Understanding Prenatal Iodine Deficiency

Iodine is a micronutrient essential for the synthesis of thyroid hormones1. The thyroid gland takes iodine from the diet, stores it and subsequently incorporates it into other molecules, to produce two types of thyroid hormones as a final product: triiodothyronine (T3) and thyroxine (T4) containing three and four iodine atoms respectively. Both circulate in blood bound to proteins and act on specific receptors. The free T3 is metabolically more active, but the T4 is, as we shall see, indispensable at specific developmental stages.


Introduction
Iodine deficiency is a worldwide Public Health problem, mainly in pregnant women and infants, which causes permanent and irreversible sequels in the Central Nervous System (CNS) of the progeny when daily iodine intake does not reach optimal levels. Pharmacological iodine supplements have been recommended during pregnancy and lactation periods in regions with low iodine intake diet.
In recent years, maternal hypothyroxinemia has been recognized as the biochemical condition responsible for the alterations in the processes of neural development in the embryo and fetus associated to iodine deficiency.
Research Methods: The objective of this study was to review the available scientific evidence on the crucial role of iodine in early stages of neural development, to understand the international scheduling recommendations about an adequate iodine intake in vulnerable populations groups.
Iodine is a micronutrient essential for the synthesis of thyroid hormones 1 . The thyroid gland takes iodine from the diet, stores it and subsequently incorporates it into other molecules, to produce two types of thyroid hormones as a final product: triiodothyronine (T3) and thyroxine (T4) containing three and four iodine atoms respectively. Both circulate in blood bound to proteins and act on specific receptors. The free T3 is metabolically more active, but the T4 is, as we shall see, indispensable at specific developmental stages.
The thyroid hormones are involved in many metabolic and developmental processes, and they exert a broad range of actions on every tissue of the body: body temperature regulation, somatic growth. Further, it is essential for the proper development and function of the Central Nervous System. 2 Since the first epidemiological studies conducted by Pharoah 3 and Thilly 4 in the 70's, the association between iodine deficiency in pregnant women and fetal neurological damage has been extensively reviewed and proven in scientific literature. In fact, the need to provide iodine supplementation to pregnant women in iodine-deficient regions is considered as proven by scientific evidence. 5 Many of these studies are focused on regions where severe iodine deficiency is endemic and coexisting with mixedematous cretinism. 6 The understanding of the neurological effects of hypothyroidism on infants was partially obtained from mothers with clinically overt hypothyroidism. 7.8 All these factors have contributed to a general awareness that iodine deficiency is a problem restricted to specific geographic areas and to well-defined at-risk populations (hypothyroidism, goiter and malnutrition) 9 For a long time, there has been a prevailing belief that the main factor responsible for alterations in fetal neurological development was maternal hypothyroidism (defined as elevated serum TSH levels) in the early stages of pregnancy. 8,10 Thus, when a pregnant woman was found to have normal thyroid function, neurodevelopmental alterations in the fetus were systematically discarded. 11 Along history, some contradictions have arisen from mixing different concepts as endemic cretinism, congenital hypothyroidism, iodine deficiency, etc 12 . Fortunately, such contradictions have been clarified by the advances in our understanding of thyroid physiology during pregnancy 13,14 , the transfer of maternal thyroid hormones to the fetus 15,16 and the increasingly complete characterization of thyroid hormone receptors in placental and embryo tissues. 17 Nevertheless, only the most recent studies have given satisfactory explanation of the possible role of thyroid hormones (maternal and fetal) during critical stages of fetal neurological development. 18 Basing on these recent works, the relevance of an adequate balance of iodine during the early stages of life is considered proven.

