Neurodevelopment normal

FIGURE 4—6. Neurons are formed in excess prenatally (top panel of neurons). Some are healthy and others may be defective. Normal neurodevelopment chooses the good neurons (left), but in a developmental disorders, some defective neurons may be chosen and thus cause a neurological or psychiatric disorder later in life when that neuron is called on to perform its duties (right panel). 

Neuronal cultures derived from human stem cells can possibly serve as renewable source of normal (non-transformed) cells with the capacity to differentiate into any cell type present in the nervous system. The major advantage of human cell types-based in vitro models is that the results do not require extrapolation from animal data to the human situation. The detailed characterization of human stem/progenitor cell-based assays for neurodevelop-mental toxicity testing is described in Chap. 16 of this book by E. Eritsche. 

The epidemiological and experimental findings of the last few decades have demonstrated the critical need for adequate fetal thyroid hormone concentrations from the earhest stages of pregnancy, in order to achieve normal neurodevelopment. 

Maternal hypothyroxinemia is not detected in most pregnant women early in pregnancy, since it does not necessarily result in cfinical or subcfinical hypothyroidism. The mother herself may synthesize and secrete enough T4 and T3 to meet her own needs, but the amount of T4 reaching the fetus might not be sufficient for normal neurodevelopment. 

Neurodevelopment delay has been attributed to long-term amiodarone exposure in a child with fetal junctional reciprocating tachycardia and normal thyroid function [39" ]. A refractory persistent tachycardia was treated in utero with digoxin 0.5 mg/day until delivery and amiodarone 100 mg/day from 26 to 35 weeks of gestation. The baby was delivered at 38 weeks, weighed 3550 g, and had normal acid-base balance. 

Clinical concern Transient hypothyroxinemia of prematurity (THOP) occiu s in 50% of extremely low gestational age neonates (ELGANs 24-28 weeks) and is a major factor of neurodevelopment abnormalities (cognitive delay, cerebral palsy, hearing loss, mental retardation, blindness or epilepsy) [9 ]. THOP characterised by very low total and free T4 levels and normal TSH may be safely treated with continuous infusion of 4 gg/kg/day levothyroxine for 42 days to produce a biochemical euthyroid state (phase I/II trials) [1(P]. There is a pressing need for a phase III trial of thyroid hormone that is of sufficient duration and size to determine whether a clinically important reduction in risk of developmental impairments in ELGANs can be achieved [11 ]. 

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