For more than a century, severe thyroid hormone deficiency in new-borns, termed as congenital hypothyroidism, was known to cause irreversible damages to the brain and lead to intellectual disabilities in children.1 Yet, the critical role of thyroid hormones in brain development during early gestation remained less clear for a long time.[2], [3] Findings from animal models revealed that nuclear thyroid hormone receptors appear in the brain before mid-gestation, indicating a prominent role of thyroid hormones in the brain development, even before the function of the foetal thyroid gland fully begins.4
During prenatal development, the thyroid gland appears firstly as an epithelial proliferation in weeks 3–4 of gestation, and completes its formation at the end of the first trimester. Foetal secretion of thyroid hormones reaches clinically significant levels in the second trimester (around 16–20 weeks of gestation), and the full regulatory feedback system of hypothalamus, pituitary, and thyroid is achieved at birth.[4], [5], [6], [7] Before 12–14 weeks of gestation, that the foetal thyroid gland is not fully mature, maternal free thyroxine (T4) serves as the only source of thyroid hormones for the developing foetus.8 Given the low levels of triiodothyronine (T3) in foetal fluids, T3 is generated locally from maternal T4 in the foetal brain before mid-gestation.9 In line with this molecular evidence, clinical and epidemiological studies demonstrated that the children of pregnant women with untreated hypothyroidism in early pregnancy [low free T4 and high thyrotropin (TSH) levels] had poor neuropsychological outcomes.[10], [11]
Our knowledge on the mechanisms of action of thyroid hormones in the brain is derived mainly from experimental studies in animals. In early gestation, maternal thyroid hormones are necessary for neural proliferation and migration.6 From mid-gestation onwards both maternal and foetal thyroid hormones are crucial for neurogenesis, neuron migration, axonal growth, dendritic arborizations and synaptogenesis.[6], [9], [12] Further, the onset of myelination at later stages of gestation depends largely on thyroid hormones.6 The structural and functional abnormalities in response to thyroid hormone insufficiency occur in multiple brain regions including the neocortex, medial ganglionic eminence, the cerebellum, the hippocampus and myelinated white matter tracts such as the corpus callosum.[13], [14], [15] Thyroid deficiency at different stages of pregnancy affects different brain regions. For example, basal ganglia are affected by early thyroid hormone deficiency and cerebellar and hippocampal development is influenced by late thyroid dysfunction.[4], [6] Based on these animal studies, various neuropsychological abnormalities could occur in the child in response to thyroid hormone deficiency in pregnancy, such as impairment in general intelligence, language function, visuospatial and memory problems or neurodevelopmental disorders such as autism.[16], [17]
During normal pregnancy, the maternal hypothalamic-pituitary-thyroid system undergoes physiological changes to adapt to the high demand for both mother and child.18 An increase in the serum thyroxine binding globulin (TBG) causes a transient decrease in the free thyroid hormones and therefore a rise in serum TSH levels within the normal range. The increase in TSH levels provokes a rise of T4 levels in maternal serum. In parallel, in the first trimester of pregnancy, human chorionic gonadotropin (hCG) rises considerably, binds to the TSH receptors and stimulates the thyroid gland to produce T4. This adaption leads to an increase in the production of T4 in iodine sufficient women. Nonetheless, pregnant women with normal TSH levels may have low levels of free T4 specific for the stage of pregnancy, even in areas in which iodine intake is typically sufficient in the general population. This condition, i.e. maternal hypothyroxinaemia, has first been described by Man et al. in the 1970s[19], [20], [21] and has been defined as a normal maternal TSH concentration in conjunction with free T4 concentrations in the lower 5th or 10th percentile of the reference range for gestation.22 Although this condition was long thought as being without major consequences for mother and child, recent studies confirm the reports of Man and colleagues and show that maternal hypothyroxinaemia in early pregnancy may have adverse consequences for the child including psychomotor delay and attention deficit/hyperactivity disorders (ADHD).[23], [24] However, methodological problems such as small sample size, confounding, time of thyroid hormone assessment, lack of a consistent definition for maternal hypothyroxinaemia, lack of reference values for normal TSH in pregnancy, and short follow-up of the children of hypothyroxinaemic mothers remain concerns and temper the inferences possible.
Two main causes of thyroid hormone deficiency in women of reproductive age are known as iodine deficiency and thyroid autoimmune diseases.3 Iodine is a micronutrient essential for biosynthesis of thyroid hormones, and an adequate amount of this micronutrient in the diet is needed for the normal function of the thyroid gland and thyroid hormone secretion. In a recent report published by the World Health Organization (WHO) on iodine status of the population in industrialized countries, Europe is reported to have the highest prevalence of iodine deficiency, with specific concern regarding iodine insufficiency during pregnancy.25 Because of high requirement as well as high clearance during pregnancy, pregnant women are the most susceptible to iodine deficiency among all age groups.
In iodine sufficient areas, thyroid autoimmunity is the main known cause of thyroid hormone deficiency. Among thyroid autoantibodies, thyroid peroxidise antibodies (TPO-Abs) are the most sensitive and specific marker of thyroid autoimmunity.26 In pregnancy, the presence of TPO-Abs is commonly associated with subclinical hypothyroidism in the mother and can also lead to hypothyroxinaemia.22 However, even with normal thyroid function, thyroid autoimmunity can happen in 10% of pregnant women and is related to pregnancy complications and poor child outcomes.[27], [28]
Against this background, we aimed to examine the effect of early pregnancy thyroid hormone levels across the entire range on children's cognitive functioning and behavioural problem. Thyroid autoimmunity and iodine insufficiency, as the two main underlying factors of low thyroid function in pregnant women, were investigated in relation to maternal and neonatal thyroid function as well as children's cognitive and behavioural outcomes. For this aim, we used the data on maternal and neonatal thyroid function and the children's cognition and behaviour from an ongoing population-based birth cohort in Rotterdam, the Netherlands: the Generation R Study.