Iodine deficiency

Iodine Deficiency

Michael B. Zimmermann

- Author Affiliations

Human Nutrition Laboratory, Swiss Federal Institute of Technology Zürich, CH-8092 Zürich, Switzerland; and Division of Human Nutrition, Wageningen University, 6708 Wageningen, The Netherlands

Address requests for reprints to: Michael B. Zimmermann, Laboratory for Human Nutrition, Swiss Federal Institute of Technology Zürich, Schmelzbergstrasse 7, LFV E19, CH-8092 Zürich, Switzerland. E-mail: michael.zimmermann@ilw.agrl.ethz.ch


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Abstract

Iodine deficiency has multiple adverse effects in humans, termed iodine deficiency disorders, due to inadequate thyroid hormone production. Globally, it is estimated that 2 billion individuals have an insufficient iodine intake, and South Asia and sub-Saharan Africa are particularly affected. However, about 50% of Europe remains mildly iodine deficient, and iodine intakes in other industrialized countries, including the United States and Australia, have fallen in recent years. Iodine deficiency during pregnancy and infancy may impair growth and neurodevelopment of the offspring and increase infant mortality. Deficiency during childhood reduces somatic growth and cognitive and motor function. Assessment methods include urinary iodine concentration, goiter, newborn TSH, and blood thyroglobulin. But assessment of iodine status in pregnancy is difficult, and it remains unclear whether iodine intakes are sufficient in this group, leading to calls for iodine supplementation during pregnancy in several industrialized countries. In most countries, the best strategy to control iodine deficiency in populations is carefully monitored universal salt iodization, one of the most cost-effective ways to contribute to economic and social development. Achieving optimal iodine intakes from iodized salt (in the range of 150–250 μg/d for adults) may minimize the amount of thyroid dysfunction in populations. Ensuring adequate iodine status during parenteral nutrition has become important, particularly in preterm infants, as the use of povidone-iodine disinfectants has declined. Introduction of iodized salt to regions of chronic iodine deficiency may transiently increase the incidence of thyroid disorders, but overall, the relatively small risks of iodine excess are far outweighed by the substantial risks of iodine deficiency.

I. Introduction

II. Ecology

III. Dietary Sources

IV. Absorption and Metabolism

A. Thyroidal adaptation to iodine deficiency

B. Goitrogens

V. Requirements

A. Definitions

B. Adulthood

C. Pregnancy and lactation

D. Infancy

E. Childhood

VI. Methods to Assess Status

A. Thyroid size

B. Urinary iodine concentration

C. Thyroid stimulating hormone

D. Thyroglobulin

E. Thyroid hormone concentrations

F. Assessing status during pregnancy

G. Assessing status during lactation

H. Assessing status during infancy

VII. Effects of Deficiency through the Life Cycle

A. Pregnancy and infancy

B. Childhood

C. Adulthood

VIII. Epidemiology

IX. Treatment and Prevention

A. Salt fortification with iodine

B. Other fortification vehicles

C. Iodine supplementation

D. Strategies to prevent or correct deficiency during pregnancy and lactation

X. Enteral and Parenteral Nutrition

A. Infancy

B. Childhood

C. Adulthood

XI. Increasing Iodine Intakes in Populations and Iodine Excess

A. Cross-sectional studies: the epidemiology of thyroid disorders in areas of low and high intakes

B. Longitudinal studies: the effects of increasing intakes in populations on thyroid function

XII. Conclusions

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I. Introduction

IODINE (atomic mass, 126.9 amu) is an essential component of the hormones produced by the thyroid gland. Thyroid hormones, and therefore iodine, are essential for mammalian life. In 1811, Courtois discovered iodine as a violet vapor arising from seaweed ash while manufacturing gunpowder for Napoleon’s army. Gay-Lussac identified it as a new element, and named it iodine, from the Greek for “violet.” Iodine was found in the thyroid gland by Baumann in 1895 (1). In 1917, Marine and Kimball showed that thyroid enlargement (goiter) was caused by iodine deficiency and could be prevented by iodine supplementation (2). Goiter prophylaxis through salt iodization was first introduced in Switzerland and the United States in the early 1920s.

In 1980, the first global estimate from the World Health Organization (WHO) on the prevalence of goiter was reported; it estimated that 20–60% of the world’s population was iodine deficient and/or goitrous, with most of the burden in developing countries. But little attention was paid to iodine deficiency in public health programs in most countries—goiter was considered a lump in the neck primarily of cosmetic concern. This changed during the period of 1970–1990. Controlled studies in iodine-deficient regions showed that iodine supplementation not only eliminated new cases of cretinism but also reduced infant mortality and improved cognitive function in the rest of the population (3). The term “iodine deficiency disorders” (IDD) was coined, and IDD became widely recognized as a spectrum of related disorders potentially affecting 1.5 billion individuals. Programs against IDD had clear political appeal because its human, economic, and social consequences could be averted by a low-cost intervention, universal salt iodization (USI). Since 1990, elimination of IDD has been an integral part of many national nutrition strategies (4).
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II. Ecology

Iodine (as iodide) is widely but unevenly distributed in the earth’s environment. In many regions, leaching from glaciations, flooding, and erosion have depleted surface soils of iodide, and most iodide is found in the oceans. The concentration of iodide in sea water is approximately 50 μg/liter. Iodide ions in seawater are oxidized to elemental iodine, which volatilizes into the atmosphere and is returned to the soil by rain, completing the cycle (5). However, iodine cycling in many regions is slow and incomplete, leaving soils and drinking water iodine depleted. Crops grown in these soils will be low in iodine, and humans and animals consuming food grown in these soils become iodine deficient. In plant foods grown in deficient soils, iodine concentration may be as low as 10 μg/kg dry weight, compared with approximately 1 mg/kg in plants from iodine-sufficient soils.

Iodine-deficient soils are common in mountainous areas (e.g., the Alps, Andes, Atlas, and Himalayan ranges) and areas of frequent flooding, especially in South and Southeast Asia (for example, the Ganges River plain of northeastern India). Although many inland areas, including central Asia and Africa and central and eastern Europe are iodine deficient, iodine deficiency may also affect coastal and island populations. Iodine deficiency in populations residing in these areas will persist until iodine enters the food chain through addition of iodine to foods (e.g., iodization of salt) or dietary diversification introduces foods produced outside the iodine-deficient area. The current global prevalence of iodine deficiency is discussed in Section VIII.
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III. Dietary Sources

The native iodine content of most foods and beverages is low. In general, commonly consumed foods provide 3 to 80 μg per serving (6, 7). Foods of marine origin have higher iodine content because marine plants and animals concentrate iodine from seawater. Iodine in organic form occurs in high amounts in certain seaweeds. Inhabitants of the coastal regions of Japan, whose diets contain large amounts of seaweed, have remarkably high iodine intakes amounting to 50 to 80 mg/d. In the United States, the median intake of iodine from food in the mid-1990s was estimated to be 240 to 300 μg/d for men and 190 to 210 μg/d for women (8). Major dietary sources of iodine in the United States are bread and milk (9). In Switzerland, based on direct food analysis, mean intake of dietary iodine is approximately 140 μg/d, mainly from bread and dairy products (7). In many countries, use of iodized salt in households for cooking and at the table provides additional iodine. Boiling, baking, and canning of foods containing iodated salt cause only small losses (≤10%) of iodine content (10).

