Thyroid hormones and cognitive function

Keywords::

• cognitive function
• iodine
• neurodevelopment
• pregnancy
• thyroid
• thyroid hormone

Iodine is essential for the synthesis of thyroxine (T4), which is critical for the maturation of the fetal brain and nervous system. Maternal circulating T4 deficiency (as in severe iodine deficiency) results in the disruption of nervous system development, which may lead to cretinism. In an iodine-sufficient area, maternal gestational thyroid dysfunction results in neurointellectual impairment of the child; specific effects will depend on when maternal hormone deficiency occurs during the pregnancy. In addition to clinical trials, fundamental research into the factors influencing brain development is required. Screening for thyroid function in pregnancy for obstetric reasons and possible prevention of adverse developmental effects is attracting wide interest.

More than a century ago, severe iodine deficiency was noted to result in cretinism (profound mental retardation, deaf mutism and motor rigidity), implying an IQ of 40 or less [1]. We now know that iodine is essential for T4 synthesis, which is critical for the maturation of the fetal brain and nervous system [2]. The demonstration that maternal T4 crosses the placenta implies that any reduction in fetal T4 supply may have significant effects on fetal neurodevelopment; however, the details of this process are still not fully understood. Thyroid hormone nuclear receptors are found in the fetal brain from the eighth or ninth week of gestation. The fetal brain is responsive to triiodothyronine (T3) generated by type II 5′-iodothyronine deiodinase from maternal T4. T3 contributes to neuronal development and the initiation of neuronal migration in the cerebral cortex and other subcortical structures. This process, together with neurogenesis, axonal growth, dendritic branching, glial differentiation and migration, and the onset of myelination occurring later in gestation, contributes to the process whereby thyroid hormone influences brain maturation. It is not surprising that in the situation of a significant lack of maternal circulating T4 (as in severe iodine deficiency), nervous system development is so disrupted as to lead to cretinism.

Although iodine deficiency is still present in many parts of the world including Europe, it is usually mild to moderate in severity. Nevertheless, this has significant adverse effects on brain development, and this was shown by a reduction in psychointellectual development in 3-year-old Spanish children born to mothers whose urinary iodine concentrations were less than 100 µg/l at 12 weeks of gestation [3]. Of importance is a nonrandomized observation that children whose mothers had received an iodine supplement of 300 µg per day during the first trimester of pregnancy had higher scores on the Psychomotor Developmental Index and Behaviour Rating Scale than children whose mothers had received no iodine supplements [4]. The children receiving iodine were studied at 5.5 months, whereas the control group was studied at 12.4 months; these results were, therefore, regarded as preliminary. As the maternal T4 concentration is an important factor related to delayed neurobehavioral development, Berbel et al. evaluated the effect of iodine supplementation on neurocognitive performance in 18-month-old children of mothers who were hypothyroxinemic in gestation with or without iodine supplements [5]. The study showed that a delay of 6–10 weeks in iodine supplementation of hypothyroxinemic mothers in early gestation increased the risk of neurodevelopmental delay in the progeny. Previous studies of iodine supplementation in pregnancy between 1991 and 2002 had not evaluated child neurocognitive function but had demonstrated an amelioration of features of iodine deficiency in the mothers.

