In 2001, the World Health Organization officially endorsed recommendations made by international organizations such as the ICCIDD (International Council for Control of Iodine Deficiency Disorders) and UNICEF (United Nations Children’s Fund) to eliminate iodine deficiency disorders, on the basis that iodine deficiency present at critical stages during pregnancy and early childhood resulted in impaired development of the brain and consequently in impaired mental function [91]. Although a variety of methods exists for the correction of iodine deficiency, the most commonly accepted and applied method is universal salt iodization (USI), i.e., the addition of suitable amounts of potassium iodide (or iodate) to all salt for human and livestock consumption.

In 2005, a WHO Technical Consultation has produced new guidelines for the iodine requirements and monitoring of iodine nutrition status in high risk groups such as pregnant and lactating women [1, 92-94]. Before becoming pregnant, women should ideally have an average daily iodine intake of 150 μg, to ensure that their intra-thyroidal iodine stores are replenished before pregnancy. Population studies carried out in the 1990s have shown that when women with an iodine intake of <100 μg/d become pregnant, the pregnancies are frequently associated with thyroid function abnormalities (mainly maternal hypothyroxinemia), resulting in excessive thyroidal stimulation and goiter formation in both the mother and offspring [4, 95-99]. The general consensus reached by the WHO Technical Consultation in 2005 was that the recommended nutrient intake (RNI) for iodine during pregnancy and breast-feeding should range between 200 and 300 μg per day, with an average of 250 μg per day. Several pregnancy population studies, carried out between 1981 and 2002, have shown that iodine supplementation maintained a normal thyroid function, thus allowing maternal hypothyroxinemia to be avoided and maternal and neonatal goitrogenesis to be prevented [11, 100-106].

With regard to the upper limit of safety for the iodine intake in pregnancy, excessive levels of iodine intake may potentially cause more disease. Furthermore, certain individuals must be identified who may have side effects from excessive iodine intake, such as patients with known or underlying autoimmune thyroid disorders or autonomous thyroid tissue. Since there is no strong evidence to define clearly “how much more iodine may become too much iodine,” the most reasonable recommendation was to indicate that there is no proven further benefit in providing pregnant women with more than twice the daily RNI.

Finally with regard to iodine nutrition during breast-feeding, thyroid hormone production and urinary iodine excretion return to normal, but iodine is efficiently concentrated by the mammary gland. Since breast milk provides approximately 100 μg/d of iodine to the infant, it is recommended that the breast-feeding mother should continue to take 250 μg per day of iodine (see Table 14-2).

Following the introduction of a policy of universal salt iodization (USI), remarkable progress has been accomplished towards the control and eradication of iodine deficiency disorders [107]. A recent review of the ‘Thyromobil’ campaigns by Delange et al., that concerned several surveys of over 38,000 schoolchildren from 32 countries across four continents, showed that the progress in the control of IDD worldwide was due to the implementation of effective programs of USI [108].

What is the iodine nutritional situation concerning women in the childbearing age. Despite national efforts to implement the mandatory use of iodized salt, that has been in place in Switzerland – a naturally iodine-deficient country for many years –, two recent studies have shown that mild iodine deficiency still prevailed in pregnant women in the Bernese area [109, 110]. Only by constantly monitoring the iodine nutritional status in the general population, and particularly that of women in the reproductive age and during pregnancy, was the new tendency towards a resurgence of iodine deficiency discovered. These findings eventually led the sanitary Swiss authorities in 1988 to further increase the iodine content of household salt above the 20 μg I/g salt content that had been in place since 1980.

Another study deserves a comment. Authors have investigated changes in serum TSH near the end of pregnancies in Columbia, a country where iodized salt is used to correct IDD. In pregnant women who were submitted to salt restriction during pregnancy, a significant fraction of them (~50%) showed a significant TSH elevation at the time of delivery, with a rapid normalization in the weeks following parturition. Such data emphasize the important public health concept that in areas where the use of iodized salt has been implemented to prevent iodine deficiency, any cause of dietary salt restriction, when it is superimposed to the iodine restriction which is common in the pregnant state, may aggravate further the risk of becoming hypothyroid. Therefore, when salt restriction is prescribed, it is highly recommended to monitor serum TSH changes and provide supplements of iodine during pregnancy [111].

