CONTEXT: The currently applied reference ranges for thyroid function are under debate. Despite evidence that thyroid function within the reference range is related with several cardiovascular disorders, its association with the risk of stroke has not been evaluated previously.

DESIGN AND SETTING: We identified studies through systematic literature search and the Thyroid Studies Collaboration, a collaboration of prospective cohort studies. Studies measuring baseline thyroid-stimulating hormone (TSH), free thyroxine (FT4) and stroke outcomes were included and we collected Individual Participant Data (IPD) from each study, including thyroid function measurements and incident all stroke (combined fatal and non-fatal) and fatal stroke. The applied reference range for TSH levels was between 0.45-4.49 mIU/L.

RESULTS: We collected IPD on 43,598 adults with TSH within the reference range from 17 cohorts, with median follow-up of 11.6 years (interquartile range 5.1-13.9), including 449,908 person-years. Age- and sex-adjusted pooled HR for TSH was 0.78 (95% Confidence Interval [CI], 0.65-0.95, across the reference range of TSH) for all stroke and 0.83 (95% CI, 0.62-1.09) for fatal stroke. For the FT4 analyses, the HR was 1.08 (95% CI, 0.99-1.15, per SD increase) for all stroke and 1.10 (95% CI, 1.04-1.19) for fatal stroke. This was independent of cardiovascular risk factors including systolic blood pressure, total cholesterol, smoking and prevalent diabetes.

CONCLUSION: Higher levels of TSH within the reference range may decrease risk of stroke, highlighting the need for further research focusing on the clinical consequences associated with differences within the reference range of thyroid function.