Maternal thyroid status and immune adaptation at the maternal-fetal interface: distinguishing direct from indirect pathways

Pregnancy depends on coordinated endocrine and immune adaptation to support fetal tolerance, antimicrobial defense, trophoblast invasion, and vascular remodeling. Maternal thyroid dysfunction is associated with adverse pregnancy outcomes, but serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) do not define T4/T3 exposure in placental or decidual cells. This Mini Review examines direct and indirect immune pathways, distinguishing maternal thyroid status from local thyroid hormone (TH) transport and metabolism, receptor-dependent signaling, and thyroid autoimmunity. Placental hormone handling has the strongest experimental support: MCT8/MCT10 and DIO2/DIO3 regulate local availability, although much of the transport evidence comes from term placentas. Human trophoblast and endometrial or decidual stromal studies suggest context-dependent effects on decidualization and trophoblast behavior. These responses could affect immune adaptation indirectly through changes in the immune, metabolic, and vascular niche. Evidence for direct TH effects on uterine natural killer (uNK) cells and decidual macrophages remains limited and gestational-age dependent. Direct evidence for decidual regulatory or effector T cells and dendritic cells is lacking, and many proposed mechanisms come from animal or nonpregnant settings. The available data do not support a single TH-driven immune phenotype or establish whether maternal thyroid status acts mainly through immune cells or surrounding tissues. Studies combining paired blood and interface tissue, longitudinal sampling, local T3/T4 measurements, pathway-specific perturbation, and human multicellular models are needed to test both routes and connect hormone supply and metabolism with immune and vascular function. Thyroid autoimmunity should be analyzed separately from local TH receptor signaling.