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13.1 Introduction

13.1.1 Iodine Sources and Metabolism

Iodine is a micronutrient essential for mammalian life because it is critical for the synthesis of thyroid hormones, thyroxine (T4), and triiodothyronine (T3), which contain in their molecules four and three atoms of iodine, respectively. Thyroid hormones (TH) are important for the growth and development of different tissues, especially the central nervous system and the skeleton, for the cardiac and gastrointestinal function, and for the regulation of the energy homeostasis throughout life. Disturbances in TH availability during early embryonic development, as in maternal iodine deficiency, cause severe neurological abnormalities in the newborns [1]. The World Health Organization (WHO) considers iodine deficiency to be “the single most important preventable cause of brain damage” worldwide [2]. Despite the great improvements in global iodine nutrition in the last century, it is currently estimated that iodine deficiency still affects 241 million school-aged children [3].

The only source of iodine is the diet. While most iodine is found in the oceans, its amount in potable water and vegetables and then in animal food is poor in many areas, where it was removed by the surface soil because of wide glaciations. Only foods of marine origin have high iodine content because marine plants and animals are able to concentrate iodine from seawater. Therefore, in the absence of iodine prophylaxis programs, iodine intake may be insufficient. More commonly affected by iodine deficiency are the extraurban populations, especially rural, that eat nonindustrial local foods, poor in iodine. Indeed, the economic status more than the geographic location is the main determinant of the quality of the food and of its iodine content. In many countries, salt, bread, and milk are fortified with iodine, as an effort to eradicate iodine deficiency. Other sources of iodine are compounds used by industry and agriculture as well as supplements and disinfectants and medicines.

The iodine contained in the food is absorbed by about 90 % in the stomach and duodenum [4]. The absorbed iodine and that resulting from the peripheral metabolism of thyroid hormones and iodothyronines constitute the extrathyroidal pool of inorganic iodine, which is in equilibrium with the thyroid and the kidneys. The human body contains a small amount of iodine, 70–80 % of which is concentrated by the thyroid [5] through the sodium iodide symporter (NIS) that is located on the basolateral surface of thyrocytes [6]. On the apical surface of the thyrocytes, the thyroperoxidase (TPO) catalyzes the synthesis of monoiodotyrosine (MIT) and diiodotyrosine (DIT) and then the coupling of two DITs to produce T4 or of a MIT and a DIT to produce T3. A normal adult utilizes about 80 μg/day of iodine to produce thyroid hormones, 55 μg of which come from the diet and 25 μg from the peripheral metabolism of TH. Ninety percent of the plasma iodine is excreted by the kidney and only a small amount in the feces. When iodine intake is slightly insufficient (i.e., <100 mg/day), TSH induces a higher NIS expression with an increase of thyroid iodine uptake and preferential synthesis of T3, thus allowing a normal content of intrathyroidal iodine. In chronic iodine deficiency, the thyroid content of iodine progressively decreases, the metabolic balance of iodine becomes negative, and goiter and hypothyroidism with its sequelae ensue.

The thyroid content in iodine of fetal thyroid changes with the gestational age: it is very low during the first stages of development, increases quickly after the 15th week of gestation, when the thyroid starts to actively concentrate the iodine, and reaches a plateau at the end of gestation. The total content in iodine of the thyroid of full-term newborns depends on the dietary iodine intake. Compared to adults, newborns and infants have less effective adaptative mechanisms to iodine deficiency.

