Optimizing Thyroid Management in Pregnancy Beyond TSH: Free Hormones, Placental Deiodinases, and Iodine Kinetics—A Systematic Review with Narrative Synthesis

Maternal thyroid assessment during pregnancy continues to rely predominantly on serum thyrotropin (TSH), despite well-recognized physiological adaptations that alter its interpretive value. Rising thyroxine-binding globulin concentrations, gestational changes in iodine requirements, and placental regulation of thyroid hormone metabolism collectively weaken the link between maternal TSH and fetal thyroid exposure. To address this disconnect, we conducted a systematic review with narrative synthesis of human studies examining maternal free thyroxine (FT4) and triiodothyronine (FT3), placental deiodinase activity or thyroid hormone transport, and iodine status in relation to maternal, neonatal, or early developmental outcomes. A comprehensive search of MEDLINE, Embase, Web of Science, Scopus, CENTRAL, CINAHL, ClinicalTrials.gov, WHO-ICTRP, and grey literature was performed from inception through October 2025 without language restrictions. Two reviewers independently screened records, assessed eligibility, extracted data, and evaluated risk of bias using design-appropriate tools for observational, mechanistic, and physiological studies. Given marked heterogeneity in populations, exposure definitions, and outcome measures, quantitative pooling was not undertaken. From 1243 identified records, 35 primary studies met inclusion criteria. Across cohorts, lower maternal FT4 trajectories—particularly in the context of mild to moderate iodine deficiency—were associated with gestational diabetes, impaired fetal growth, and markers of adverse neurodevelopment. Placental studies consistently demonstrated high expression and activity of type 3 iodothyronine deiodinase, reinforcing the placenta’s role as an active regulator that can limit fetal thyroid hormone availability even when maternal TSH is normal. Iodine kinetics studies further highlighted divergence between maternal biomarkers and fetal thyroid exposure. Collectively, the evidence supports a shift toward pregnancy-specific thyroid management that integrates calibrated free hormone assessment, placental biology, and iodine sufficiency, rather than reliance on TSH alone.