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

Area of Science:

• Endocrinology
• Reproductive Medicine
• Clinical Chemistry

Background:

• Thyroid function tests (TFTs) interpretation during pregnancy is complicated by varying reference intervals.
• Methodological inconsistencies between studies limit the generalizability of existing TFT reference ranges.

Purpose of the Study:

• To compile published reference intervals for thyrotropin (TSH) and free thyroxine (FT4) in pregnant individuals.
• To evaluate the impact of common methodological differences on TFT reference intervals using a meta-analysis of individual participant data.

Main Methods:

• Systematic literature search of Ovid MEDLINE, EMBASE, and Web of Science up to December 2021.
• Individual participant data (IPD) meta-analysis conducted on data from the Consortium on Thyroid and Pregnancy cohorts.
• Assessment of methodological differences and their consequences on reference interval calculations.

Main Results:

• Significant methodological variations were found, with only 11 of 102 studies adhering to current guidelines.
• Meta-analysis included 22 cohorts (63,198 participants).
• Excluding thyroid peroxidase antibody-positive individuals notably altered upper TSH limits (e.g., +17.4% in the first trimester). Use of the 95th percentile also caused substantial shifts in TSH and FT4 upper limits.

Conclusions:

• Clinically relevant reference intervals for TSH and FT4 in pregnancy are presented.
• Future research can utilize a simplified study design without additional exclusion criteria, improving consistency and applicability of TFT reference intervals.