13.1.2 Modification of Thyroid Function and Iodine Metabolism During Pregnancy

An adequate iodine intake is particularly important during pregnancy for the possible consequences of iodine deficiency (ID) both on the mother and fetus. Pregnancy is associated with relevant changes in thyroid physiology [7] (Fig. 13.1). During early gestation, serum thyroxine-binding globulin (TBG) increases markedly, under the influence of elevated estrogen concentration, and the clearance of plasma iodine increases as a consequence of the higher glomerular filtration. ID induces a relative hypothyroxinemia (low T4 levels) in pregnancy, which in turn stimulates TSH secretion, enhances thyroid stimulation, and increases thyroid volume in both the mother and the fetus. At the end of the first trimester, there is a transient thyroid stimulation by high levels of human chorionic gonadotropin (hCG) while during the second half of the gestation the placental type 3 iodothyronine deiodinase increases the metabolism of maternal T4. As a consequence, the maternal thyroid gland is required to increase its hormonal production, through an increase of iodine uptake and a depletion of intrathyroidal stores. Later in gestation, the passage of iodine to the fetal-placental unit is another cause of deprivation of maternal iodine. For these reasons, as described in European areas with mild iodine deficiency, there is an increase of goiter formation during pregnancy that is only partially reversible postpartum. In addition, iodine deficiency correlates with a larger thyroid volume in newborns, and therefore goiter formation may start during the fetal thyroid development [7]. In presence of severe maternal iodine deficiency during pregnancy, there is a reduction in maternal thyroxine production, inadequate placental transfer of maternal thyroxine, and impairment of fetal neurological development.

Fig. 13.1
figure 1

The scheme shows the mechanisms which concur in the stimulation of maternal thyroid function during a normal pregnancy (Modified from Ref. [7])

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13.1.3 Iodine Requirements

Although with some limitations, several studies have established the iodine requirement at different age and physiological conditions.

The WHO recommends 90 μg of iodine daily for infants and children up to 5 years, 120 μg for children 6–12 years, 150 μg daily for children ≥12 years and adults, and 250 μg daily during pregnancy and lactation [2] (Table 13.1). The US Institute of Medicine–recommended minimum daily intake of iodine is similar: 90 μg daily for children 1–8 years old, 120 μg for children 9–13 years, 150 μg daily for older adolescents and nonpregnant adults, 220 μg for pregnant women, and 290 μg for lactating women [8].

Table 13.1 WHO recommendations for iodine intake by age or population group (Ref. [2])
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The iodine requirements are higher in pregnant women because of the above-listed changes in thyroid physiology.

13.1.4 Assessment of Iodine Intake

The methods for the assessment of iodine nutrition in the populations are goiter prevalence, urinary iodine concentration (UIC), serum TSH in newborns, and serum thyroglobulin (Tg). The urinary iodine concentration indicates current iodine nutrition, while thyroid size and the serum thyroglobulin concentration reflect iodine nutrition over a period of months or years.

Goiter

goiter can be measured by neck inspection and palpation or by thyroid ultrasonography. According to WHO/ICCIDD, grade 0 is a thyroid that is not palpable or visible, grade 1 is a goiter that is palpable but not visible when the neck is in the normal position, and grade 2 is a goiter that is clearly visible when the neck is in a normal position. Thyroid ultrasound is more sensitive and specific than palpation but requires valid references of thyroid volume data. Goiter surveys as indicators of iodine sufficiency are usually done in school-age children because they are easily recruitable and hopefully reflect the actual impact on humans of iodine deficiency, although enlarged thyroids in children who were iodine deficient during the first years of life may not regress completely after introduction of salt iodization [9]. The WHO has established total goiter rate in schoolchildren to define severity of iodine deficiency in populations: below 5.0 % indicates iodine sufficiency, 5.0–19.9 % mild deficiency, 20.0–29.9 % moderate deficiency, and above 30.0 % severe deficiency. In addition, a reduction of goiter rate by ultrasound indicates that iodine deficiency has disappeared, and therefore a frequency of goiter under 5 % in schoolchildren must be considered as a parameter of iodine sufficiency [10].

Urinary iodine concentration

because >90 % of dietary iodine eventually appears in the urine, the UIC is an excellent indicator of recent iodine intake. It is measured in spot urine specimens from a representative sample of a population and expressed as the median, in μg/L. The median urinary iodine concentration in a population has been used to develop a system for classifying iodine deficiency and sufficiency (Table 13.2) [2]. The most usual survey group is school-age children, but their nutrition must reflect that of the community in order for the data to be meaningful. Mild iodine deficiency is defined as a median urinary iodine concentration of 50–99 μg/L, moderate deficiency as 20–49 μg/L, and severe deficiency as <20 μg/L [11]. Pregnant women require special attention because their renal threshold for iodine is lower, the needs of the fetus are greater, and dietary salt (including iodized salt) is often restricted [12, 13]. In pregnant women, urinary iodine concentrations of 150–249 μg/L are considered adequate [14].