Iodine deficiency and pregnancy
Pregnancy is accompanied by dramatic changes in the thyroid function, which are the result of a complex combination of factors specific to pregnancy that altogether stimulate the maternal thyroid machinery. 14 During the first half of gestation the maternal thyroid undergoes some changes:


Progressive increase of thyroglobulin, which reduces free fraction of thyroxine.  The human chorionic gonadotropin has TSH-like effect and acts by directly stimulating the maternal thyroid.  Meanwhile, the fetal thyroid is kept inactive and will not be functioning until 20 weeks of gestation.  The only source of thyroid hormones in the fetus throughout the first half of pregnancy is thyroxine of maternal origin.
In healthy pregnant women with adequate iodine levels, pregnancy mainly involves a higher demand of thyroid hormones. The thyroid gland regulates the release of hormones to achieve a new balance, and maintains this balance until the end of the gestation process 19 . In general, the higher hormone need can only be met by a proportional increase in hormone release, which directly depends on the intake of iodine through the diet. At present, we know that iodine nutritional needs increase in all pregnant women due both to the higher hormone need and to the higher glomerular filtration rate 20 . This adaptation is achieved without difficulty by the thyroid machinery 21 . www.intechopen.com Conversely, when the thyroid gland fails -due, for example, to iodine deficiency-, such changes in thyroid parameters may not be adequately compensated and adaptation mechanisms fail 13,21 Obviously, the more severe iodine deficiency, the more serious fetal and maternal consequences are. However, it has been shown that such alterations can be found when pregnancy occurs in healthy women residing in moderately iodine-deficient areas 22 .

Background
In 1888, the Clinical Society of London prepared a report which emphasized the key role of the thyroid gland for normal brain development 23 . The members of this committee reached this conclusion after observing that patients with both endemic and sporadic cretinism showed clear evidence of mental retardation. 24 Initially, endemic cretinism was thought to be a congenital disease 25,26 . However, the prenatal origin of this syndrome was confirmed when a clinical trial with iodized oil showed that it could be successfully prevented exclusively when iodine was supplied to the mother before conception. 3 The classic works by Pharoah et al. 3,27 in Papua New Guinea in the 70's, and later by Thilly et al 4 in Ubangi (Zaire) and Malawi, provided a thorough description of the clinical symptoms of endemic cretinism (in its myxedema and neurological forms), which were characteristic of regions with severe endemic goiter.
These early studies supported the idea that severe iodine deficiency in the mother produces irreversible neurological damage in the fetus during critical development stages 12 . Cases of intrauterine deaths, miscarriages, death in childhood and the birth of cretins to women with biochemical evidence of iodine deficiency (very low free T4 levels) without clinical signs of hypothyroidism were described. 28,29 In 1976, Pharoah et al 27 pointed out that iodine deficiency was different from untreated myxedema and from congenital hypothyroidism, which are usually associated with menstrual disorders, infertility or repeated miscarriage.
Later, studies on iodine deficiency and its effects at the reproductive age and on progeny almost fell into oblivion in the scientific scene. It was believed that iodine deficiency had an impact only in certain geographic areas with severe endemic goiter, and that such dramatic consequences had been eradicated both in Europe and in the United States. 30 Thus, a misconception of the pathophysiology of neurological deficit caused by iodine deficiency was established. The placenta was thought to prevent the transfer of thyroid hormones. 31 According to this theory, the fetal brain would develop in the absence of maternal transfer of these hormones 32 and, therefore, neurological damage could be prevented by hormone supplementation therapy at birth. 13 In the following years in Europe, further clinical experience emphasized the significance of getting the diagnosis of congenital hypothyroidism, and initiating appropriate supplementation therapy as soon as possible after birth. The development of increasingly more precise 33,34 screening tests of thyroid function allowed to identify congenital hypothyroidism at birth and begin treatment without delay 35 .
However, clinical reports in regions with severe iodine deficiency suggested a different reality: there was a clear correlation between maternal hypothyroxinemia levels and the severity of neurological damage in the progeny. The lower the maternal FT4, the more serious the effects on the fetus, causing irreversible neurological and mental abnormalities at birth that could only be prevented by treating maternal hypothyroxinemia throughout the first half of gestation. 36 Subsequent interventions could not prevent all disorders.
But it was not until 1999 -when Haddow et al. 37 published their classic article in the New England Journal of Medicine-that iodine deficiency in pregnant women in developed countries was seen again as a problem also affecting populations that were so far thought to be safe from this endemic disease. Haddow et al. 37 found that infants of women with undiagnosed hypothyroidism (TSH above the 98 th percentile) during pregnancy had lower scores on tests related to intelligence, attention, language, reading skills, school and visualmotor performance, and that such differences with the other infants were statistically significant in the 15 tests performed.
That same year, Pop et al 38 published an article proving that fetal neural development is not only affected when the mother has subclinical hypothyroidism, but it is just enough that there is a previous stage of "maternal hypothyroxinemia" in the early stages of pregnancy. In their article, the authors showed that infants of mothers with T4 levels below the 10 th percentile at the 12 th week of gestation had significantly lower scores on the Bayley Psychomotor Development Scale at 10 months of age, compared with infants of mothers with higher free T4 levels.
In 2000, Morreale de Escobar et al. 36 presented epidemiological and experimental evidence strongly suggesting that first-trimester hypothyroxinemia (a low for gestational age circulating maternal free T4, whether or not TSH is increased) produces an increased risk for poor neuropsychological development of the fetus. The damage would be caused by decreased availability of maternal T4 to the developing brain.
Further, poor brain development occurs both in regions with severe iodine deficiency, and in regions with slight or moderate deficiency. 22,28 The identification of hypothyroxinemia as a factor which causes neurological damage in progeny -regardless whether or not the mother has hypothyroidism-is a landmark for the study of iodine deficiency in Europe. 32,36 Figure 1 shows the differences between the classic and current understanding of the physiopathology of iodine deficiency.