Another important epidemiological consideration is that the risk of iodine deprivation during pregnancy needs to be assessed locally and also closely monitored over time, because mild to moderate iodine deficiency may occur in areas that are not immediately recognized as iodine-deficient. For instance, the southwestern city of Toulouse (France) was not particularly known to be iodine deficient because of its relative proximity from the sea and the fish-eating habits in the population. Nevertheless, a study performed in 1997 in a cohort of pregnant women from this area clearly showed that the urinary iodine excretion levels were too low, with over 75 % of pregnant women having excretion levels below 100 μg/L [95].

Yet another epidemiological concept relates to the notion that the iodine intake in a given country may vary unexpectedly from one area to another. This occurs frequently in regions with mild to moderate iodine deficiency, because of significant variations in the ‘natural’ iodine content of food and water. A good example of this geographical variation was illustrated by a Danish study [97]. In Copenhagen, pregnant women without iodine supplements had a median iodine excretion level of 62 μg/g creatinine, compared with only 33 μg/g creatinine in East Jutland. Furthermore, these striking differences were not alleviated in the pregnant women from the same two areas who received iodine supplements: 74 μg/g creatinine in Copenhagen versus 34 μg/g creatinine in East Jutland. These results indicated that iodine supplementation was insufficient and their beneficial effects did not show up in urinary excretion values, presumably because the iodine supplements were entirely taken up by the iodine-deficient – and hence stimulated – maternal thyroid glands.

A final general epidemiological concept is that iodine deficiency requires constant monitoring, even after the implementation of iodine supplementation in pregnant women. Since our initial studies on iodine deficiency during pregnancy in the early 90s, the majority of pregnant women nowadays receive multivitamin pills in Brussels, containing 100-125 μg iodine as a daily supplement. Despite this public health effort and improved medical awareness, a recent study of neonates in Brussels showed that their iodine nutrition status, albeit improved, had not yet normalized [112].

What about the iodine nutrition status in pregnant women in the USA? The Public Health Affairs committee of the American Thyroid Association has recently reviewed the status of iodine nutritional requirements in women in the childbearing period and during pregnancy [113]. The committee reviewed the different sources of dietary iodine in the population of the USA & Canada (salt, dairy products, vitamin/mineral preparations, etc.) and recommended a daily iodine intake for non-pregnant (and non-lactating) adults of 150 μg/day of iodine.

The committee assessed the available information on iodine excretion levels in the USA. The successive National Health and Nutrition Examination (NHANES) surveys in the USA have clearly identified a marked decrease in urinary iodine concentrations (UIC), from a median of 321 μg/L (1971-1974) to 145 μg/L (1988-1994), with a stabilisation thereafter: 161 μg/L (2000) and 168 μg/L (2001-2002) [114, 115]. Concerning the women in childbearing age and pregnant, the two most recent NHANES surveys also showed that median urinary iodine excretion levels were adequate overall: 127 and 141 μg/L, respectively (1988-94), and 132 and 173 μg/L, respectively (2001-02). However, and despite the adequacy of iodine nutrition in the general population in the USA, it was important to note that 11-12% of the general population had a UIC <50 μg/L, naturally raising a concern that iodine deficiency might still be present during pregnancy [116, 117]. For women in the reproductive age (15-44 yrs), the prevalence of this target population excreting less than 50 μg of iodine/L reached 15.3% in 1988-1994 and increased slightly to 16.8% in 2001-2002. A similar trend was observed for the small number of pregnant women who were included in these surveys, with 6.9% of them excreting <50 μg/L of iodine (1988-1994) and 7.3% (2001-2002) [118].