Iodine content in foods is also influenced by iodine-containing compounds used in irrigation, fertilizers, and livestock feed. Iodophors used for cleaning milk cans and teats can increase the native iodine content of dairy products. Traditionally, iodate was used in bread making as a dough conditioner, but it is being replaced by non-iodine-containing conditioners. Erythrosine is a red coloring agent high in iodine that is widely used in foods, cosmetics, and pharmaceuticals. Dietary supplements often contain iodine. Based on data from the Third National Health and Nutrition Examination Survey (NHANES III), 12% of men and 15% of nonpregnant women took a supplement that contained iodine, and the median intake of iodine from supplements was approximately 140 μg/d for adults (8). Other sources of iodine include water purification tablets, radiographic contrast media, medicines (e.g., a 200-mg tablet of amiodarone, an antiarrhythmic drug, contains 75 mg), and skin disinfectants (e.g., povidone-iodine contains approximately 10 mg/ml).
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IV. Absorption and Metabolism

Iodine is ingested in several chemical forms. Iodide is rapidly and nearly completely absorbed in the stomach and duodenum. Iodate, widely used in salt iodization, is reduced in the gut and absorbed as iodide. In healthy adults, the absorption of iodide is greater than 90% (11). In animal models, the sodium/iodine symporter (NIS) is functionally expressed on the apical surface of enterocytes and mediates active iodine accumulation (12). Organically bound iodine is typically digested and the released iodide absorbed, but some forms may be absorbed intact; for example, approximately 70% of an oral dose of T4 is absorbed intact (13).

The distribution space of absorbed iodine is nearly equal to the extracellular fluid volume (14). Iodine is cleared from the circulation mainly by the thyroid and kidney, and whereas renal iodine clearance is fairly constant, thyroid clearance varies with iodine intake. In conditions of adequate iodine supply, no more than 10% of absorbed iodine is taken up by the thyroid. In chronic iodine deficiency, this fraction can exceed 80% (14, 15, 16). During lactation, the mammary gland concentrates iodine and secretes it into breast milk to provide for the newborn (17). The salivary glands, gastric mucosa, and choroid plexus also take up small amounts of iodine. Iodine in the blood is turned over rapidly; under normal circumstances, plasma iodine has a half-life of approximately 10 h, but this is shortened if the thyroid is overactive, as in iodine deficiency or hyperthyroidism (14, 15, 16).

The body of a healthy adult contains 15 to 20 mg of iodine, of which 70 to 80% is in the thyroid (18). In chronic iodine deficiency, the iodine content of the thyroid may fall below 20 μg. In iodine-sufficient areas, the adult thyroid traps approximately 60 μg of iodine per day to balance losses and maintain thyroid hormone synthesis (14, 15, 16). A transmembrane protein in the basolateral membrane, the NIS, transfers iodide into the thyroid at a concentration gradient 20 to 50 times that of plasma (19). The human NIS gene is located on chromosome 19 and codes for a protein of 643 amino acids (20). The NIS concentrates iodine by an active transport process that couples the energy released by the inward translocation of sodium down its electrochemical gradient to the simultaneous inward translocation of iodine against its electrochemical gradient (19). The decrease in thyroidal iodide transport from excess iodide administration is related to a decrease in NIS expression (21).

At the apical surface of the thyrocyte, the enzymes thyroperoxidase (TPO) and hydrogen peroxide oxidize iodide and attach it to tyrosyl residues on thyroglobulin to produce monoiodotyrosine (MIT) and diiodotyrosine (DIT), the precursors of thyroid hormone (22). TPO then catalyzes the coupling of the phenyl groups of the iodotyrosines through a diether bridge to form the thyroid hormones (22, 23). Linkage of two DIT molecules produces T4, and linkage of a MIT and DIT produces T3. Thus, T3 is structurally identical to T4 but has one less iodine (at the 5′ position on the outer ring). Iodine comprises 65 and 59% of the weights of T4 and T3, respectively. In the thyroid, mature thyroglobulin (Tg), containing 0.1 to 1.0% of its weight as iodine, is stored extracellularly in the luminal colloid of the thyroid follicle (22, 23). After endocytosis, endosomal and lysosomal proteases digest Tg and release T4 and T3 into the circulation. Degradation of T4 and T3 in the periphery—the half-life of circulating T4 is 5–8 d, and for T3, 1.5 to 3 d—releases iodine that enters the plasma iodine pool and can be taken up by the thyroid or excreted by the kidney (24). More than 90% of ingested iodine is ultimately excreted in the urine, with only a small amount appearing in the feces.
A. Thyroidal adaptation to iodine deficiency

The thyroid adapts to low intakes of dietary iodine by marked modification of its activity, triggered by increased secretion of TSH by the pituitary. In most individuals, if iodine intake falls below approximately 100 μg/d, TSH secretion is augmented, which increases plasma inorganic iodide clearance by the thyroid through stimulation of NIS expression. TSH exerts its action at the transcription level of the NIS gene through a thyroid-specific enhancer that contains binding sites for the transcription factor Pax8 and a cAMP response element-like sequence (25). As a greater fraction of circulating iodide is cleared by the thyroid, there is a progressive reduction in renal iodide excretion. TSH also stimulates breakdown of Tg and preferential synthesis and release of T3 into the blood (26). As long as daily iodine intake remains above a threshold of approximately 50 μg/d, despite a decrease in circulating plasma inorganic iodine, absolute uptake of iodine by the thyroid remains adequate, and the iodine content of the thyroid remains within normal limits (≈10–20 mg). Below this threshold, despite high fractional clearance of plasma inorganic iodine by the thyroid, absolute intake falls, the iodine content of the thyroid is depleted, and many individuals develop goiter (27).

In large colloid goiter, the configuration of Tg is abnormal, reducing the efficiency of thyroid hormone synthesis (28). Initially, goiters are characterized by diffuse, homogeneous enlargement, but over time, nodules often develop (Fig. 1⇓). Many thyroid nodules derive from a somatic mutation and are of monoclonal origin (29); the mutations appear to be more likely in nodules under the influence of a growth promoter, such as iodine deficiency. Although iodine deficiency produces diffuse goiter in all age groups, it is also associated with a high occurrence of multinodular toxic goiter mainly seen in women older than 50 yr (30). The characteristic pattern of circulating thyroid hormones in children in areas of moderate-to-severe iodine deficiency is a variably elevated TSH, a low serum T4, and a normal or high-normal T3; this pattern is also seen in adults, but less predictably, and it may not be present (31). The serum Tg concentration is typically elevated (32). Thyroid failure and cretinism usually develop only in regions of chronic, severe iodine deficiency where individuals show low circulating T4 and T3 and dramatically elevated TSH (33, 34). It should be emphasized that the effects of iodine deficiency on the development of goiter and thyroid hypofunction are extremely variable among populations and individuals, even in endemic areas. The dietary, environmental, and/or genetic factors that account for this variability in the expression of iodine deficiency from one locality to the next remain largely undefined.
Fig. 1.
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Fig. 1.