Thyroid hormones and fetal neurological development
In humans, cerebral cortical development occurs between the 6 th and the 24 th week of gestation. The cortical plate begins to form around day 54 (8 weeks of gestation). Cortical neuronal migration mostly occurs between the week 8 th and 24 th (before the end of the second trimester), and generally before the onset of fetal thyroid hormone secretion occurs in the middle of gestation 39 .
From a didactical perspective, fetal neurological development takes place in three stages relying on the thyroid hormone 40 ( Figure 2): 1. The first stage takes place before the fetus starts producing thyroid hormones, and ends between the week 16 th and 20 th of gestation. During this period, thyroid hormone exposure comes only from maternally synthesized hormones, which influence neuronal proliferation and migration of neurons into the neocortex and hippocampus. 2. The second stage occurs during the remainder of pregnancy after the onset of the fetal thyroid function, when the developing brain derives its supply of thyroid hormones from both the fetus and the mother. At this moment, thyroid hormones will trigger neurogenesis, neuronal migration, axonal outgrowth, dendritic branching and synaptogenesis, and the onset of glial cell differentiation and migration, and myelination. 3. The third stage takes place during the neonatal and post-natal period when thyroid hormone supplies to the brain are entirely derived from the child and critical for continuing maturation. At this stage, thyroid hormones affect granule cell migration in the hippocampus and cerebellum, including the migration of cerebellar Purkinje cells. Gliogenesis and myelination continue during this stage.
Thyroid hormone receptors (TR alpha and beta) bind T3 with very high affinity, and act as ligand-induced transcription factors modulating the expression of different T3-dependent target genes 18 . Thus, although circulating levels of T4L are 4-fold higher than those of T3L, the thyroid hormone receptor has at least 15-fold more affinity for T3 40 , which indicates that T4 is a prohormone that must be converted into T3 before the onset of thyroid hormone function. TR alpha and beta receptors express in most tissues, but their distribution varies from one tissue to another, which constitutes a control mechanism of T3 action that is specific in time and space. 41,42 Towards the end of the first trimester, development of the hypothalamic-pituitary axis has occurred and causes an increase in TSH secretion that marks the onset of fetal thyroid hormone production. Then starts the activating deiodinase enzyme ID-II expression and increases the occupation of thyroid hormone receptors by T3.
Continuing development of the brain in the second and third trimesters relies increasingly on the T4 produced by both the fetus and mother. Continued post-natal development is entirely dependent on neonatal thyroid hormone secretion.
Thyroid hormones intervene directly or indirectly in most of the neurodevelopmental processes of the embryo and the fetus. This would explain that thyroid deficiency in early pregnancy causes irreversible effects 43,44 .
Thyroid hormone receptors have been proven to express profusely both in neurons and in glial cells (astrocytes and oligodendrocytes) 45,46 .
At neuronal level, thyroid hormones would act as "cofactors", favoring the expression of certain patterns of genes involved in axonal and dendrite outgrowth, and in the formation of synapses, myelination, cell migrations, and proliferation of specific cell populations 39 .
For a proper neuronal function (synaptic transmission, laminar cytoarchitecture of the cerebral cortex) appropriate interaction with glial cells is required 47 . In this sense, thyroid hormones favor proliferation of oligodendrocyte precursor cells and their differentiation into mature oligodendrocytes (which make the myeline sheath) 46 .
At the same time, thyroid hormones are involved in the maturation of radial glial cells, which are directly involved in neuronal migration into the different layers of the cerebral cortex. 48 Finally, thyroid hormones are directly involved in the development and maturation of glial cells in specific brain areas, as the hippocampus or the cerebellum. 44 Thorough this sequence of events, it should be considered: -That fetal neurodevelopment follows a very precise and limited sequence of events 47 . The response period of the cell is what is called competence. The same cell will not respond before or after this period. -That the maturation sequence is not formed by a succession of independent events, but rather by cascading events where each anomaly. 49,50