Thus, America’s diet appears to be generally iodine-sufficient, although it is highly variable from food to food, and even among foods within the same category (dairy products, for instance). There are likely to be some outliers where iodine intake may be insufficient for some people (and potentially excessive for others). One of the weaknesses of the NHANES surveys is that their design (with total anonymity) did not allow to pinpoint the geographical regions or socio-economic sections of North America where these ‘outliers’ may be more prevalent. The current data did not lead the committee to recommend iodine fortification in the diet for the population as a whole. However, for the specific case of pregnant women and women in the childbearing period, the committee did encourage manufacturers to include 150 μg of iodine in all vitamin/mineral preparations labeled for use during pregnancy and lactation. The committee also insisted on the importance of continuously monitoring the iodine nutrition status in the US population, including larger sampling of pregnant women in future surveys. The committee came to the conclusion that until additional physiologic outcome data become available, supplementation of pregnant and lactating women with 150 μg of iodine per day was in keeping with the current international recommendations and appeared safe. In a recent letter to the editor of Thyroid, Sullivan wrote that the recommendations of the committee to provide iodine supplementation during pregnancy had some inherent – and highly important – limitations [119]. He noted for instance that many prenatal multivitamin pills do not include iodine and also that many pregnant women will not use supplements on a regular basis.

In summary, the degree of iodine deficiency should be assessed in each concerned area specifically and the local situation correctly evaluated before embarking on medical recommendations for adequate iodine supplementation programs. Iodine deficiency becomes significant during pregnancy when the iodine intake falls below 100 μg/day (see Figure 14-8).

After reduction to iodide, dietary iodine is rapidly absorbed from the gut. Then, iodide of dietary origin mixes rapidly with iodide resulting from the peripheral catabolism of thyroid hormones and iodothyronines by deiodination, and together they constitute the extra-thyroidal pool of inorganic iodide (PII). This pool is in a dynamic equilibrium with two main organs, the thyroid gland and the kidneys. Figure 14-9 schematically compares the kinetics of iodide in non-pregnant healthy adults with two different intake levels [a) adequate = 150 μg/day; and b) restricted = 70 μg/day] to the pregnancy situation with a comparable iodine intake of 70 μg/day. A normal adult utilizes ~80 μg of iodide to produce thyroid hormones (TH) and the system is balanced to fulfill these daily needs. When the iodine intake is adequate (150 μg/day, the average situation in the U.S., for instance) in non-pregnant conditions, a kinetic balance is achieved with a 35 % uptake of the available iodine by the thyroid (Figure 9; panel A). From the 80 μg of hormonal iodide produced each day by TH catabolism, 15 μg of iodide is lost in the feces, leaving 65 μg to be redistributed between the thyroid compartment (hence, providing 25 μg for daily TH production) and irreversible urinary losses. In such conditions, the metabolic balance is in equilibrium, with 150 μg of iodide ‘in’ & the same amount ‘out’, and 80 μg available for daily hormone production. Thus, with an iodine intake level of 150 μg/day (or above) in non-pregnant healthy adults, the system is able to maintain plentiful intra-thyroidal stores, in the order of 15-20 mg of iodine. In contrast, when the iodine intake is restricted to only 70 μg/day (a situation typical of Western Europe), the system must up-regulate the glandular iodide trapping mechanisms and increase the relative iodine intake to 50 (Figure 9; panel B). The higher uptake allows to recover 35 μg of iodine from dietary intake and 33 μg from TH catabolism but, in these conditions in a non-pregnant healthy adult, this is no longer strictly sufficient to sustain requirements for the production of TH, since 80 μg of iodide is still required daily. To compensate for the missing amount (i.e. ~10-12 μg), the system must use the iodine that is stored in the gland, which therefore becomes progressively depleted to lower levels (~2-5 mg of stable iodine). Over time, if the nutritional situation remains unchanged and despite some adaptation of urinary iodine losses, the metabolic balance becomes negative. The thyroid gland tries to adapt by an increased uptake, glandular hypertrophy, and a higher setting of the pituitary thyrostat.

During pregnancy, two fundamental changes take place. There is a significant increase in the renal iodide clearance (by ~1.3- to ~1.5-fold) and, concomitantly, a sustained increment in TH production requirements (by ~1.5-fold), corresponding to increased iodine requirements, from 80 to 120 μg iodide/day. Since the renal iodide clearance already increases in the first weeks of gestation and persists thereafter, this constitutes a non-avoidable urinary iodine loss, which tends to lower circulating PII levels and, in turn, induce a compensatory increase in the thyroidal clearance of iodide. These mechanisms underline the increased physiologic thyroidal activity during pregnancy. Panel C in Figure 9 indicates that when the daily iodine intake is only 70 μg during pregnancy, and despite an increase in glandular uptake to 60 %, the equilibrium becomes more or less rapidly unbalanced, since the iodide entry resulting from both uptake and recycling is insufficient to fulfill the increased requirements for TH production.

