadi, Wichor M. Bramer, Eila Suvanto, Jun Yoshinaga, Kun Huang, Judit Bassols, Laura Boucai, Ulla Feldt-Rasmussen, Elena N. Grineva, Elizabeth N. Pearce, Erik K. Alexander, Victor J. M. Pop, Scott M. Nelson, John P. Walsh, Robin P. Peeters, Layal Chaker, Kypros H. Nicolaides, Mary E. D'Alton, Tim I. M. Korevaar

Research output: Contribution to journalReview articlepeer-review

19 Citations (Scopus)


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 thyrotropin (TSH) and free thyroxine (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 December 12, 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 thyroid peroxidase antibody-positive participants led to a rise in 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. Conclusion 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.
Original languageEnglish
Pages (from-to)2925-2933
Number of pages9
JournalJournal of Clinical Endocrinology & Metabolism
Issue number10
Early online date21 Jul 2022
Publication statusPublished - 1 Oct 2022


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