Thyroid hormone transfer and maternal hypothyroxinemia
In humans, maternal thyroid hormones are transferred to the fetus and the embryo during pregnancy. In fact, during the first half of gestation, the mother is the sole source of thyroid hormones 51,52 .
Under normal conditions, embryonic tissues have a set of security mechanisms protecting their development. Some of these mechanisms are physical barriers (placenta and extraembryonic membranes) that avoid free transfer of maternal thyroid hormones into the fetus, and expose it to the same plasma fluctuations that occur in maternal blood serum 53,54. Another security mechanism is the presence of deiodinase enzymes in fetal cerebral tissues 55,56. Deiodinase enzymes take maternal free thyroxine (T4L) and subsequently convert it into T3, but do not allow direct transfer of maternal T3 57 . FNAs were made to obtain samples of fetal serum, and T4 concentrations in fetal serum were found to rely directly on maternal thyroxinemia 58 .
In case of nutritional iodine deficiency, the organism activates self-regulating mechanisms where T3 is synthesized prevailingly over T4, as a way to save iodine 15 ( Figure 3). This leads to a situation of maternal hypothyroxinemia, which is the fall of T4L levels in plasma, but presenting normal circulating T3L and TSH levels 36,57. Maternal hypothyroxinemia is defined as: At present there is solid evidence that maternal hypothyroxinemia (low T4L) during the first half of gestation is the main cause of neurological alterations in the embryo and the fetus 57,59 . Such alterations are permanent and irreversible.
All levels of iodine deficiency (low, moderate or severe) affect the maternal and neonatal thyroid function, and infant's mental development 22 .

Hypothyroxinemia and neurodevelopment
Animal models for iodine deficiency during pregnancy on development of the CNS have been developed for monkeys, sheep and rats. 2 These studies have shown changes in cerebellum with reductions in weight and cell number, and delayed maturation. The influence of maternal hypothyroxinemia on neocortical development has been recently studied in rats and mice. 60

Altered migration during corticogenesis
The cerebral cortex is composed of neuronal layers with specific functions. 39 To form this cytoarchitecture, neurons undergo a Tangential migration from the basal epithelium into the upper layers of the cortex 44 . Neuronal migration is highest between the 11 th and the 14 th week of gestation, coinciding with the T4 peak in maternal blood serum during gestation. 32 During this migration, neurons use glial cells like the steps of a stairway to climb into the upper layers 39,47 . This interaction between glial cells and neurons is enabled by thyroid hormones. 50,60 Studies on radial migration during corticogenesis have revealed that in cerebral cortex of hypothyroid rats, the radial positioning of migrating neurons is altered 48,49 , resulting in abnormally located Heterotopic neurons in the subcortical white matter (Figure 3

Abnormal cortical cytoarchitecture and connectivity
Any situation compromising maternal thyroid hormone transfer to the fetus will disturb the neuronal migration process. As a result, neurons will not reach their final destination in the upper layers and their abnormal positioning will cause alterations in the laminar architecture of the cerebral cortex. 44 In biopsies performed in experimental animals maternal thyroid hormone deficiency was found to cause permanent and irreversible lesions in the cerebral cortex cytoarchitecture. As in gestational hypothyroidism, hypothyroxinemia accuse neocortical layering blurred.