Calculations show that, in such conditions, ~20 μg of iodine are missing daily and, in order to sustain TH production, the glandular machinery must draw from already depleted intra-thyroidal iodine stores. Thus in about one trimester after conception, the already low intra-thyroidal iodine stores become even more depleted and, when iodine deprivation prevails during the first half, it tends to become more severe with the progression of gestation to its final stages. A second mechanism of iodine deprivation for the mother occurs later in gestation, from the passage of a part of the available iodine from maternal circulation to the fetal-placental unit. The extent of iodine passage has not yet been precisely established. At mid-gestation, the fetal thyroid gland has already started to produce TH, indispensable for the adequate development of the fetus. In summary, augmentation of iodide trapping is the fundamental mechanism by which the thyroid adapts to changes in the iodine supply, and such mechanism is the key to understanding thyroidal adaptation to iodine deficiency. During pregnancy, increased hormone requirements and iodine losses alter the preconception steady-state. When the iodine supply is restricted (or more severely deficient), pregnancy triggers a vicious circle that leads to excessive glandular stimulation [120].

More than a decade ago, a novel concept was introduced. Iodine deficiency occurring during pregnancy, even when it is considered to be only mild, results in prolonged enhanced thyroidal stimulation, and leads to goitrogenesis in both the mother and the fetus [3, 4, 6]. It was proposed to consider that pregnancy should be viewed as an “environmental” factor to trigger the thyroid machinery and, in turn, induce thyroid pathology in areas with a marginally reduced iodine intake.

In clinical practice, simple biochemical parameters have been identified to represent useful markers of enhanced thyroidal stimulation during an otherwise normal pregnancy, when iodine restriction was present. The first marker is relative hypothyroxinemia, i.e. serum free T4 concentrations that tend to cluster near (or below) the lower limit of normality. The second marker is preferential T3 secretion, reflected by an elevated total T3/T4 molar ratio. The third parameter is related to the pattern of changes in serum TSH. After the initial transient lowering phase of serum TSH due to high hCG levels in 1st trimester, serum TSH levels tend to remain stable in iodine-sufficient conditions, while they continue to progressively increase until term in iodine-deficient conditions. Serum TSH may reach levels that are twice (or even higher) the preconception serum TSH levels [99]. The last parameter is related to the changes in serum thyroglobulin (TG). In mild to moderate iodine deficiency conditions, serum TG increases progressively during gestation, so that at delivery, two thirds of women may have supra-normal TG concentrations. It is important to emphasize that monitoring serum TG changes during pregnancy in iodine-deficient conditions is of particular clinical value, because TG increments correlate well with gestational goitrogenesis, and hence constitute a useful prognostic marker of goiter formation, and its prevention by iodine supplementation [11].

Thus, relatively simple criteria can be used to assess the regulation of thyroid function during a normal pregnancy and help defining enhanced thyroidal stimulation, based on the determinations of serum total T4 and T3, TBG, free T4, TSH, and TG levels. However, it is necessary to correctly interpret the changes occurring in each parameter as gestation progresses, with a clear understanding of the underlying mechanisms that lead to an adequate (versus a less than adequate) adjustment of the thyroidal economy to the changes associated with pregnancy, particularly in conditions with marginal iodine restriction and overt deficiency [90, 120, 121].

Iodine deficiency is a preponderant causal factor to explain gestational goitrogenesis, affecting both mother and progeny. While goiter formation was not observed in pregnant women who reside in iodine-sufficient regions such as in the USA, several studies from Europe have shown that the thyroid volume (TV) increases significantly during pregnancy [5, 88, 90, 122]. In European regions with a sufficient iodine intake, changes in TV remained minimal (10-15% on the average), consistent mainly with vascular thyroid swelling during pregnancy [98, 123]. In other European regions with a lower iodine intake, the changes were much larger, with TV increments ranging between 20-35% on the average, and many women exhibiting a doubling in thyroid size between 1st trimester and term [104, 105]. In Brussels for instance before iodine supplementation was systematically prescribed, almost 10% of women developed a goiter during pregnancy, which was only partially reversible after parturition [124]. Furthermore, precise measurements of TV in newborns of these mothers indicated that TVs were 40% larger in newborns from non supplemented mothers (compared with newborns from iodine-supplemented mothers), and thyroid hyperplasia already present in 10% of these infants soon after birth (compared with none in newborns from the iodine-receiving mothers) [11]. Even in regions with borderline iodine sufficiency (such as in Hong Kong), recent studies showed a high rate of maternal goiter formation, and the changes in TV were correlated positively with the changes in serum TG and negatively with urinary iodine concentrations [96].

