Asymmetric U-shaped association between first-trimester maternal free thyroxine levels and the risk of preeclampsia: a large-scale cohort study

OBJECTIVE: This study aimed to define the nonlinear relationship between maternal free thyroxine (FT4) levels in early pregnancy and the risk of preeclampsia. METHODS: This study used a large-scale retrospective cohort of 46 592 women with singleton pregnancies. Thyroid function parameters and preeclampsia outcomes were collected. A restricted cubic spline model analyzed the nonlinear relationship between FT4 levels and preeclampsia risk. Odds ratios were calculated using multivariable logistic regression, adjusting for confounders. Preeclampsia risk was also assessed based on thyroid disease classifications. Sensitivity analyses validated the robustness of the results. RESULTS: The study found a U-shaped relationship between FT4 levels in early pregnancy and preeclampsia risk. The risk was lowest at 15 pmol/l, with a significant increase as FT4 deviated from this value, especially at lower FT4 levels. A physiological optimal range of 13.9-17.3 pmol/l was identified. Compared to women in this range, low FT4 levels (< 11.7 pmol/l) had a significantly higher risk of preeclampsia (adjusted odds ratio, aOR = 2.23). Even women with FT4 at the lower end of the normal range (11.7-13.9 pmol/l) had increased risk (aOR = 1.26), indicating a latent high-risk group. In traditional thyroid classification, only hypothyroxinemia was a significant independent risk factor. Sensitivity analyses confirmed result stability. CONCLUSION: This study reveals that low FT4 level is an independent risk factor for preeclampsia, with a dose-dependent effect. These findings support targeted prevention strategies and provide a new approach for precise preeclampsia prevention.