Table 13.2 Epidemiological criteria from WHO for assessment of iodine nutrition in school-aged children, pregnant and lactating women, and infants based on median or range of UI (Ref. [2])
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TSH

TSH concentration obtained during the neonatal screening of congenital hypothyroidism (CH) is useful to assess iodine nutrition, because the increase of fetal TSH is an adaptative mechanism to iodine deficiency. Compared with the adult, the newborn thyroid contains less iodine but has higher rates of iodine turnover. When iodine supply is low, maintaining high iodine turnover requires increased TSH stimulation. Therefore, iodine deficiency causes a shift toward higher TSH values in the neonatal screening of CH. A TSH value >5 mU/L in whole blood collected 3–4 days after birth that lasts for few weeks in more than 3 % of newborns indicates iodine deficiency in the population [2]. Studies suggest also that newborn TSH is a sensitive indicator of iodine nutrition during pregnancy along with determination of the median UIC [15].

Serum Tg

Tg is the most abundant intrathyroidal protein. Serum Tg is higher in iodine-deficient than in iodine-sufficient areas as a consequence of the TSH stimulation and the higher rate of goiter, and its concentrations fall quickly with the implementation of iodine prophylaxis. In iodine-deficient infants and children, serum Tg concentrations are high more often than are serum TSH concentrations. Although a nonspecific test, since any type of thyroid stimulation or injury can raise the serum Tg concentrations, the values correlate well with the severity of iodine deficiency. Tg has also been shown to be a sensitive measure of excess iodine intake in school-age children [16]. Moreover, in one study the serum Tg level was better than thyroid volume measurement by ultrasound as an indicator of iodine nutrition [17].

13.2 Consequences of Iodine Deficiency

The clinical consequences of inadequate iodine intake are collectively termed “the iodine deficiency disorders” (IDD) (Table 13.3) [18]. When severe iodine deficiency occurs during pregnancy, it is associated with cretinism and increased neonatal and infant mortality. Mild iodine deficiency is associated with thyroid enlargement and learning disabilities in children. All these consequences of iodine deficiency stem from the associated hypothyroidism.

Table 13.3 Iodine deficiency disorders (IDD) by age group
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Additional factors that can exacerbate the effects of iodine deficiency include coexistent deficiencies of iron, selenium, and vitamin A [19] and the ingestion of foods such as cassava or millet containing goitrogenic substances.

Goiter is the most frequent manifestation of iodine deficiency and can affect individuals of all ages. It represents a compensatory response to iodine deficiency. Low iodine intake leads to reduced T4 and T3 production, which results in increased TSH secretion in an attempt to restore iodothyronine production to normal. TSH also stimulates thyroid growth. The goiter is initially diffuse but eventually becomes nodular because the cells in some thyroid follicles proliferate more than others. Therefore, in regions of iodine deficiency, children and adolescents generally have diffuse goiters, while adults who lived in conditions of long-standing iodine deficiency have nodular goiter.

This chapter will focus on the consequences of iodine deficiency from fetal life to childhood.

13.2.1 Consequences of Iodine Deficiency During Pregnancy and Infancy

13.2.1.1 Neurological Development

Goiter is the most common clinical manifestation of iodine deficiency, but another important consequence is a defective development of central nervous system because brain development depends on thyroid hormones during fetal and early postnatal life.