Large nodular goiter in a 14-yr-old boy photographed in 2004 in an area of severe IDD in northern Morocco, with tracheal and esophageal compression and hoarseness, likely due to damage to the recurrent laryngeal nerves.
B. Goitrogens

Dietary substances that interfere with thyroid metabolism can aggravate the effect of iodine deficiency, and they are termed goitrogens (35). Cruciferous vegetables, including cabbage, kale, cauliflower, broccoli, turnips, and rapeseed, contain glucosinolates; their metabolites compete with iodine for thyroidal uptake. Similarly, cassava, lima beans, linseed, sorghum, and sweet potato contain cyanogenic glucosides; these may be metabolized to thiocyanates that compete with iodine for thyroidal uptake. For example, linamarin is a thioglycoside found in cassava, a staple food in many developing counties. If cassava is not adequately soaked or cooked to remove the linamarin, it is hydrolyzed in the gut to release cyanide, which is metabolized to thiocyanate (36). Cigarette smoking is associated with higher serum levels of thiocyanate that may compete with iodine for uptake via the NIS into both the thyroid and the secretory epithelium of the lactating breast; smoking during the period of breastfeeding is associated with reduced iodine levels in breast milk (37).

Soy and millet contain flavonoids that may impair TPO activity. Use of soy-based formula without added iodine can produce goiter and hypothyroidism in infants, but in healthy adults, soy-based products appear to have negligible effects on thyroid function (38). Unclean drinking water may contain humic substances that block thyroidal iodination, and industrial pollutants, including resorcinol and phthalic acid, may also be goitrogenic (35). Perchlorate is a competitive inhibitor of thyroidal iodine uptake (39), but 6-month exposure to perchlorate at doses up to 3 mg/d has no effect on thyroid iodide uptake or serum levels of thyroid hormones (40). It appears that most of these goitrogenic substances do not have a major clinical effect unless there is coexisting iodine deficiency.

Deficiencies of selenium, iron, and vitamin A exacerbate the effects of iodine deficiency. Glutathione peroxidase and the deiodinases are selenium-dependent enzymes. In selenium deficiency, accumulated peroxides may damage the thyroid and deiodinase deficiency impairs thyroid hormone metabolism, and these effects have been implicated in the etiology of myxedematous cretinism (41). Iron deficiency reduces heme-dependent TPO activity in the thyroid and impairs production of thyroid hormone. In goitrous children, iron deficiency anemia blunts the efficacy of iodine prophylaxis whereas iron supplementation improves the efficacy of iodized oil and iodized salt (42). Pregnant women are highly vulnerable to iron deficiency anemia, and poor maternal iron status predicts both higher TSH and lower T4 concentrations during pregnancy in an area of borderline iodine deficiency (43). Vitamin A deficiency in iodine-deficient children increases TSH stimulation and risk for goiter through decreased vitamin A-mediated suppression of the pituitary TSHβ gene (44, 45).
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V. Requirements

Several methods have been used to estimate the requirement for iodine. Daily uptake and turnover of radioactive iodine can be used to estimate the requirement for iodine, provided that the subjects tested have adequate iodine status and are euthyroid (18, 46, 48). Several studies have estimated iodine requirements from balance studies (49, 50, 51, 52, 53), but these have serious limitations: many ingested substances contain unrecognized iodine, and strict control of iodine intake is difficult. Moreover, because of the need to consider the iodine in the thyroidal compartment in addition to iodine intake and excretion, even in prolonged balance studies equilibrium may not be clearly established (49).
A. Definitions

The following definitions are from the U.S. Institute of Medicine (IOM) (8) (Table 1⇓):

The estimated average requirement (EAR) is the daily iodine intake that meets the requirement of half of the healthy individuals in a particular life stage. The EAR is not meant to be used in the assessment of intake in individuals, but it can be used for groups.

The recommended dietary allowance (RDA) for iodine is the average daily intake sufficient to meet the iodine requirement of 97–98% of healthy individuals in a life stage. It can be used as a goal for daily iodine intake by individuals. The RDA is derived from the EAR, considering the estimated variability in individual requirements.

The adequate intake (AI) is given if there is insufficient scientific evidence to calculate an EAR. For example, the AI for iodine in infancy is based on observed mean iodine intakes by healthy full-term breastfed infants in iodine-sufficient areas. The AI is expected to meet or exceed the amount of iodine needed in “essentially all” individuals in the specified population group, and it can be used as a goal for individual intake.

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TABLE 1.

Recommendations for iodine intake (μg/d) by age or population group

The following definition is from the WHO (54):

The recommended nutrient intake (RNI) for iodine is the intake estimated to cover the needs of “nearly all” healthy individuals in the specified life stage.

B. Adulthood

Iodine turnover, thyroidal radioiodine uptake, and balance studies in euthyroid adults have suggested that the average daily requirement for iodine is 91–96 μg/d (18, 46, 50). There is no evidence to suggest that the average iodine requirement in adults varies with age. Thus, the EAR for iodine for men and nonpregnant, nonlactating women at least 14 yr of age from the IOM has been set at 95 μg/d (8). The corresponding RDA (defined as the EAR plus twice the coefficient of variation in the population, rounded to the nearest 50 μg) is 150 μg/d (8). This agrees with the WHO recommendation for adequate daily iodine intake of 150 μg/d for men and nonpregnant, nonlactating women (54).
C. Pregnancy and lactation

The iodine requirement during pregnancy is increased due to: 1) an increase in maternal T4 production to maintain maternal euthyroidism and transfer thyroid hormone to the fetus early in the first trimester, before the fetal thyroid is functioning; 2) iodine transfer to the fetus, particularly in later gestation; and 3) an increase in renal iodine clearance (55). Balance studies have found that the average iodine retention of full-term infants is 7.3 μg/kg · d (56, 57); the mean retention of a healthy fetus with a weight of 3 kg would be approximately 22 μg/d. Estimated daily fetal iodine retention added to the EAR of 95 μg/d for nonpregnant women would yield an EAR of 117 μg/d, but this would not take into account the iodine needed to increase maternal T4 production and balance additional urinary losses. Dworkin et al. (49) found five pregnant women were at balance when consuming approximately 160 μg/d, with no significant differences pre- and postpartum.