Physiopathology of fetal cerebral damage
Within this broad framework, three different situations can be found, with different results: When maternal hormone transfer is deficient -as in cases of maternal hypothyroidism or hypothyroxinemia-, the hormone concentrations transferred to the embryo and the fetus are inadequate during early pregnancy. Later, at the onset of fetal thyroid function, there is increased secretion of T4 and T3 by the fetal thyroid gland, though it fails to meet successfully the early disruption of maternal hormone supply. Thus, T4 and T3 concentrations in fetal tissues are fairly normal when the fetus reaches term, but its intrauterine development will have suffered alterations. 38,64 However, as the secretion of thyroid hormones increases, the fetal thyroid cannot store them. Therefore, neonates to mothers with thyroid malfunction have higher difficulty to meet the hormonal needs at birth than neonates to mother with normal thyroid function. This situation can lead to permanent neurological abnormalities 38,40 .
When the maternal thyroid function is normal, but the fetal function is not -as it is the case in congenital hypothyroidism-, maternal T4 and T3 supply can partly mitigate fetal hypothyroidism. Although maternal T4 supply cannot replace completely the fetal thyroid www.intechopen.com function, it is crucial for brain development, where it does maintain normal T3 concentrations. However, such concentrations are not maintained in other tissues at normal levels. 65 However, although maternal T3 levels are normal, this does not mitigate T3 deficiency in the fetus. The reason is that the fetal brain is totally dependent on the conversion of T4 into T3 by local action of 5'D-II, as T3 cannot be taken directly from plasma. 38,66 Thus, these findings prove that maintaining adequate T4 levels in the mother is crucial, as it protects the brain of fetuses with congenital hypothyroidism until birth. Conversely, although the mother has normal T3 concentrations maintaining maternal euthyroid status, this hormone does not protect the fetal brain in mothers with hypothyroxinemia 38,40 .
When both the maternal and the fetal thyroid function are abnormal -as in the case of chronic iodine deficiency-mothers have very low levels of T4, though T3 concentrations are normal. In this situation, embryos and fetuses have deficient T4 levels during gestation and become increasingly deficient in T3. 64 When the fetal thyroid gland should start working, it cannot compensate for the disrupted maternal supply, since it does not have enough iodine for the synthesis and secretion of T4. At the same time, the fetal brain has not preferential protection from maternal T4, as this hormone cannot be biosynthesized due to the deficiency of iodine. As a result, fetal tissues -including the fetal brain-are very deficient in T4 and T3 during very important stages of cerebral neurogenesis and maturation. 41,68 .
These data suggest that the pathogenic mechanisms that lead to cretinism and severe hypothyroidism are multifactorial, and the effects of severe iodine deficiency can be amplified by the deleterious effects of thiocyanate overload, selenium deficiency, and glandular destruction and fibrosis occurring gradually during childhood 69 . By contrast, when iodine supplementation is given to women in regions with endemic iodine deficiency, cretinism can be eradicated, and neonatal hypothyroidism prevented 70 .

