Maternal hypothyroidism

Morreale de Escobar G, Obrcgon MJ, Escobar del Rey F. 2000. Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia J Clin Endocrinol Metab 85(11) 3975-3987. 

A deficiency of thyroid hormone during fetal development due to untreated or undertreated maternal hypothyroidism results in a neurological deficit in the offspring. In congenital hypothyroidism, a normal maternal thyroid can meet the fetal requirements for thyroid hormone. However, in the postnatal period these infants require a prompt thyroid hormone replacement therapy throughout their life, beginning in the first few weeks of life. If untreated, they inevitably develop growth and mental retardation. Thyroid hormone is essential for maturational development of the CNS and is required for the development of axonal projections and myelination. One of the important effects of thyroid hormone is to promote the synthesis of myelin basic protein. 

A. Brain damage caused by maternal/fetal/neonatal iodine deficiency A. Brain damage caused by maternal hypothyroidism ... 

Earher data indicating the effect of maternal hypothyroidism from other causes on childrens subsequent cognitive performance provide further support for this concept (Man et al., 1971). 

DeLong (1987), as a result of careful clinical neurological studies in a number of endemic diseases, has concluded that the major defaults are intellectual deficiency, deafness and motor rigidity, which indicate that the most affected parts of the CNS are the cerebral neocortex, the cochlea and the basal ganglia. They all undergo rapid changes in the second trimester, and would be vulnerable to the effects of iodine deficiency through maternal hypothyroidism at that time. 

In 1971, maternal hypothyroidism seemed an unlikely cause, as no such syndrome as cretinism had been noted in children born to hypothyroid mothers infants suffering from congenital hypothyroidism do not show the features of deaf mutism or neuromuscular defect as seen in the common form of cretinism. This made elemental iodine deficiency an attractive hypothesis (Pharoah et aL, 1971). 

There has been no support for the role of elemental iodine deficiency from the animal models. The effect of iodine deficiency in early gestation now appears to be due to maternal hypothyroidism, with reduced T4 transfer across the placental barrier. However, an additional direct effect of iodine itself cannot be excluded from the existing data. 

The above-mentioned facts form the basis of a new concept of the adverse effects of not only maternal hypothyroidism, but also maternal hypothyroxinemia without overt hypothyroidism, on fetal brain development. This concept focuses on the necessity for therapeutic correction of maternal hypothyroxinemia detected in pregnancy. MRS, a quantitative laboratory and imaging technique, may be used to show the effects of hypothyroxinemia due to iodine deficiency and its correction in the human brain in an objective manner. 

The relationship between maternal hypothyroidism and neurological damage in the offspring has already been established by several epidemiological studies in areas with severe ID (Delange, 1994) or normal dietary iodine intake (Haddow et al., 1999) and in animal models (Friedhoff et al., 2000 Dowling et al., 2000). Conversely, maternal... 

Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia drew attention to the relationship between low maternal free-thyroxine concentrations and impaired neuropsychological development in children (Morreale de Escobar et al., 2004). This hypothesis has since been supported by further clinical and basic data, reinforcing the idea that screening programs should be implemented systematically in order to correct any maternal thyroid underfunction promptly and ultimately prevent fetal brain damage. 

Fetal TH must come from the maternal circulation before the fetal thyroid gland and pituitary—thyroid axis become functional (gestation day (GD) 17—18 in rats and 90 in humans). Maternal transfer of thyroxine (T4) constitutes a major fraction of fetal TH even after the onset of fetal thyroid secretion, they may contribute to the maintenance of fetal development (Burrow et ai, 1994). Therefore, changes in maternal TH levels have an affirmative effect on fetal TH metabolism. Depending on the dose of iodine, the susceptibility of individuals, and previous conditions of the gland, iodine excess can induce maternal hypothyroidism or hyperthyroidism. In a case reported by Serreaul et al. (2004), an obvious thyroid goiter was found in the fetus after excessive maternal iodine... 

There are three types of TH deficiency known to impact fetal development, including (Figure 108.1) isolated fetal hypothyroidism (congenital hypothyroidism CH), combined maternal and fetal hypothyroidism (endemic cretinism EC), and isolated maternal hypothyroidism (primary maternal hypothyroidism). According to the review of CH (American Academy of Pediatrics, 2006), TH deficiency originates from birth and is mainly due to the failure of... 

Zoeller and Rovet (2004) summarized the models of maternal hypothyroidism, hypothyroxinemia and CH. If TH deficiency occurs early in pregnancy, the children... 