Several authors have roughly estimated iodine requirements during pregnancy by correlating the effects of iodine supplementation with changes in thyroid volume during pregnancy; in studies by Romano et al. (58) and Pedersen et al. (59), total daily iodine intakes of approximately 200 μg/d and 250–280 μg/d, respectively, during pregnancy prevented an increase in thyroid volume, whereas in a study of Glinoer (60), total daily iodine intake of approximately 150 μg/d was insufficient to prevent an increase in thyroid size. On the basis of the above data, the IOM set the EAR at 160 μg/d for pregnancy in women at least 14 yr of age and the RDA, set at 140% of the EAR rounded to the nearest 10 μg, at 220 μg/d (8). WHO recommends a daily iodine intake of 250 μg/d for pregnant women, a value approximately 10% higher than the RDA (54).

Based on mean breast milk excretion of 0.78 and 0.6 liters/d in the first and second 6 months of infancy, respectively (8), and a mean breast milk iodine concentration (BMIC) of 146 μg/liter in iodine-sufficient women from the United States, the average daily loss of iodine in breast milk has been estimated to be approximately 115 μg/d (8). Added to the EAR for nonpregnant women of 95 μg/d, the EAR for lactating women at least 14 yr of age is set at 209 μg/d by the IOM (8). The RDA is 140% of the EAR rounded to the nearest 10 μg, or 290 μg/d of iodine. WHO recommends a daily iodine intake of 250 μg/d for lactating women (54).
D. Infancy

Because no functional criteria are available that reflect iodine intake in infants, recommended intakes are based on mean iodine intake of healthy full-term infants fed human milk. The IOM based their recommendation on the median BMIC of women in the United States in the early 1980s, that is 146 μg/liter (8). Based on estimates of mean daily breast milk excretion, the mean amount of iodine secreted in human milk is estimated to be approximately 115 μg/d (8). Considering these data, the AI for iodine for infants ages 0–6 and 6–12 months from the IOM has been set at 110 and 130 μg/d, respectively (8), and WHO recommends a daily iodine intake of 90 μg/d for infants (54). But because iodine intakes in the U.S. population were excessive in the early 1980s (61), the BMIC used was at the upper end of the range of 78–167 μg/liter reported for iodine-sufficient countries (62). Although high maternal iodine intakes can result in high BMIC, iodine intakes by the infant greater than his or her requirements will simply be excreted in the urine. Thus, iodine requirements during lactation should be based on infant balance studies rather than the measured but variable amount excreted in breast milk from women in iodine-sufficient countries. Balance studies in full-term infants fed 20 μg/kg · d of iodine found that iodine retention was 7.3 μg/kg · d (57). If the reference body weight at 6 months of age is 7 kg (8), daily retention of iodine in a 6-month-old infant in positive balance is approximately 50 μg.
E. Childhood

In a balance study in children aged 1.5 to 2.5 yr (63), the median iodine intake was 63.5 μg/d, and the average iodine balance was +19 μg/d. Children 8 yr of age who consumed approximately 40 μg/d of iodine were in negative iodine balance (−23 to −26 μg/d), indicating that the average minimum requirement is approximately 65 μg/d (64). No other studies for assessing iodine requirements for young children are available; therefore an EAR of 65 μg/d was set for ages 1–8 yr (8). For the remainder of childhood and adolescence, there are few data available for estimating an average requirement, so the EAR was set by extrapolating down from adult data (8). The RDAs for childhood were then set at 140% of the EAR. WHO recommends a daily intake of iodine of 90 μg for preschool children (0 to 59 months) and 120 μg for schoolchildren (6 to 12 yr) (54).
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VI. Methods to Assess Status

Four methods are generally recommended for assessment of iodine nutrition in populations: urinary iodine concentration (UI), the goiter rate, serum TSH, and serum Tg. These indicators are complementary, in that UI is a sensitive indicator of recent iodine intake (days) and Tg shows an intermediate response (weeks to months), whereas changes in the goiter rate reflect long-term iodine nutrition (months to years).
A. Thyroid size

Two methods are available for measuring goiter: 1) neck inspection and palpation; and 2) thyroid ultrasonography. By palpation, a thyroid is considered goitrous when each lateral lobe has a volume greater than the terminal phalanx of the thumbs of the subject being examined. In the classification system of WHO (54), grade 0 is defined as 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 (i.e., the thyroid is not visibly enlarged), and grade 2 goiter is a thyroid that is clearly visible when the neck is in a normal position. Goiter surveys are usually done in school-age children.

However, palpation of goiter in areas of mild iodine deficiency has poor sensitivity and specificity; in such areas, measurement of thyroid volume by ultrasound is preferable (65). Thyroid ultrasound is noninvasive, quickly done (2–3 min per subject), and feasible even in remote areas using portable equipment. However, interpretation of thyroid volume data requires valid references from iodine-sufficient children. In a recent multicenter study, thyroid volume was measured in 6- to 12-yr-old children (n = 3529) living in areas of long-term iodine sufficiency on five continents. Age- and body surface area-specific 97th percentiles for thyroid volume were calculated for boys and girls (66). Goiter can be classified according to these international reference criteria, but the criteria are only applicable if thyroid volume is determined by a standard method (66, 67). Thyroid ultrasound is subjective and requires judgment and experience. Differences in technique can produce interobserver errors in thyroid volume as high as 26% (68).

In areas of endemic goiter, although thyroid size predictably decreases in children in response to increases in iodine intake, thyroid size may not return to normal for months or years after correction of iodine deficiency (69, 70). During this transition period, the goiter rate is difficult to interpret because it reflects both a population’s history of iodine nutrition and its present status. Aghini-Lombardi et al. (69) suggested that enlarged thyroids in children who were iodine deficient during the first years of life may not regress completely after introduction of salt iodization. If true, this suggests that to achieve a goiter rate below 5% in children may require that they grow up under conditions of iodine sufficiency. A sustained salt iodization program will decrease the goiter rate by ultrasound to less than 5% in school-age children, and this indicates disappearance of iodine deficiency as a significant public health problem (54). WHO recommends that the total goiter rate be used to define severity of iodine deficiency in populations using the following criteria: below 5%, iodine sufficiency; 5.0–19.9%, mild deficiency; 20.0–29.9%, moderate deficiency; and above 30%, severe deficiency (54).
B. Urinary iodine concentration

Because more than 90% of dietary iodine eventually appears in the urine (12, 53), UI is an excellent indicator of recent iodine intake. UI can be expressed as a concentration (micrograms per liter), in relationship to creatinine excretion (micrograms iodine per gram creatinine), or as 24-h excretion (micrograms per day). For populations, because it is impractical to collect 24-h samples in field studies, UI can be measured in spot urine specimens from a representative sample of the target group and expressed as the median, in micrograms per liter (54). Variations in hydration among individuals generally even out in a large number of samples, so that the median UI in spot samples correlates well with that from 24-h samples. For national school-based surveys of iodine nutrition, the median UI from a representative sample of spot urine collections from approximately 1200 children (30 sampling clusters of 40 children each) can be used to classify a population’s iodine status (54) (Table 2⇓). Although the median UI does not provide direct information on thyroid function, a low value suggests that a population is at higher risk of developing thyroid disorders.
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TABLE 2.