Studies carried out in Europe over the last decade in pregnant women with mild-moderate iodine deficiency have shown that goitrogenesis associated with pregnancy may, in fact, constitute one of the environmental factors to explain the preponderance of goiters in the female population. If true, it would be expected that an association be observed between parity and thyroid volume. Such an association has now been confirmed in a retrospective study of women from a moderately iodine-deficient region in Italy [125]. The authors observed a significant association between increased thyroid volume and parity, providing the first clinical demonstration of a cumulative goitrogenic effect of successive pregnancies. Another recent study from Denmark also investigated the relationship between thyroid volume and parity [126]. The authors confirmed that in Danish women aged 18-65 yrs, TVs were larger in the parous versus nulliparous women; they also showed that in this population, the differences in TV were aggravated by active smoking. Recently, a case report showed that, in rare instances, a pre-existing goiter may present an abrupt size increase during gestation, leading to tracheal compression and respiratory symptoms. The woman did not take iodine supplements and had a low urinary iodine concentration (<50 μg/L). The acute increase in goiter size was related to intrathyroidal hemorrhage that probably resulted from the thyroidal stimulation associated with the pregnant state [127]. Altogether, these results confirm the notion that several environmental factors may play a role in explaining goiter formation, tending to reinforce each other: iodine deficiency as the background, successive pregnancies as the triggering factors, and smoking habits as an additional reinforcement causal agent.

In summary, pregnancy is a strong goitrogenic stimulus for both the mother and fetus, even in areas with only a moderate iodine restriction or deficiency. Maternal goiter formation can be directly correlated with the degree of prolonged glandular stimulation that takes place during gestation. Goiters formed during gestation only partially regress after parturition, and pregnancy therefore constitutes one of the environmental factors that may help explain the higher prevalence of goiter and thyroid disorders in women, compared with men. Most importantly, goiter formation also takes place in the progeny, emphasizing the exquisite sensitivity of the fetal thyroid to the consequences of maternal iodine deprivation, and also indicating that the process of goiter formation already starts during the earliest stages of the development of the fetal thyroid gland.

The best single parameter to evaluate the adequacy of iodine nutrition in a population is provided by measurements of the urinary iodine excretion (UIE) levels in a representative sample of the population. However, although UIE is highly useful for public health estimations of iodine intake in populations, UIE alone is not a valid diagnostic criterion in individuals. To assess the adequacy (i.e. the long term sufficiency) of iodine nutrition in an individual, the best single parameter would be to estimate the amount of iodine stored within the thyroid gland, corresponding to ~10-20 mg of stable iodine. This parameter is, however, not measurable in practice. Therefore in a given pregnant woman, the best surrogate is to evaluate those thyroid parameters that have been shown to be sensitively altered when a pregnancy takes place in iodine-deficient women: lowering in serum free T4, rise in serum TSH, progressive increase in serum TG, elevation of the total molar T3/T4 ratio, and finally increase in TV.

Concerning the implementation of iodine fortification during pregnancy, several epidemiological situations must be distinguished. In countries with a longstanding and well-established USI program, pregnancies are not at risk of having iodine deficiency. Therefore, no systematic dietary fortification needs to be organized in the population. It should be recommended individually to pregnant women to use vitamin/mineral tablets specifically prepared for pregnancy requirements and containing iodine supplements. In countries without efficient USI program, or with an established USI program where the coverage is known to be only recent and/or partial, complementary approaches are required to reach the RNI for iodine. Such approaches include the use of iodine supplements in the form of potassium iodide (100-200 μg/d) or the inclusion of KI (125-150 μg/d) in vitamin/mineral preparations manufactured for pregnancy requirements. Finally in areas with severe iodine deficiency and generally no accessible USI program and difficult socioeconomic conditions, it is recommended to administer iodized oil orally as early during gestation as possible.