THs have no influence on very early stages of neurological development but regulate its later processes, which include neurogenesis, myelination, dentrite proliferation, and synapse formation [20, 21]. In particular, three stages of thyroid hormone–dependent neurological development can be recognized. The first occurs before the onset of fetal thyroid hormone synthesis, which occurs at 16–20 weeks post conception in humans. During this period, TH exposure comes only from maternal hormones [1, 22] and influences proliferation and migration of neurones in the cerebral cortex, hippocampus, and medial ganglionic eminence [23, 24]. The second stage occurs during the remainder of pregnancy after the onset of fetal thyroid function when the developing brain derives its supply of TH from both the fetus and the mother [1, 22]. During this period, thyroid hormone regulates neurogenesis, neuron migration, axonal outgrowth, dendritic branching, and synaptogenesis, together with the initiation of glial cell differentiation and migration and the onset of myelination [25]. The third stage occurs in the neonatal and postnatal period when thyroid hormone supplies to the brain entirely derive from the child and are critical for continuing maturation. During this period, while continuing gliogenesis and myelination, THs regulate migration of granule cells in the hippocampus and cerebellum, pyramidal cells in the cortex, and Purkinje cells in the cerebellum [25].

The frequency and severity of the neurological impairment are proportional to the magnitude of iodine deficiency. In areas of severe chronic iodine deficiency, maternal and fetal hypothyroxinemia can occur from early gestation onward.

13.2.1.2 Endemic Cretinism

The clinical manifestations caused by chronic severe iodine deficiency are referred to as endemic cretinism. In its classical description, endemic cretinism includes a neurological and a myxedematous form [26].

The neurological cretinism presents with severe mental retardation with squint, deaf-mutism, motor spasticity, and goiter. The mental deficiency is characterized by a marked impairment of abstract thought, whereas autonomic and vegetative functions and memory are relatively well preserved, except in the most severe cases. The motor disorder is characterized by proximal rigidity of both lower and upper extremities and the trunk, whereas spastic involvement of the feet and hands is unusual, therefore most cretins can walk.

The myxedematous form has less severe mental retardation and more pronounced hypothyroid features, including severe growth retardation, incomplete maturation of the facial skeleton with naso-orbital configuration abnormalities and atrophy of mandibles, puffy features, dry and thickened skin, dry and rare hair, and delayed sexual maturation. In this form, goiter is usually absent, and the thyroid is usually atrophic.

In many instances, cretinism may present as a mixed form with features of both. Therefore, it can be often difficult to differentiate the two forms [27].

Studies suggest that selenium deficiency combined with severe iodine deficiency can more specifically induce forms of atrophic rather than goitrous hypothyroidism and therefore of myxedematous rather than neurological cretinism [28]. Selenium is normally present in high concentrations in the normal thyroid and is essential for the synthesis of selenoproteins such as glutathione peroxidase (GPX), which acts as antioxidant, and type I 5’-deiodinase, which metabolizes thyroid hormones. The mechanism would be the following: iodine deficiency causes thyroid hyperstimulation by TSH that leads to increased production of H2O2 within the thyroid follicular cells; selenium deficiency also results in accumulation of H2O2 due to GPX deficit. Excess of H2O2 can induce thyroid cell destruction and myxedematous cretinism. On the other hand, deficiency of the selenoenzyme 5′-deiodinase causes decreased catabolism of T4–T3 with increased availability of T4 for the fetal brain and prevention of neurological deficits; T4, in fact, crosses the brain–blood barrier more easily than T3.

Cases of overt myxedematous, neurological, or mixed endemic cretinism are reported in areas of severe iodine deficiency such as Africa and Asia.

The only way to prevent neurological cretinism is by administration of iodine to women early in gestation or even before they become pregnant. In a randomized trial and several population-based studies of women living in severely iodine-deficient regions, iodine supplementation to women prior to conception or during early pregnancy was associated with substantially better neurological and developmental outcomes in children [29–31].

13.2.1.3 Subclinical Neurological Defects

Severe iodine deficiency has been almost eradicated through extensive iodine prophylaxis programs worldwide. As a consequence, new cases of cretinism have disappeared. However, several regions of mild to moderate iodine deficiency still exist [32].

Several reports have described cases of neurological deficits or minor neuropsychological impairments also in children born to mothers exposed to mild to moderate iodine deficiency during pregnancy. These defects may be detected by appropriate neuropsychological tests [33]. In Tuscany, neuropsychological performance was tested in 107 children living in a village characterized by mild iodine deficiency (UIC = 64 μg/L) by a block design subtest of the Wechsler Intelligence Scale for Children and simple reaction times to visual stimuli. The results obtained in these children were compared with those obtained in children born and living in an iodine-sufficient area. The block design test was not different between the two groups of children, while reaction times were significantly delayed in children living in the iodine-deficient village. These data indicate that mild iodine deficiency may impair the rate of motor response to perceptive stimuli even in the absence of general cognitive defects. Mild to moderate iodine deficiency was also shown to be associated with minor neurological deficits in Sicily [34].