Epidemiological criteria from the WHO for assessment of iodine nutrition in a population based on median or range of UI (Refs. 4 and 54 )

However, the median UI is often misinterpreted. Individual iodine intakes and, therefore, spot UIs are highly variable from day to day (72), and a common mistake is to assume that all subjects with a spot UI less than 100 μg/liter are iodine deficient. To estimate iodine intakes in individuals, because of day-to-day variability, several 24-h collections are preferable but would be difficult to obtain. An alternative is to use the age- and sex-adjusted iodine:creatinine ratio in adults, but this also has limitations (73). Creatinine may be unreliable for estimating daily iodine excretion from spot samples, especially in malnourished subjects where creatinine concentration is low. Daily iodine intake for population estimates can be extrapolated from UI, using estimates of mean 24-h urine volume and assuming an average iodine bioavailability of 92% using the formula: urinary iodine (μg/liter) × 0.0235 × body weight (kg) = daily iodine intake (8). Using this formula, a median UI of 100 μg/liter corresponds roughly to an average daily intake of 150 μg.
C. Thyroid stimulating hormone

Because serum TSH is determined mainly by the level of circulating thyroid hormone, which in turn reflects iodine intake, TSH can be used as an indicator of iodine nutrition. However, in older children and adults, although serum TSH may be slightly increased by iodine deficiency, values often remain within the normal range (27, 31, 32, 33, 34). TSH is therefore a relatively insensitive indicator of iodine nutrition in adults. In contrast, TSH is a sensitive indicator of iodine status in the newborn period (74, 75), as discussed in Section VI.H.
D. Thyroglobulin

Tg is synthesized only in the thyroid and is the most abundant intrathyroidal protein. In iodine sufficiency, small amounts of Tg are secreted into the circulation, and serum Tg is normally less than 10 μg/liter (76). In areas of endemic goiter, serum Tg increases due to greater thyroid cell mass and TSH stimulation (43). Serum Tg is well correlated with the severity of iodine deficiency as measured by UI (77). Intervention studies examining the potential of Tg as an indicator of response to iodized oil and potassium iodide (KI) have shown that Tg falls rapidly with iodine repletion and that Tg is a more sensitive indicator of iodine repletion than TSH or T4 (78, 79). However, commercially available assays measure serum Tg, which requires venipuncture, centrifugation, and frozen sample transport, which may be difficult in remote areas.

A new assay for Tg has been developed for dried blood spots taken by a finger prick (80, 81), simplifying collection and transport. In prospective studies, dried blood spot Tg has been shown to be a sensitive measure of iodine status and reflects improved thyroid function within several months after iodine repletion (80, 81). However, several questions need to be resolved before Tg can be widely adopted as an indicator of iodine status. One question is the need for concurrent measurement of anti-Tg antibodies to avoid potential underestimation of Tg; it is unclear how prevalent anti-Tg antibodies are in iodine deficiency or whether they are precipitated by iodine prophylaxis (82, 83). Another limitation is large interassay variability and poor reproducibility, even with the use of standardization (76). This has made it difficult to establish normal ranges and/or cutoffs to distinguish severity of iodine deficiency. However, recently an international reference range and a reference standard for dried blood spot Tg in iodine-sufficient schoolchildren (4–40 μg/liter) has been made available (81).
E. Thyroid hormone concentrations

In contrast, thyroid hormone concentrations are poor indicators of iodine status. In iodine-deficient populations, serum T3 increases or remains unchanged, and serum T4 usually decreases (27, 31). However, these changes are often within the normal range, and the overlap with iodine-sufficient populations is large enough to make thyroid hormone levels an insensitive measure of iodine nutrition (54).
F. Assessing status during pregnancy

The median UI is recommended by WHO/International Council for the Control of Iodine Deficiency Disorders (ICCIDD)/UNICEF (54) for assessing iodine nutrition in pregnant women. The expected UI in micrograms per liter can be extrapolated from a recommended daily iodine intake, assuming median 24-h urine volumes for girls aged 7–15 yr of 0.9 ml/h/kg (84) and for adult women of approximately 1.5 liters (85), and assuming a mean iodine bioavailability of 92%. Thus, the recommended daily iodine intakes for pregnancy of 220 to 250 μg (8, 54) would correspond to a UI of approximately 135–150 μg/liter. Pregnancy may occur in adolescence, particularly in developing countries; in a 15-yr-old girl weighing approximately 50 kg, daily iodine intake of 220 and 250 μg would correspond to a UI of approximately 185–215 μg/liter.

However, during pregnancy this estimation of intake from UI may be less valid due to an increase in glomerular filtration rate (86) and, possibly, renal iodine clearance (RIC) (87). If RIC increases in pregnancy, the daily iodine intake extrapolated from the UI in pregnancy would be lower than that in nonpregnancy. However, the evidence for an increase in RIC and a decrease in plasma inorganic iodide (PII) concentration during pregnancy is equivocal. One study (87) suggested an increase in RIC using an indirect method, whereas Liberman et al. (88) directly measured PII and reported no significant difference in PII or UI during pre- and postpartum in 16 women, but they were from an area of high iodine intake. The iodine balance study by Dworkin et al. (49) also found no differences in UI pre- and postpartum. It is unclear whether pregnancy per se significantly increases UI.

Considering this uncertainty, a recent WHO expert group recommended the median UI that indicates adequate iodine intake during pregnancy to be 150–249 μg/liter (54) (Table 2⇑). However, WHO emphasized that the scientific evidence on which the recommendation is based is weak, and that more data are needed on the level of iodine intake (and the corresponding UI) that ensures maternal and newborn euthyroidism. Also, the median UI is a population indicator and should not be used for the purpose of individual diagnosis and treatment of pregnant women (89).

Using a median cutoff of 150 μg/liter, several recent studies have found marginal or deficient iodine status in pregnant women from areas with only partial household coverage with iodized salt, including Italy, India, Thailand, and the United States (90, 91, 92, 93). Traditionally, the median UI in school-aged children is recommended for assessment of iodine nutrition in populations. If the median UI is adequate in school-aged children, it is usually assumed that iodine intakes are also adequate in the remaining population, including pregnant women. However, a recent Thai study within families eating from the same household food basket found that the median UI in schoolchildren was 200 μg/liter, whereas the median UI in their pregnant mothers was only 108 μg/liter (92). Thus, the median UI in school-aged children may not always be a good surrogate for monitoring iodine status in pregnancy; it may be prudent to monitor pregnant women directly. More studies in other populations are needed to clarify this issue.
G. Assessing status during lactation

Because the mammary gland is able to concentrate iodine, iodine supply to the newborn via the breast milk may be maintained even in the face of maternal iodine deficiency (94, 95). This may help explain why, in areas of iodine deficiency, BMICs are often greater than expected based on the UI of the lactating mother (95, 96, 97). For example, a recent study in lactating women in the United States with a median UI of 114 μg/liter reported a median BMIC of 155 μg/liter (range, 3–1968 μg/liter) (96).