Bernal (2005) reviewed the morphological aspects in the brain of the hypothyroid rat and found (1) altered cell migration, particularly in the cerebellum and cerebral cortex (2) increments in cell density, caused by a reduction in the neuropil (3) markedly reduced dendritic arborization in the Purkinje cells of the cerebellum, and decreased and altered distribution of the pyramidal dendritic spines in the cortex layer V and finally (4) delayed myelination and poor myelin deposit in the white matter and fewer myelinated axons. This study further showed that hypothyroidism produces changes in the colossally projecting neurons, which may be due to the maintenance of juvenile patterns of projections. In addition, a recent report (Lavado-Autric et al., 2003) indicates that focusing on maternal hypothyroidism can produce migration defects in the fetal cortex, when... 

Figure 113.1 Etiology of maternal hypothyroidism and its repercussion on the fetus. Iodine defioienoy and autoimmune thyroiditis are the main causes of maternal hypothyroidism. The iodine deficiency can affect both mother and fetus. TSBAb, TSH receptor inhibiting antibodies 131 radioiodine.

Maternal hypothyroidism is known to have serious adverse effects on the pregnancy outcome, both maternal as well as fetal. Therefore, maternal hypothyroidism should be avoided. 

Thyroid hormones, T3 and T4, have been i cwn to play significant but poorly understood roles in development and differentiation of rodent and human brain (1-7). In the human, disorders of maternal and fetal thyroid function include maternal and secondary fetal iodine deficiency, maternal hypothyroidism or hyperthyroidism, as well eis disorders related to deficient fetal autcxiomous thyroid hormcaie secretion, i.e., goiter or i radic oongenitel hypothyroidism. These disorders are identifiable causes of mental retardation (4, 8, 9, 10), cer ral peilsy (11, 12), and other significant neurological abnormalities (5, 6, 11) ... 

In the light of the available data and observations on the sheep, it may be concluded that the effects of severe iodine deficiency are mediated by a combination of maternal and fetal hypothyroidism, the effect of maternal hypothyroidism being earlier than the onset of fetal thyroid secretion. This would infer an effect on neuroblast multiplication which... 

Rey, F. Effects of maternal hypothyroidism on weight and thyroid hormone content of rat embryonic tissues,before and after onset of fetal thyroid function. Endocrinology 117 1890-1900 (1985). 

Therefore, maternal hypothyroidism could result in decreased availability of thyroid hormone during the initial phases of development. It is known that maternal hypothyroxinemia results in lowered I.Q. of the progeny, even in areas without iodine deficiency s. ... 

The LID fetuses developed goiter, and their thyroidal total iodine was 4.7 % of that of LID + I fetuses. The concentrations of T4 and T3 in different embryonic and fetal samples are shown in Figs. 8 and 9, where they are compared to data from age-paired samples obtained from C and T dams. Before onset of fetal thyroid function (11-day-old embryotrophoblasts and 17-day old fetuses) T4 concentrations are decreased by LID to a degree comparable to that of concepta taken from T mothers. T3 concentrations did not differ initially from those of the LID + I group. By 17 gd, however, T3 concentrations were lower both in the fetus, and placenta (not shown). Once fetal thyroid function starts, important differences become apparent between fetuses from T and LID dams. The activated secretion of T4 and T3 by the thyroid in fetuses from T mothers is able to compensate for previous differences related to maternal hypothyroidism, at least as far as the brain is concerned. But this is not possible for fetuses faced with a very low iodine supply, and cerebral T3 is quite low. Similar results were later obtained in another experimental series ... 

Bonet B, Herrera E 1987 Different responses to maternal hypothyroidism during the first and second half of gestation in the rat. Endocrinology 122 450 (1988)... 

In the human, the concentration of reverse T3 (rT3), an iodothyronine generated from 5-deiodination of T4, in amniotic fluid (AF) far exceeds its concentration in maternal serum. Rat models of fetal hypothyroidism, maternal hypothyroidism and combined maternal-fetal hypothyroidism were enoployed to explore the source (s) of AF rT3 since it had earlier been suggested that AF rT3 concentration mi t be used as a means of diagnosing fetal hypothyroidism in utero. These studies indicated that AF rT3 content was influenced by maternal and not fetal thyroid function (Table 1) and that rT3 itself was poorly trani rted from maternal serum into the amniotic cavity. Fetal serum rT3 concentration is dependent ipon both maternal and fetal thyroid function. Suzuki et al., have also r rted that changes in rat AF rT3 concentration are mainly dependent ipon maternal thyroid function. These findings suggested to us that tissues in contact with both maternal serum and fetal serum, or maternal tissues and the... 

Table 1. Amniotic fluid (AF) reverse T3 (rT3) in rat models of maternal-fetal hypothyroidism (MFH), maternal hypothyroidism (MH) and fetal hypothyroidism (FH)...

Bonet and Herrera and Esa ar et al have recently reported that thyroid hormones cross the placenta from dam to fetus and that maternal hypothyroidism does affect fetal growth and development and brain T3 cc itent. Further studies in the rat and other species, inclxiding man, will further clarify this question. 

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