Fetal tissues are exposed to biologically relevant free thyroxine concentrations during early phases of development

Maternal hypothyroxinemia in early pregnancy is often associated with irreversible effects on neuropsychomotor development. To evaluate fetal tissue exposure to maternal thyroid hormones up to midgestation, we measured total T-4 and free T-4 (FT4), T-3, rT(3), TSH, and possible binding proteins in first trimester coelomic and amniotic fluids and in amniotic fluid and fetal serum up to 17 wk. Samples were obtained before interruption of maternal-fetal connections. The concentrations in fetal compartments of T-4 and T-3 are more than 100-fold lower than those in maternal serum, and their biological relevance for fetal development might be questioned. We found, however, that in all fetal fluids the concentrations of T-4 available to developing tissues, namely FT4, reach values that are at least one third of those biologically active in their euthyroid mothers. FT4 levels in fetal fluids are determined by both their T-4-binding protein composition and the T-4 or FT4 in maternal serum. The binding capacity is determined ontogenically, is independent of maternal thyroid status, and is far in excess of the T-4 in fetal fluids. Thus, the availability of FT4 for embryonic and fetal tissues would decrease in hypothyroxinemic women, even if they were euthyroid. A decrease in the availability of FT4, a major precursor of intracellular nuclear receptor-bound T-3, may result in adverse effects on the timely sequence of developmental events in the human fetus. These findings ought to influence our present approach to maternal hypothyroxinemia in early pregnancy regardless of whether TSH is increased or whether overt or subclinical hypothyroidism is detected.