Based on the balance studies of Delange et al. (57), the full-term infant’s requirement for iodine is approximately 7 μg/kg. Based on mean breast milk excretion of 0.78 liters in the first 6 months of infancy (8), and assuming that the iodine in breast milk is 95% absorbed, a BMIC of at least 80 μg/liter would likely cover the infant’s iodine requirement (approximately 50 μg/d) until weaning foods are begun. Most infants begin weaning by the second half of the first year, and some of the iodine requirement during that period will be met by weaning foods. Semba and Delange (97) proposed that a potential indicator of iodine status in a population could be the proportion of lactating women whose BMIC is at least 100 μg/liter. There is no consensus on what an adequate BMIC is, and WHO has not made a recommendation on this issue. A review of BMIC among the iodine-sufficient countries reported a wide range of mean or median concentrations, from 50 μg/liter in Finland to 270 μg/liter in the United States, but sample sizes were small and not representative, making it difficult to draw conclusions (62).

For the mother, although the iodine requirement is high (200–290 μg/d), after accounting for iodine losses into breast milk, the median UI in lactating women that indicates adequate iodine nutrition is the same as that of nonpregnant, nonlactating women (54) (Table 2⇑).
H. Assessing status during infancy

WHO recommendations state that a median UI of at least 100 μg/liter in infants is sufficient (54). At the same time, they recommend an iodine intake of 90 μg/d during infancy (54) and suggest extrapolating from this to a median UI assuming a urine volume of 300–500 ml/d, but this would produce a higher cutoff of at least 180 μg/liter. To clarify this, UI was recently measured in a representative national sample of healthy, full-term, iodine-sufficient, euthyroid, breastfeeding Swiss infants in the first week after birth (98). Median UI was 77 [95% confidence interval (CI), 76–81] μg/liter, suggesting that the current WHO median UI cutoff for iodine sufficiency in infancy (≥100 μg/liter) may be too high for the first week after birth. Extrapolating from this median UI, assuming a urine volume of 300–500 ml/d, suggests that the mean daily iodine intake in iodine-sufficient Swiss newborns in the first week is 30–50 μg/d. This estimated iodine intake is consistent with data from balance studies in infants that suggest that the mean iodine requirement is likely not more than 8–10 μg/kg · d, and the estimated infant requirement of 40 μg iodine/d in the 1989 U.S. RDA extrapolated from the relative energy requirements of adults (98, 99). These data suggest that the current recommendations for iodine intake in early infancy of 90–110 μg/d (8, 54) are too high. More data are needed to clarify this issue. Worldwide, access by health workers to newborns in the first few days after birth is generally good; establishing a firm UI reference range for iodine-sufficient newborns and a simple collection system would facilitate use of UI as an indicator of iodine status in this age group.

TSH screening in newborns may also be useful in assessing iodine status (100, 101, 102, 103, 104, 105). TSH is used in many countries for routine newborn screening to detect congenital hypothyroidism. If already in place, such screening offers a sensitive indicator of iodine nutrition (54). Newborn TSH is an important measure because it reflects iodine status during a period when the developing brain is particularly sensitive to iodine deficiency. Compared with the adult, the newborn thyroid contains less iodine but has higher rates of iodine turnover. Particularly when iodine supply is low, maintaining high iodine turnover requires increased TSH stimulation. Serum TSH concentrations are therefore increased in iodine-deficient infants for the first few weeks of life, a condition termed transient newborn hypothyroidism. In areas of iodine deficiency, an increase in transient newborn hypothyroidism, indicated by more than 3% of newborn TSH values above the threshold of 5 mU/liter whole blood collected 3 to 4 d after birth, suggests iodine deficiency in the population (54). Recent data from a large representative Swiss study suggest that newborn TSH, obtained with the use of a sensitive assay on samples collected 3–4 d after birth, is a sensitive indicator of even marginal iodine nutrition in pregnancy (75). This cutoff needs confirmation in other iodine-sufficient countries with newborn screening programs.
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VII. Effects of Deficiency through the Life Cycle

Iodine deficiency has multiple adverse effects on growth and development in animals and humans. These are collectively termed the iodine deficiency disorders (IDDs) (Table 3⇓) and are one of the most important and common human diseases (3, 4). They result from inadequate thyroid hormone production due to lack of sufficient iodine.
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TABLE 3.

IDDs by age group (Refs. 3 and 4 )
A. Pregnancy and infancy

In areas of iodine sufficiency, healthy women maintain iodine stores of 15–20 mg in the thyroid. During pregnancy, to help meet the approximately 50% increase in maternal iodine requirements, women may draw on this significant iodine store (55, 106, 107). However, in areas of chronic iodine deficiency, women enter pregnancy with already depleted iodine stores. With little thyroidal iodine to draw on to meet the increased maternal iodine requirement, pathological changes—goiter and hypothyroidism—may occur that can adversely affect maternal and fetal health.
1. Neurological development of the offspring

In areas of severe chronic iodine deficiency, maternal and fetal hypothyroxinemia can occur from early gestation onward (108). Thyroid hormone is required for normal neuronal migration; myelination of the brain during fetal and early postnatal life and hypothyroxinemia during these critical periods causes irreversible brain damage, with mental retardation and neurological abnormalities (109). The consequences depend upon the timing and severity of the hypothyroxinemia.

In McCarrison’s (109) original description of cretinism in northern India, he delineated a neurological form, with predominantly neuromotor defects, and a myxedematous form, marked by severe hypothyroidism and short stature. His observations were expanded on by subsequent authors (110, 111). The three characteristic features of neurological cretinism in its fully developed form are severe mental retardation with squint, deaf mutism, and motor spasticity (Fig. 2A⇓). 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. Vision is unaffected, whereas deafness is characteristic. This may be complete in as many as 50% of cretins, as confirmed by studies of auditory brainstem-evoked potentials. The motor disorder shows proximal rigidity of both lower and upper extremities and the trunk, and corresponding proximal spasticity with exaggerated deep tendon reflexes at the knees, adductors, and biceps (100). Spastic involvement of the feet and hands is unusual, and their function is characteristically preserved so that most cretins can walk. This may be useful in differentiating cretinism from other forms of cerebral palsy commonly encountered in endemic areas, such as cerebral palsy from birth injury or meningitis.
Fig. 2.
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Fig. 2.

Neurological cretinism. This 2007 photograph of a 9-yr-old girl from western China demonstrates the three characteristic features: severe mental deficiency together with squint, deaf mutism, and motor spasticity of the arms and legs. The thyroid is present, and frequency of goiter and thyroid dysfunction is similar to that observed in the general population. B, Myxedematous cretinism. This 2008 photograph of a 7-yr-old girl from western China demonstrates the characteristic findings: profound hypothyroidism, short stature (height, 106 cm), incomplete maturation of the features including the naso-orbital configuration, atrophy of the mandible, myxedematous, thickened and dry skin, and dry hair, eyelashes, and eyebrows. The thyroid typically shows atrophic fibrosis.

