3,3=-diiodothyronine sulfate (T 2 S) derived from T 3 of fetal origin is transferred to the maternal circulation and contributes significantly to the maternal urinary pool. The present study quantitatively assesses the fetal to maternal transfer of T 4 metabolites compared with those of T 3 . Labeled T 4 or T 3 was infused intravenously to four singleton fetuses in utero in each group at gestational age 138 Ϯ 3 d. Maternal and fetal serum and maternal urine samples were collected hourly for 4 h and at 24 h (serum) or in pooled 4 -24 h samples (urine). Radioactive metabolites were identified by HPLC and by specific antibody in serum and urine extracts and expressed as percentage infusion dose per liter. The results demonstrate a rapid clearance of labeled T 3 from fetal serum (disappearance T 1/2 of 0.7 h versus 2.4 h for T 4 in the first 4 h). The metabolites found in fetal serum after labeled T 3 infusion were T 2 S Ͼ T 3 Ͼ T 3 S; in maternal urine, T 2 S Ͼ unconjugated iodothyronines (UI) Ͼ T 3 S Ͼ unknown metabolite (UM). After labeled T 4 infusion, the metabolites in fetal serum were rT 3 Ͼ T 3 Ͼ T 2 S Ͼ T 4 S in the first 4 h, and rT 3 ϭ T 3 ϭ T 4 S ϭ T 2 S Ͼ T 3 S at 24 h; in maternal urine we found T 2 S Ͼ UM Ͼ UI Ͼ T 4 S Ͼ T 3 S in the first 4 h and UM Ͼ T 2 S Ͼ UI in 4 -24 h pooled sample. In conclusion, the conversion of T 3 to T 2 S followed by fetal to maternal transfer of T 2 S and other iodothyronines appears to contribute importantly to maintaining low fetal T 3 levels in late gestation. (Pediatr Res 59: 102-106, 2006) K inetic studies in fetal sheep in late gestation (Ͼ135 d of gestational age; term, 150 d) showed that mean fetal T 4 CR and PR are significantly higher than the corresponding values in adult sheep (1). The ratio of mean PR of rT 3 to T 4 is similar in fetal and adult sheep, whereas the PR ratio of T 3 to T 4 in fetal sheep is much lower than that in adult sheep. These data in the ovine fetus indicate that the prevailing low serum T 3 concentration is due both to increased CR and decreased PR, whereas the elevated serum rT 3 levels are due to decreased CR and increased PR. We and others showed that sulfated iodothyronines, including T 4 S, T 3 S, rT 3 S, and 3,3=-T 2 S are major T 4 metabolites in ovine fetuses (2,3). The PR of T 4 S, T 3 S, rT 3 S, and rT 3 significantly exceed the PR of T 3 .Thus, peripheral thyroid hormone metabolism in the ovine fetus, in contrast to the adult, is shunted to inactivation rather than production of active hormone.In a recent study, we showed that a significant amount of 3,3=-diiodothyronine (T 2 ), the inner-ring deiodinated metabolite of fetal T 3 , is found in maternal urine as sulfated T 2 when 125 I-T 3 is infused in venously catheterized fetuses (4,5). In contrast, when a supraphysiological dose of T 3 , about 200-fold the fetal T 3 PR, was infused into fetuses, both T 2 S and T 3 S were found in maternal urine (6). To exclude the possibility that the observed fetal-to-maternal transfer of metabolites could be a pharmacological dose...