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Department of Medicine Yale University School of Medicine New Haven, Connecticut 06520
Address all correspondence and requests for reprints to: Gerard N. Burrow, M.D., Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520-8055.
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Placental transfer depends on protein binding, lipid solubility, molecular weight, and placental metabolism. Agents with thyroid effects like iodides, thioamides, and thyroid-stimulating immunoglobulins traverse the placental barrier with ease in contrast to TSH and similar glycoproteins. In early studies, both T4 and T3 appeared to cross the placental barrier with difficulty. However, serum precipitable radioactivity was measured rather than 131I-T4 and 131I-T3, although similar findings of limited placental transfer were also reported in pregnant women infused at term with 500–800 mg T4 (6).
The thyroid hormone molecule can be modified to facilitate placental transfer. A nonhalogenated thyroid hormone analog, 3–5 dimethyl-3' isopropyl-l-thyronine (DIMIT), is more lipid soluble with lower molecular weight, decreased protein binding, and resistance to deiodinase (7). DIMIT prevented clinical and chemical hypothyroidism in a pregnant monkey whose thyroid gland and that of her fetus had been radioablated and prevented the major clinical manifestations of cretinism in the athyreotic fetus (8).
Both T3 and T4 have been found in human embryos before the onset of fetal thyroid hormone production (9, 10). In addition, T3 receptors exist in the brain at an early stage of fetal development. Strong evidence for significant but limited maternal transfer of thyroid hormone in the human came from the studies of Vulsma et al. (11). Pregnant women with complete organification defects gave birth to 25 neonates who also had the complete organification defect. Serum T4 concentrations at birth in affected neonates ranged from 35–70 µmol/liter compared with normal values of 80–176 µmol/liter, indicating that limited transfer of thyroid hormone from the treated mothers does occur.
In this issue, Piosik and co-workers (12) describe pregnancy outcomes in "Dutch goats" with congenital hypothyroidism due to an autosomal recessive defect in thyroglobulin synthesis. This model is of particular interest because both affected and unaffected fetuses could be studied in relation to affected and unaffected mothers. Unless supplemented with iodine, the affected mothers also became iodine deficient and severely hypothyroid because, due to the defect, proteins other than thyroglobulin are being iodinated and excreted. Affected fetuses are able to avert severe hypothyroidism if the maternal iodide supply of affected mothers is adequate. To maintain the pregnancy in affected goats, mothers were given supplementary iodine for 60 days after conception. Therefore, maternal thyroid status in this study can only be related to the second half of gestation. Whether the affected fetuses produce sufficient thyroid hormone or maternal thyroid hormone transfer is increased during the second half of gestation could not be determined in the present study as designed. Experiments with 131I-T4 in these mothers would have provided information about placental transfer. Measurements of iodine excretion during the second half of pregnancy would also have been helpful. The use of primates for studies of placental transfer makes them much more applicable to humans, but the strength of the current study is the genetic defect in thyroglobulin synthesis.
Decreased brain and cerebellum weight occurred in the affected fetuses of affected mothers. Maternal phenotype, presumably thyroid hormone status, was the determining factor. The degree of goitrous enlargement was similarly dependent on maternal phenotype. In rats, maternal T4 has a protective effect on the fetal brain in congenital hypothyroidism. In an iodine deficient mother, the low serum T4 results in more severe congenital hypothyroidism (13). Although placental transfer of thyroid hormone differs in rats, maternal hypothyroxinemia secondary to thyroidectomy resulted in reductions in fetal brain weight and fetal DNA (14).
Maternal status is clearly an important determinant in fetal development. Whether the availability of maternal thyroid hormone to the fetus or the maternal milieu is the major determinant is not clear. IGF-1 is important for growth and development and is modulated by thyroid status. In the present study, plasma IGF-1 levels did not differ significantly among the groups. The role of placental transfer is not well understood in regard to the transfer of thyroid hormone. Because placental transfer varies with species, human studies are important but extremely difficult. Finally, the importance of maternal thyroid status on fetal development has profound public health implications. Iodine deficiency is the world’s leading cause of preventable mental retardation, and further studies are needed to define the importance of the maternal contribution of thyroid hormone in early pregnancy (15).
Received October 23, 1996.
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