TSH and FT4 reference intervals in pregnancy: a systematic review and individual participant data meta-analysis

Abstract

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: +17.4range +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.