To prevent gestational goitrogenesis, women should ideally be provided with an adequate level of iodine intake (~150 μg/day) already long before conception. Only then can a long term steady-state be achieved with plentiful intra-thyroidal iodine stores (10-20 mg), thus avoiding the triggering of the thyroid machinery that occurs once gestation begins. To achieve such goals, public health authorities ought to implement national dietary iodine supplementation programs in the population. Correcting this public health problem has been the aim of a massive global campaign that was undertaken 10-15 years ago worldwide, based on universal salt iodization (USI), and that has shown remarkable progress so far [116, 117, 128, 129]. Until 1992, most European countries used to be moderately or more severely iodine deficient. A survey carried out in 12 European countries (using a mobile unit, the ‘ThyroMobil’ van) has indicated that children’s iodine nutrition status had markedly improved in many - albeit not in all - countries surveyed [130]. As an example, the iodine status in Belgian school age children remains a vexing paradox. The ‘ThyroMobil’ surveys have indicated that the iodine nutritional status had only slightly improved in recent years, with a median urinary iodine excretion level of 80 μg/L (compared with 55 μg/L earlier) and a goiter prevalence of 6% (compared with 11% earlier) in a cohort of representative 6-12 year-old schoolchildren [131]. These as well as other available data demonstrate that silent iodine prophylaxis is not sufficient to restore an adequate iodine balance, and that more stringent prophylactic measures need to be taken by public health authorities.

How much supplemental iodine should be given to prevent goitrogenesis remains a matter of local appreciation and depends primarily on the extent of pre-existing iodine deprivation [100]. Since the ultimate goal is to restore and maintain a balanced iodine status in expecting mothers, this can be achieved in most instances with supplements of 100-200 μg of iodine per day given during pregnancy (see Figure 14-10). In practice, this requires the administration of multivitamin pills, especially designed for pregnancy purposes, and containing iodine supplements. It should be remembered, however, that because of the longstanding restriction in dietary iodine before the onset of a pregnancy, a lag period of approximately one trimester is inevitable before the benefits of iodine supplementation to improve thyroid function can be observed [11, 88]. Because of salt restriction, the use of iodinated salt is obviously not the ideal vector to supplement mothers during gestation [132]. Finally, some caution is needed to avoid iodine excess to the fetal thyroid, due to iodine supplementation implemented during pregnancy. It is well known that the fetal thyroid gland is exquisitely sensitive to the inhibitory effects of high iodine levels, and a recent study showed that inhibitory effects of high iodine loads could lead to opposite variations in maternal and neonatal thyroid function, i.e. with facilitation of thyroid function in the mother but aggravation in the neonate [103].

Because of the difficulties inherent to field studies in most areas with severe iodine deficiency, there have been no systematic studies to carefully assess pregnancy-related changes in goiter size. Until a decade ago, it was practically not feasible to obtain echographic measurements of the thyroid gland on a large and representative scale; it was even more difficult to sequentially observe goitrogenic changes associated with gestation. This situation is presently rapidly evolving, due to the possibility to adapt and use the ThyroMobil technology to field studies in remote areas in Eastern Europe, Africa, and Asia, and the introduction of universal salt iodization programs [133].

In areas with severe iodine deficiency, iodine supplements have been administered to pregnant women using iodized salt, potassium iodide drops and iodized oil (given intramuscularly or orally), as emergency prophylactic and therapeutic approaches to avoid endemic cretinism. Several such programs have conclusively demonstrated their remarkable efficiency to prevent and treat endemic goiter, as well as to eradicate endemic cretinism [134]. The results of such studies have indicated that pregnant women who reside in severely iodine-deficient regions can adequately be managed with iodine supplementation. However, except for emergency situations, there is presumably no need to use supra-physiologic amounts of iodine to normalize thyroid function parameters. Although it has not been possible, thus far, in the setting of difficult field studies to evaluate quantitatively the reduction in goiter size or goiter prevalence associated with the clear improvement in thyroid function, goiter reduction is undoubtedly a side benefit of the overall improvement in the iodine nutritional status [106, 135-138].