The onset of active fetal thyroid function (FTF) coincides with full maturation of the pituitary portal vessels at 16-20 weeks of gestation . Before the period of FTF, the neocortex of the fetal brain undergoes important phases of development which are largely dependent on the presence of thyroxine (T4) and triiodothyronine (T3) [1, 2]. Low concentrations of T4 and T3 are present in early embryonic and fetal tissue before the onset of FTF in concentrations that are directly influenced (especially the T4 levels) by those in the maternal circulation [3-14]. When maternal T4 and T3 concentrations are abnormally low in the first trimester, fetal brain development is adversely affected and there is a defect in the histogenesis and cerebral cortex cytoarchitecture, defective neuronal migration at the beginning of fetal neocorticogenesis, and a defective cortical expression of several genes in the fetal brain such as neuroendocrine-specific protein A [15, 16]. At the time of neural tube closure thyroid hormone receptor (TR) isoforms are already present in the fetal brain and these most likely mediate the biological effects of the T3 that has been locally generated from T4
transferred from the mother. Consequently, if the mother has T4 deficiency then the fetus will be T3-deficient even if maternal T3 is normal. This is because during early development serum-derived T3 essentially does not contribute to cerebral T3. Studies have shown that normal concentrations of T3 alone in the maternal or fetal circulation without normal T4 concentrations have no protective effect on the fetal brain because during fetal and postnatal development cerebral structures depend entirely on the local generation of T3 from T4 by type II 5'-iodothyronine deiodinase (D2), the activity of which is inversely related to the availability of T4 . This might explain why in most cases of congenital hypothyroidism in a newborn with a mother who has normal thyroid function there is no permanent severe central nervous system damage when T4 is administered in the first 3 months of neonatal life. In this case, the fetal brain has not been severely damaged before birth and normal development can still be achieved by prompt administration of T4 [18-22]. The most severe brain damage occurs when both the mother and fetus have low T4 levels during the entire gestational period as occurs in iodine-deficient environments. Iodine deficiency during pregnancy can result in a global loss of 10-15 intellectual quotient points at a population level in the offspring and it constitutes the world's greatest single cause of preventable brain damage and mental retardation [23-27].
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