The typical myxedematous cretin (Fig. 2B⇑) has a less severe degree of mental retardation than the neurological cretin but has all the features of severe hypothyroidism present since early life, including severe growth retardation, incomplete maturation of the features including the nasoorbital configuration, atrophy of the mandibles, puffy features, myxedematous, thickened and dry skin, dry and rare hair, and delayed sexual maturation. In contrast to the general population and with neurological cretinism, goiter is usually absent, and the thyroid is usually atrophic (101). Circulating T4 and T3 are extremely low, often undetectable, and TSH is dramatically high. It may be difficult to differentiate between these two forms of cretinism; cretinism may present as a mixed form with features of both (100, 101).

Whether mild-to-moderate maternal iodine deficiency causes more subtle impairment of cognitive and/or neurological function in the offspring is uncertain. Two case-control studies in iodine-sufficient women with mild thyroid hypofunction have reported developmental impairment in their offspring. In the United States (112), the IQ scores of 7- to 9-yr-old children of mothers with subclinical hypothyroidism during pregnancy (an increased TSH in the second trimester) were 7 points lower compared with children from mothers with normal thyroid function during pregnancy. In The Netherlands (113), infant development to 2 yr was impaired in children of women with a free T4 (FT4) below the 10th percentile at 12 wk gestation. These studies suggest that cognitive deficits may occur in the offspring even if maternal hypothyroidism is mild and asymptomatic. However, the maternal thyroid dysfunction in these studies was presumably not due to iodine deficiency because they were done in iodine-sufficient populations. It is unclear whether maternal hypothyroxinemia and/or subclinical hypothyroidism occurs in otherwise healthy pregnant women with mild-to-moderate iodine deficiency (see discussion in Section VII.A).
2. Controlled interventions in severe deficiency

In a landmark trial in an area of severe iodine deficiency in Papua New Guinea (114, 115), alternate families received saline (control) or iodized oil injection. The primary outcome was the prevalence of cretinism at 4- and 10-yr follow-up, with more sensitive diagnostic tests applied at the 10-yr follow-up. Iodine supplementation was associated with a significant reduction in the prevalence of endemic cretinism: at 4 yr of age, the relative risk (95% CI) was 0.27 (0.12–0.60), and at 10 yr of age, the relative risk (95% CI) was 0.17 (0.05–0.58). The authors carried out a long-term follow-up on a small subsample of noncretinous children at 11 and 15 yr of age (116) and found no significant differences in motor and cognitive function between the children born to supplemented families and controls.

In a study in Zaire, participants were pregnant women attending antenatal clinics in an area of severe iodine deficiency with a 4% cretinism rate (117, 118, 119). Pregnant women were randomly allocated to two groups: one received iodized oil injection, the other an injection of vitamins. Women were on average 28 wk pregnant when they were treated. Psychomotor development scores were measured in the offspring at approximately 72 months of age, but there was a loss to follow-up of approximately 50% in both groups. The psychomotor development scores were significantly higher in the iodine group (mean psychomotor development score, 91 ± 13 vs. 82 ± 14), and treatment resulted in far fewer children with low psychomotor scores (0.5% with a score ≤.60 vs. 9.7% in the control group).

In a study in western China, an area of severe iodine deficiency and endemic cretinism, participants were groups of children from birth to 3 yr and women at each trimester of pregnancy (120). Untreated children 1–3 yr of age, who were studied when first seen, served as controls. The intervention was oral iodized oil, and treated children and the babies born to the treated women were followed for 2 yr. The main outcomes were neurological examination, head circumference, and indexes of cognitive and motor development. A small subsample was followed to approximately 7 yr of age (121). The prevalence of moderate or severe neurological abnormalities among the infants whose mothers received iodine in the first or second trimester was 2%, as compared with 9% among the infants who received iodine during the third trimester (through the treatment of their mothers) or after birth. Treatment in the third trimester of pregnancy or after delivery did not improve neurological status, but head growth and developmental quotients improved slightly. Treatment at the end of the first trimester did improve neurological outcome. The prevalence of microcephaly was 27% in the untreated children compared with 11% in the treated children. The mean (±sd) developmental quotient at 2 yr of age was higher in the treated than in the untreated children (90 ± 14 vs. 75 ± 18) (120).

In the long-term follow-up study (121), development of children (range, 4 to 7.3 yr) whose mothers received iodine during pregnancy and children who received iodine first in their second year was examined. A second group of children (range, 5.8 to 6.9 yr) whose mothers received iodine while pregnant were examined 2 yr later. Head circumference was improved for those who received iodine during pregnancy (compared with those receiving iodine at age 2) and for those supplemented before the end of the second trimester (relative to those supplemented during the third trimester). Iodine before the third trimester predicted higher psychomotor test scores for children relative to those provided iodine later in pregnancy or at 2 yr (121).

In a randomized Peruvian trial (122, 123), women of childbearing age from three Andean villages in an area of severe iodine deficiency with a 1–3% cretinism rate were studied. The treatment group received iodized oil injection either before conception or during pregnancy; the control group did not receive an injection. Cognitive development scores were done in a subsample of their children between 1 and 4 yr of age. The initial publication did not find a statistical difference in cognitive outcomes (122). A subsequent reanalysis reassigned children to two groups, iodine-deficient or iodine-sufficient at time of cognitive testing, based on their UI and concentration of T4. This analysis found a significantly higher IQ score in the iodine-sufficient group compared with the iodine-deficient group (85.6 ± 13.9 vs. 74.4 ± 4.8) (123).

In two villages in Ecuador with severe iodine deficiency and a cretinism rate of up to 8%, one village received iodine treatment, and one did not and served as an iodine-deficient control (124). Participants were all women of childbearing age, pregnant women, and children, and coverage with iodine was estimated to be about 90%. The treatment group received one iodized oil injection at baseline and were followed at 4-yr intervals for approximately 20 yr. A series of follow-up studies was done to look at the effects in offspring (124, 125). No more cretins were born in the treated village. Two years after treatment began, the mean developmental quotient in infancy was not significantly different between villages. However, mean IQ measured in first- and second-grade children was higher by approximately 10 points in the treated village than in the control village. Five years after treatment began, the treated group was divided into three subgroups: 1) children born after treatment had begun; 2) children whose mothers had received iodine during pregnancy; and 3) children whose mothers had received iodine before conception. The latter subgroup had significantly higher IQ than the first two groups (72.3 vs. 65.2 vs. 76.8, respectively). Studies done several years later in these children also suggested that iodine treatment late in pregnancy or afterward had no benefits for children’s IQ at 3–5 yr of age, but treatment early in pregnancy or before conception improved IQ (83.7 ± 13.4 vs. 72.7 ± 14.0 in treated vs. control villages) (125).

