Child Development

Thyroid hormones are major factors for the normal development of the brain. The mechanisms of actions of thyroid hormones in the developing brain are mainly mediated through two ligand-activated thyroid hormone receptor isoforms [50]. It is known that thyroid hormone deficiency may cause severe neurological disorders resulting from the deficit of neuronal cell differentiation and migration, axonal and dendritic outgrowth, myelin formation and synapto-genesis [23]. This is the situation well documented in iodine-deficient areas where the maternal circulating thyroxine concentrations are too low to provide adequate fetal levels particularly in the first trimester. Recent work has raised concern that in an iodine-sufficient area maternal thyroid dysfunction (hypothyroidism, subclinical hypothyroidism or hypothyroxinaemia) during pregnancy results in neuro-intellectual impairment of the child. Two studies, have shown that a low thyroid hormone concentration in early gestation can be associated with significant decrements of IQ of the children when tested at

7 years and 10 months, respectively [51, 52]. Pop et al. [53] have also shown a significant decrement in IQ in children aged 5 years whose mothers were known to have circulating anti-TPO antibodies at 32 weeks gestation and were biochemically euthyroid. Haddow et al. [51] found that the full IQ scores of children whose mothers had a high TSH during gestation were 7 points lower than controls (p < 0.005) and that 19% of them had scores of less than 85 compared to 5% of controls (p < 0.007). More recently, the Dutch group [54] have again confirmed that maternal hypothyroxinaemia during early gestation is an independent determinant of neurodevelopmental delay. Further, they have suggested that when FT4 concentrations increase during gestation in women who have had low FT4 in early pregnancy infant development is not adversely affected [54]. The neurodevelopmental impairment is similar to that seen in iodine-deficient areas and implies that iodine status should be normalised in regions of deficiency. However, much of the USA and parts of Europe are not iodine-deficient which raises the question of routine screening of thyroid function during early pregnancy or even at preconception. Another reason for screening could be to focus on the risk for postpartum thyroiditis [55]. The following numerical issues should be considered in relation to such a strategy: the incidence of an elevated TSH in pregnancy is around 2.5%; the prevalence of anti-TPO antibodies is 10% as ascertained at a routine antenatal booking clinic; the incidence of thyroid dysfunction observed in anti-TPO-positive pregnancies is up to 15%. While these numbers are impressive the question as to whether there is any effective intervention must be addressed. Although one study has reported an improved psychological outcome in children from thyroxine-treated mothers (compared to those children from inadequately treated mothers) there are no results of any formal prospective randomised trials examining, for example the effect of T4 intervention therapy given to susceptible women on subsequent child development. These considerations emphasize that it is important to ensure an adequate thyroid hormone supply to the developing fetus in all areas of the world whether iodine-deficient or not [56]. Further studies in this area are required to answer questions relating to thyroid function screening before and during pregnancy.

Nodular Thyroid Disease

Thyroid nodules are claimed to be detected in up to 10% of pregnant women. Fine needle aspiration biopsy is the first investigation of choice which may yield a malignancy/suspicious result in 35% [57]. When malignancy is diagnosed it is usually a differentiated tumour which may be surgically resected in the second trimester or in some cases safely left until the postpartum period before therapy is started. The impact of pregnancy on thyroid cancer seems to be minimal in that there is no difference in rates of metastases or recurrence compared to non-pregnant women with the same disease [58]. Whether women already treated for thyroid malignancy should become pregnant is of concern but current evidence suggests that differentiated thyroid cancer should not inhibit an intended pregnancy. Previous 131I therapy does not result in demonstrable adverse events in subsequent pregnancies although miscarriage appears to be more frequent during the year preceding conception [59].

Neonatal Thyrotoxicosis

About 1-5% of children born to mothers with Graves' disease will develop neonatal thyrotoxicosis due to transplacental passage of maternal thy-rotrophin receptor stimulating IgG antibodies [60]. It has been established that the presence of TsAb at 36 weeks gestation in women with Graves' disease has a significant positive predictive value for the probability of neonatal hyperthy-roidism. Fetal hyperthyroidism is associated with intrauterine growth retardation, craniosynostosis and fetal death. In neonates cardiac failure, arrhythmias, hepatosplenomegaly and jaundice may be seen. In addition they may have vomiting, poor weight gain and be hyperkinetic. Treatment includes the administration of iodine, PTU, dexamethasone and adequate sedation. Reassurance may be given to the parents that the disease will remit permanently in 8-20 weeks due to the known half-life of IgG and remission by 10 months is nearly always achieved [61]. A subset of infants with neonatal hyperthyroidism appear to produce their own thyroid-stimulating immunoglobulins and therefore will not respond as readily to antithyroid drug therapy and require ablative treatment.

In the absence of maternal thyroid immune disorder, non autoimmune hyperthyroidism due to an activating thyrotropin receptor germ line gene mutation must be considered as a cause for neonatal hyperthyroidism. The condition may be sporadic or be inherited in an autosomal, dominant pattern and is characterised clinically by a variable severity of hyperthyroidism and goitre, absence of thyroid associated ophthalmopathy and dermopathy and negative thyroid antibodies [61]. Other clinical features including craniosynostosis, advanced bone age, low head circumference and psychomotor retardation have been described. A recent analysis of all reported cases of non autoimmune hyperthyroidism [62] drew attention to the observation that the mean gestation duration was significantly less than that seen in children with congenital hypothyroidism due to inactivating mutations of the TSH receptor (35.8 vs. 39.4 weeks, p = 0.003). The role of excess thyroid hormone in premature delivery is not yet established but is clearly relevant and requires further investigation. It is critical to determine if there is an activating TSH receptor mutation as the treatment in this case must be thyroid ablation to achieve long-term remission.

Neonatal hyperthyroidism has occurred due to the McCune-Albright syndrome [60], a condition characterised by a somatic activating mutation in the gene GNAS1 that encodes the a-subunit of GTP-binding protein that stimulates adenylate cyclase. In the murine D3 knock out mouse referred to previously [23], observation has shown that the lack of D3 function resulted in a probable overexposure of T3 during a critical period of thyroid axis development followed later by central hypothyroidism.

In conclusion a considerable increase in our appreciation of the physiology, immunology and clinical aspects of thyroid function in relation to gestation has occurred during the past decade. Important research into thyroidal influence on fetal development as well as delivery of thyroid hormones to the fetus will drive future clinical studies to improve recognition and management of thyroid disease before, during and after pregnancy.

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