Clinical effects of prenatal iodine deficiency
Now that we know the "virtually universal" participation of thyroid hormones in the development and proliferation of fetal neural tissue, the complex clinical manifestations of thyroid hormone deficit in early pregnancy can be easily anticipated.
Therefore, maternal and fetal hypothyroxinemia caused by iodine deficiency determines permanent lesions in the upper cortical areas, hippocampus and cerebellum 48,64 , which causes neurological abnormalities with relatively well-defined characteristics: -Brain stem or medullar elements are not affected, so there is no direct motor dysfunction, but abnormal motor coordination function 39 . - The lesions affect the integration areas of the cerebral cortex -including "silent" areas of the association areas of the cortex-showing poorly defined anatomical alterations. -They do not have perinatal clinical expression, although they express later during early years of life until school age. 71,72 -Therefore, these lesions cannot be detected by modern prenatal diagnosis techniques. 30 A number of research studies conducted in regions with moderate iodine deficiency have shown the presence of irreversible alterations in the intellectual and neuro-psycho-motor development of infants and adults that were clinically euthyroid and that did not exhibit other signs or symptoms of endemic cretinism, which is the most serious form of brain damage caused by iodine deficiency.
In follow-up studies on infants of mothers with hypothyroxinemia identified in the first trimester of pregnancy, low scores were obtained on scales measuring psychomotor development (psychometric tests used to find evidence of these abnormalities are varied and include adapted intelligence tests, regardless of the subjects' culture). Such results were especially significant in those tests that assess visual-motor coordination, object manipulation, understanding the relationship between objects, imitation and early language development 38,73 . The results showed low visual-motor performance, motor skills, perceptual and neuromotor skills, and low development and intelligence quotients (IQ) 71,76 .
Bleichrodt and Born 74 conducted a meta-analysis of 19 studies on neuromotor and cognitive functions in conditions of moderate to severe iodine deficiency, and concluded that iodine deficiency leads to a loss of 13.5 IQ points, as compared with the global population. Apart from goiter, brain damage and loss of intellectual potential caused by iodine deficiency are an obstacle to the socioeconomic development of people, and must be considered as a major public health problem.
More recently, iodine deficiency -maternal hypothyroxinemia-has been identified as a causal factor of attention-deficit hyperactivity disorder 75 . www.intechopen.com
Neurological damage to the fetus resulting from severe iodine deficiency during pregnancy Lancet 1971, 1: 308

Type of participants: Total population from 27 villages in Papua Nueva
Guinea.

Type of intervention:
Administration of intramuscular iodized oil.

Type of results: Changing incidence of endemic cretinism
Controlled clinical trial in a city of 8,000 inhabitants.
Intramuscular iodized oil is effective for the prevention of endemic cretinism. To be effective, it must be administered before conception.
Maternal severe iodine deficit causes neurological damage during fetal development.
Pioneer intervention study on populations with severe iodine deficit.
The cohort monitored is very small, as compared with the initial group.
The results obtained are expressed in terms of infant mortality and endemic cretinism incidence.

Type of intervention:
Administration of intramuscular iodized oil to a group of pregnant women.
Type of results: Changing TSH, T4 and T3 concentrations in mothers and newborn babies.
Maternal thyroid function in regions with severe endemic goiter is a good indicator of the thyroid function in a neonate.
The factors responsible for this hypothetical relationship seem to be environmental factors acting simultaneously in the mother and the fetus.
Pregnant women were grouped "randomly" into two groups.
The results obtained are shown in thyroid function values of the mother and the neonate at birth. Type of participants: 220 pregnant women and 220 infants at 10 months.

Type of intervention:
Study of maternal thyroid function and evaluation of the neurological development of infants at 10 months of life.
Type of results: Scores obtained by children on the Bayley Scale of Psycho-motor development.
Low free T4 plasma concentrations during early pregnancy may be a relevant risk factor of mental retardation in the progeny.
Free T4 concentrations are defined as an independent parameter for the neurological development of the progeny.
This is the first study to prove that low free TSH levels in apparently healthy women during early pregnancy increase significantly the risk of fetal neurological damage.
Maternal TSH, fT and TPO antibodies are analyzed at the 12 th and 32 th week of gestation.

Consequences at the 12 th
week and the rest of weeks of pregnancy. Maternal T4 is the sole source of thyroid hormone for the fetal brain during the first trimester.
Normal T3 concentrations in the mother do not prevent from potential damaged caused by a low T4 supply Through analysis of the main findings made in regions with severe iodine deficiency, in regions without iodine deficiency and in studies with experimental animals.
Development of a unifying theory on the severity and frequency of neurological damage in the progeny of mothers with hypothyroxinemia, in contrast with mothers with hypothyroidism. www.intechopen.com

Studies with potassium iodide supplementation
Finally, supplementation with potassium iodide (KI) from the early stages of pregnancy in pregnant women has proven to be a safe and effective method for preventing cognitive impairment associated with nutritional iodine deficiency.