However, randomized trials of iodine supplementation to pregnant women with mild to moderate iodine deficiency have reported mixed results in terms of improvements of thyroid function parameters, which may be considered as surrogate markers of future infant development [35]. In some but not in all trials [36, 37], iodine supplementation resulted in smaller thyroid volumes and lower Tg concentrations in mothers and/or newborns compared with controls. Indeed, there was no effect on maternal or neonatal T4 concentrations in the majority of the trials. Moreover, no final conclusion can be drawn from these studies because child cognitive outcomes were not measured.

An increased auditory threshold may be another clinical manifestation of iodine deficiency. As an example, in a study of 150 school-age children in Spain, 38 % had a goiter [38]. In this subset, there was an inverse relationship between auditory threshold and urinary iodine excretion (i.e., the more iodine deficient, the higher the auditory threshold).

The potential adverse effects of mild to moderate iodine deficiency during pregnancy on cognitive and/or neurological function of the offsprings are still uncertain.

Two prospective case–control studies have reported even mild thyroid dysfunction during pregnancy may impair cognitive development of the offspring [39, 40]. Children exposed to maternal hypothyroxinemia presented reduced IQ scores, subtle deficits in cognition, memory, visuospatial ability [39], and delayed mental and motor function [40]. Animal models confirmed that maternal hypothyroxinemia induced in a critical period of active neurogenesis resulted in alteration in cell migration and cytoarchitecture of the cortex and hyppocampus in the 40-day-old progeny [23, 41]. The limitation of these previous studies is that they were conducted in iodine-sufficient areas.

In two following observational studies of women with mild to moderate iodine deficiency and mild hypothyroxinemia, neurodevelopmental outcomes were better in children whose mothers received iodine supplementation (200–300 μg potassium iodide daily) early in pregnancy (prior to the 10th week of gestation) compared with children whose mothers did not [42, 43]. The better outcomes noted in these studies may be related to improvement in maternal hypothyroxinemia. Both mild and severe maternal hypothyroxinemia have reportedly been associated with a higher risk of expressive language delay in newborns [44]. Severe maternal hypothyroxinemia also predicted a higher risk of nonverbal cognitive delay. It is possible that iodine supplementation in women with iodine deficiency severe enough to cause maternal hypothyroxinemia may improve neurodevelopmental outcomes, but this has not been assessed in randomized trials.

13.2.1.4 Birth Weight and Infant Growth

There is evidence that correction of iodine deficiency during pregnancy in severely iodine-deficient areas determines improvements of head circumference and birth weight of offspring.

In an area of western China, iodine repletion of pregnant women reduced the prevalence of microcephaly from 27 to 11 % [29]. In studies conducted in Algeria and Zaire, treatment of women with oral iodized oil just before conception or early in pregnancy resulted in respectively 6.25 % and 3.7 % higher birth weight compared with offspring of untreated mothers [45, 46]. (For the relationship between iodine deficiency and somatic growth, see Sect. 13.2.2.2.)

13.2.1.5 Neonatal and Infant Mortality

Severe iodine deficiency increases neonatal and infant mortality, an effect that can be reduced by up to 50 % with correction of severe iodine deficiency [47]. The mechanism of this benefit is not known, but multiple factors are probably involved. Hypothyroid or retarded infants may suffer more birth trauma and be more prone to infectious diseases and nutritional deficiencies typical of the poor rural communities in which iodine deficiency is so prominent.

13.2.2 Consequences of Iodine Deficiency in Childhood

13.2.2.1 Intellectual Disability

Iodine deficiency appears also to have adverse effects on growth and development in the postnatal period. Children and adolescents in regions of iodine deficiency are at risk for some degree of intellectual disability and fine motor skill abnormalities compared to children in iodine-sufficient areas.