Even in an iodine-sufficient area, maternal thyroid dysfunction (hypothyroidism, subclinical hypothyroidism or hypothyroxinemia) during pregnancy results in neurointellectual impairment of the child; therefore, maternal thyroid hormones are required through gestation for proper brain development and specific effects will depend on when maternal hormone deficiency occurs during pregnancy [6]. Man et al. first reported impaired childhood cognitive function in children born to mothers with low thyroid function in pregnancy and also noted the prevention of this impairment in a small study by maternal treatment with levothyroxine [7]. Low maternal thyroid hormone concentrations in early gestation can be associated with significant decrements of IQ in young children (reviewed in [8]), and a significant decrement in IQ is also observed in children born to euthyroid mothers with circulating anti-thyroid peroxidase antibodies [8]. Haddow et al. found in a retrospective study that the full IQ scores of children whose mothers had high levels of thyroid-stimulating hormone (TSH) during gestation were 7 points lower than those of controls (p < 0.005), and that 19% of them had scores of less than 85 compared with 5% of controls (p < 0.007) [9]. Reduction in IQ has been reported in the children of mothers with serum free T4 in the lowest tenth decile in the first trimester [8]. A Chinese study has confirmed that children aged between 25 and 30 months whose mothers were noted to have increased maternal TSH, decreased serum T4 and even elevated thyroid peroxidase antibodies had lower intelligence scores and lower motor scores than those children born to euthyroid mothers [10]. A prospective study in the same country showed that maternal subclinical hypothyroidism diagnosed up to 20 weeks of gestation resulted in neurodevelopmental delay in the infants [11]. The Generation R Study, a population-based cohort study [12], showed that there was no relationship between cognitive outcome and maternal TSH, but a significantly higher risk of expressive language delay in children of mothers with mild and severe hypothyroxinemia was observed. A further study by the same group indicated that thyroid function is crucial for fetal brain development, which determines problematic behavior later in life [13]. However, recent data have not confirmed decrements in cognitive function in relation to thyroid dysfunction in gestation. For example, in a historical cohort study in Iran, the IQ level and cognitive performance of children born to L-T4-treated hypothyroid mothers were similar to those whose mothers had untreated subclinical hypothyroidism in pregnancy and to those whose mothers had normal thyroid function [14]. In an observational, nested, case–control study, isolated hypothyroxinemia in the second trimester was not associated with impaired infant development assessed at the age of 2 years [15]. It has also been recently reported that IQ and development quotient scores indicated no apparent neurodevelopmental deficit in children whose mothers had overt hypothyroidism during the first trimester of pregnancy and normal serum T4 levels were restored by the later stages pregnancy [16]. On the other hand, evaluation of preterm infants has shown that exposure to hypothyroxinemia may be important for neurodevelopment with a decrease in neurodevelopment being found up to 5.5 years of age [17].

The evidence presented does point to a significant effect of gestational maternal thyroid dysfunction (high TSH only, hypothyroxinemia or overt hypothyroidism) on neonatal and child neurodevelopment. However, the strength of the evidence is variable due to factors such as the type of study, the numbers of subjects studied, the age at which psychological evaluation was performed and the specific tests used, as well as other unknown factors.

There are few prospective studies. A report from Moscow in a small number of subjects found that early (not later than 9 weeks of gestation) administration of 1.2 µg/kg thyroxine to women with gestational hypothyroxinemia improved neurointellectual performance of the children during the first year [18]. The Controlled Antenatal Thyroid Screening Study was an adequately powered, prospective, randomized, double-blind study in which a large number of children (390 in the screen group and 404 in the control group) were evaluated at 3 years of age [19]. Mothers of the screen group children had received 150 µg T4 from before 14 weeks of gestation, while mothers of the control group children had not received T4 therapy. The antenatal screening for thyroid function at a median of 12 weeks and 3 days and maternal treatment for hypothyroidism did not result in improved cognitive function in the children at 3 years. The discrepancy between this finding and those of previous studies may be due to the lateness of screening, the modest median TSH in the screen group and the fact that more specific cognitive impairments (such as expressive language delay, vision abnormalities and behavioral changes) were not specifically tested.

Despite the negative results from the Controlled Antenatal Thyroid Screening Study, the momentum directed at prenatal or early gestational thyroid function screening with thyroid hormone intervention continues to increase. The cost–effectiveness of no screening versus routine screening for subclinical hypothyroidism in pregnancy has demonstrated a saving of approximately US$8.3 million per 100,000 women screened. A recent report also demonstrated screening to be cost effective in various clinical scenarios, including that of untreated maternal hypothyroidism resulting in decreased child intelligence, with levothyroxine therapy being preventive in this respect [20].

Observational evidence from animal and human studies that thyroid hormone has an important influence on cognitive function, not only in childhood but also in preterm infants and the elderly, is abundant. Although the recent, randomized, prospective study has failed to show the benefit of maternal thyroxine treatment on cognitive function, more trials are required to confirm these findings, perhaps employing more specific psychological tests. In addition to clinical trials, fundamental research into the factors influencing brain development is required. Meanwhile, pragmatic screening for thyroid function in pregnancy for obstetric reasons and for the possible prevention of adverse developmental effects is attracting wide interest.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.