These five intervention trials were groundbreaking studies done under difficult conditions in remote areas (1114–125). The Papua New Guinea study had the strongest design and clearly demonstrates that iodine treatment in a population with high levels of endemic cretinism sharply reduces or eliminates incidence of the condition. The Zaire and China trials report that developmental scores were 10–20% higher in young children born to mothers treated during pregnancy or before. The studies in Peru and Ecuador were less well controlled but also suggest modest cognitive benefits for infants and children of maternal iodine treatment. Although the data from the Zaire trial indicate that correction of iodine deficiency even at mid-to-late pregnancy improves infant cognitive development, data from the other trials suggest that the neurological deficits can only be prevented when iodine is given before or early in pregnancy.
3. Controlled interventions in mild-to-moderate deficiency

The cognitive deficits associated with iodine deficiency may not be limited to remote, severely iodine-deficient areas. Several authors have argued that even mild-to-moderate iodine deficiency in pregnancy, still present in many countries in Europe, may affect cognitive function of the offspring (58, 59, 60, 126, 127, 128). The controlled trials of iodine treatment in mild-to-moderately iodine-deficient pregnant women discussed in the following paragraphs did not report data on infant or child development. However, several reported measures might be surrogate markers of future infant development, including maternal and newborn thyroid function.

Romano et al. (58) gave 120–180 μg iodine as iodized salt or control daily beginning in the first trimester to healthy pregnant Italian women (n = 35; median UI, 31–37 μg/liter). In the treated group, median UI increased 3-fold, and thyroid volume did not change. In the controls, there was no change in UI, but a 16% increase in thyroid volume. Treatment had no effect on maternal TSH. Pedersen et al. (59) randomized pregnant Danish women (n = 54) to receive either 200 μg iodine/d as KI solution or no supplement from 17 wk to term. Median UI increased from 55 to 90–110 μg/liter in the treated group. Maternal thyroid volume increased 16% in the treated group vs. 30% in controls. Maternal Tg and TSH and cord Tg were significantly lower in the treated group. No significant differences were found between groups comparing maternal or cord T4, T3, and FT4. In a double-blind, placebo-controlled trial, Glinoer et al. (60) supplemented pregnant Belgian women (n = 120; median UI, 36 μg/liter; biochemical criteria of excess thyroid stimulation) with 100 μg iodine/d or control from approximately 14 wk gestation to term. Treatment had no significant effect on maternal or cord T3, FT4, and T3/T4 ratio. The treated women had significantly higher UI, smaller thyroid volumes, and lower TSH and Tg concentrations, compared with controls. Newborns of the treated group also had significantly higher UI, smaller thyroid volumes, and lower Tg concentrations compared with controls.

Liesenkötter et al. (126) reported results from a quasi-random, controlled trial of 230 μg iodine/d from 11 wk to term in pregnant German women (n = 108; median UI, 53 μg/g creatinine; goiter rate, 42.5%). Median UI increased to 104 μg/g creatinine in the treated group, and median thyroid volume was significantly lower in the newborns of the treated women compared with controls (0.7 vs. 1.5 ml, respectively). Treatment had no significant effect on maternal TSH, T3, T4, thyroid volume, or Tg, and had no effect on newborn TSH. In a placebo-controlled, double-blind trial, Nøhr et al. (127) gave a multinutrient supplement containing 150 μg iodine/d or control to pregnant Danish women positive for anti-TPO antibodies (n = 66) from 11 wk gestation to term. Median UI was significantly higher in the treated women at term, but there were no differences in maternal TSH, FT4, or Tg between groups. Finally, in a prospective, randomized, open-label trial, Antonangeli et al. (128) supplemented pregnant Italian women (n = 67; median UI, 74 μg/g creatinine) with 50 or 200 μg iodine/d from 18–26 wk to 29–33 wk. Median UI was significantly higher in the 200-μg group than in the 50-μg group (230 vs. 128 μg/g creatinine). However, there were no differences in maternal FT4, FT3, TSH, Tg, or thyroid volume between groups.

These studies suggest that in areas of mild-to-moderate iodine deficiency, the maternal thyroid is able to adapt to meet the increased thyroid hormone requirements of pregnancy (106). Although supplementation was generally effective in minimizing an increase in thyroid size during pregnancy, only two of the six studies reported that maternal TSH was lower (within the normal reference range) with supplementation, and none of the studies showed a clear impact of supplementation on maternal and newborn total or free thyroid hormone concentrations. Thyroid hormone concentrations may be the best surrogate biochemical marker for healthy fetal development (111). Thus, the results of these trials are reassuring (106). However, because none of the trials measured long-term clinical outcomes such as maternal goiter or infant development, the potential adverse effects of mild-to-moderate iodine deficiency during pregnancy remain unclear.

In areas of mild-to-moderate iodine deficiency, pregnancy has often been suggested as an environmental factor contributing to a higher prevalence of goiter and thyroid disorders in women, compared with men. But the data to support this are scarce. In European studies, an uncontrolled prospective study in 10 women (130), a retrospective study (131), and a cross-sectional study in smoking women (132) suggest that goiters formed during pregnancy may only partially regress after parturition.
4. Infant mortality

Infant survival is improved in infants born to women whose iodine deficiency is corrected before or during pregnancy. In areas of severe iodine deficiency, there is an inverse relationship between levels of maternal T4 during pregnancy and death rates in the offspring (133). DeLong et al. (134) added potassium iodate to irrigation water over a 2- to 4-wk period in three areas of severe iodine deficiency in China and found a large reduction in both neonatal and infant mortality in the following 2–3 yr compared with areas that did not receive iodine. The median UI increased in women of childbearing age from less than 10 to 55 μg/liter, whereas the infant mortality rate (IMR) decreased in the three treated areas from a mean of 58.2 to 28.7/1000 births, from 47.4 to 19.1/1000, and from 106.2 to 57.3/1000. Similar results were also observed for neonatal mortality; the odds of neonatal death were reduced by about 65% in the population who had iodine treatment.

Iodized oil given im to iodine-deficient pregnant women in Zaire at approximately 28 wk gestation decreased infant mortality (135). In severely iodine-deficient women, the IMR in infants of treated and untreated mothers was 113/1000 and 243/1000 births, respectively, and in women with mild or moderate iodine deficiency, the IMR with and without treatment was 146/1000 and 204/1000 births, respectively. In Algeria, rates of abortion, stillbirth, and prematurity were significantly lower among women given oral iodized oil 1–3 months before conception or during pregnancy than among untreated women (136).

Infant survival may also be improved by iodine supplementation in the newborn period. A randomized, placebo-controlled trial of oral iodized oil (100 mg iodine) was conducted in an area of presumed iodine deficiency in Indonesia to evaluate the effect on mortality (137). The iodine or placebo was given in conjunction with oral poliovirus vaccine; infants (n = 617) were treated at approximately 6 wk of age and were followed to 6 months of age. There was a significant 72% decrease in risk of infant death during the first