A meta-analysis of 21 observational and experimental studies relating iodine deficiency to cognitive development suggested that iodine deficiency alone caused an average loss of 13.5 IQ points in affected subjects [48]. This evidence is suggestive, although the developmental studies in iodine-deficient regions have many limitations; among these are the inability to distinguish between the persistent effects of fetal iodine deficiency and the ongoing effects of iodine deficiency in childhood and adolescence and the presence of other environmental factors which may affect child development (i.e., socioeconomic status, accessibility and quality of education and health).

Even in developed countries, marginal iodine sufficiency may lead to intellectual compromise [49]. In Jaen province, in Spain, schoolchildren with UI below 100 μg/L had lower IQ scores: 96.4 versus 99.0 in schoolchildren with UI greater than 100 μg/L [50]. In Australia, children born to mothers with urinary iodine concentrations during pregnancy of less than 150 μg/L compared with ≥150 μg/L had reductions in spelling, grammar, and English-literacy standardized test scores at age 9 years [51]. The children grew up in a region considered to be iodine replete (median UI 108 μg/L), and therefore, the results reflect the effects of fetal rather than childhood iodine insufficiency.

Intellectual disability resulting from the effects of iodine deficiency on the central nervous system during fetal development is not reversible. In contrast, the additional impairment caused by continuing postnatal hypothyroidism and/or iodine deficiency may improve with appropriate thyroid hormone replacement and/or iodine supplementation [52]. In a double-blind intervention trial of iodine supplementation or placebo in 310 10- to 12-year-old children in Albania, iodine supplementation with 400 mg of iodine as oral iodized oil significantly improved thyroid function (prevalence of hypothyroxinemia was reduced from approximately 30 to <1 %) and performance on cognitive testing evaluating information processing, fine motor skills, and visual problem solving [53].

13.2.2.2 Somatic Growth

It is known that severe iodine deficiency in womb causes cretinism and dwarfism, while iodized oil given during pregnancy in areas of moderate iodine deficiency increases birth weight by 100–200 g [45]. More controversial is the relationship between iodine deficiency and postnatal growth. However, most of the cross-sectional studies on iodine intake and child growth showed modest positive correlation [35].

Iodine status may influence growth through its effects on thyroid function. Thyroid hormone promotes growth hormone (GH) secretion and modulates the effects of GH at receptor level [54, 55]. Insulin-like growth factor (IGF)-1 and IGF-binding protein (IGFBP)-3 are also dependent on thyroid status. Indeed, hypothyroidism decreases circulating IGF-I and IGFBP-3 levels, whereas thyroid hormone replacement increases them [56, 57]. A controlled study including 10- to 14-year-old children from Morocco, Albania, and South Africa who were given iodine as iodized salt or oil and placebo showed that the increase in median UI to >100 μg/L was associated to an increase in IGF-1 and IGFBP-3 concentrations and an improvement in somatic growth [58].

13.2.2.3 Subclinical Hypothyroidism

Compared with the adult, the child thyroid contains less iodine but has higher rates of iodine turnover. Therefore, chronic iodine deficiency causes in children more than in adults an increase in TSH concentrations and a thyroid hormone pattern consistent with subclinical hypothyroidism (SH). Because SH is associated with cardiovascular disease risk factors [59], such as abnormalities in the lipid profile, correction of iodine deficiency may be beneficial also in reducing these risks. This effect of iodine supplementation has been reported in a recent controlled study, in which treatment of moderately iodine-deficient children affected by SH due to iodine deficiency improved their lipide profile and reduced insulin levels compared with controls [60]. However, more studies are needed to confirm the findings.

13.3 Prophylaxis and Treatment of Iodine Deficiency

An optimal correction of iodine deficiency should be carried out at the level of the community rather than the individual.

13.3.1 Salt Fortification with Iodine and Other Options

Iodization of salt is the preferred method of increasing iodine intake in a community, because salt is consumed by everyone, it is technically easy to produce, does not change salt taste, and the cost is relatively low.

However, the iodization of all salt for human and livestock consumption (Universal Salt Iodization – USI) is not commonly achieved. The usual dose for salt fortification is between 20 and 40 mg of iodine/kg of salt (sodium chloride) as potassium iodide or iodate. The optimal amount to be added for a particular country or region can be calculated from the daily per capita salt consumption, the amount of iodine consumed from other sources, and any losses of iodine between production and consumption.

Alternatives are needed when salt iodization is impractical or delayed. In these cases, effective options are iodized oil (Lipiodol), iodized water, and iodine tablets or drops. Lipiodol, developed as a radiographic contrast agent, contains 480 mg iodine/mL. A single oral dose of 0.5–1.0 mL provides an adequate amount of iodine for 6 months to 1 year; intramuscular administration of the same dose provides an adequate amount for 2–3 years [61]. Iodized oil is more expensive than salt iodization and requires direct administration to each subject. If given intramuscularly, it requires skilled administration and has a risk of infection if improper technique is used. Its main advantage is that it can be implemented promptly. It has been especially valuable for women of childbearing age and children in regions of severe iodine deficiency.

Water is another occasional iodization vehicle because it is a daily necessity like salt.

Other methods of iodide administration include oral administration of potassium iodide solution every 2–4 weeks and daily administration of tablets containing from 100 to 300 μg potassium iodide. The latter is particularly recommended to meet the increased needs for iodine during pregnancy and lactation, and it can be routinely incorporated into prenatal vitamin/mineral preparations. In addition, alternative methods of food iodine enrichment are currently under study. Hydroponic experiments were carried out to investigate the possibility of enriching the iodine uptake by spinach [62] or other vegetables such as tomatoes and potatoes. A recent study [63] tested the efficiency of vegetables (potatoes, cherry tomatoes, carrots, and green salad) fortified with iodine in a group of 50 adult healthy volunteers. A daily intake of 100 g of vegetables containing 45 μg of iodine (30 % of the Recommended Daily Allowance), increased after 2 weeks the UIC by about 20 %, showing that the biofortification of vegetables with iodine can determine a mild but significative increase in UI concentration and, along with the habitual use of iodized salt, may contribute to improve the iodine nutritional status of the population without risks of iodine excess.

13.3.2 Iodine Needs During Pregnancy and Lactation

In regions where <90 % of households use iodized salt and the median UIC in children is <100 μg/L, the WHO recommends iodine supplementation in pregnancy and lactation (250 μg daily) [14]. In pregnant women, urinary iodine concentrations of 150–249 μg/L indicate adequate iodine intake.

In the USA, women who do not consume dairy products or iodized salt may have lower urinary iodine concentrations [64]. The American Thyroid Association recommends that women from the USA receive a supplement of 150 μg of iodine (in the form of potassium iodide) daily during pregnancy and lactation, which is the dose included in the majority of prenatal vitamins marketed in the USA [13]. The Institute of Medicine recommended minimum daily intake is somewhat higher: 220 μg for pregnant women and 290 μg for lactating women.

13.3.3 Adverse Effects

Iodine repletion in the doses used for iodization of salt and in prenatal supplements has few adverse effects. Iodine administration may result in hyperthyroidism in patients with endemic goiter or in patients with nodular goiters containing autonomously functioning tissue. In contrast, iodine administration may induce or exacerbate hypothyroidism in patients with underlying autoimmune thyroiditis. In regions of iodine deficiency, both hyperthyroidism and hypothyroidism have been reported after the introduction of iodine [65, 66].

Excessive iodine ingestion during pregnancy may have adverse effects on fetal thyroid function. Indeed, a sudden exposure to excess serum iodine inhibits organification of iodine through the Wolff-Chaikoff effect [67]. The fetal thyroid gland, which has not full functioning mechanisms of escape from the Wolff-Chaikoff effect, is particularly susceptible to the inhibitory effects of excess iodine, and this can result in a prolonged inhibition of thyroid hormone synthesis, an increase in TSH, and fetal goiter.

The tolerable upper intake amount for iodine, as established by European and US expert committees, ranges from 600 to 1100 μg daily for pregnant women >19 years of age [68]. For adolescents 15–17 years, it ranges from 500 to 900 μg daily and for younger children 200–450 μg/day.