Iodine Status Assessments: Considerations and Limitations

Iodine intake is a crucial determinant of iodine status but is difficult to assess. Urinary iodine concentration (UIC) is the method most commonly used to assess dietary iodine intake. UIC has been measured using spot UIC by the Centers for Disease Control (CDC) National Health and Nutrition Examination Survey (NHANES) from 1972 to the present [30]. NHANES data has consistently been the only assessment utilized for iodine sufficiency in the USA. This method provides information on iodine status based on one point in time and has limitations to its validity [42]. For population-based studies, only spot UIC collection is logistically possible, but the data may not be reflective of an individual’s iodine status; thus, when extrapolated to a population, the results should be interpreted with caution. The determination of UIC provides little information on the long-term iodine status of an individual as spot samples are a one-time glance at the concentration of excreted iodine [6, 7]. This method has inherent problems as it does not take into consideration factors affecting iodine excretion. Possibly, recent consumption of foods with high iodine content, high fluid volume, and goitrogens could account for falsely high iodine excretion. Iodine excretion may also correlate with estrogen variability of the menstrual cycle [43]. Therefore, the day of UIC collection may influence iodine excretion up or down. Another method to assess iodine levels is by 24-h UIC, which represents an individual’s single day excretion of iodine. Although this is a more accurate estimate of dietary iodine intakes, it is not feasible for a population study. The study by König, et al. reported that it would take ten spot UIC tests to have any degree of accuracy, and even one 24-h sample has only 20% reliability estimating iodine status [42]. Although spot UIC and 24-h UIC may be valid tools to evaluate population iodine status, neither can be used to critically evaluate an individual’s iodine nutrition status. Urinary iodine per gram creatinine ratio (UIC/Cr) of a single voided urine sample is another method to quantify iodine in individuals. It was thought to be the best way to compensate for variability of urine volumes as daily creatinine excretion was assumed to be relatively constant. However, limitations of assessing UIC/Cr include due to day to day variation in UCr excretion and low excretion rates in populations with inadequate protein intake [44].

For women of reproductive age, achieving iodine sufficiency should be a priority. The iodine loading protocol developed by Abraham et al. may be another option to determine individual iodine status [45]. The basis for the test is to examine how much iodine is excreted compared to the load consumed, with the reasoning being that the body will clear whatever amount of iodine/iodide is not absorbed from the loading dose of 50 mg. Excretion of 45 mg, or about 90%, means the individual is iodine sufficient [46]. This method of iodine testing, although being used by independent labs across the USA, is not a validated tool to evaluate individual iodine nutrition status. It may also be difficult to extrapolate the results of this test to the WHO/IOM criteria for the definition of iodine deficiency in populations.

Measures of thyroid function also indicate iodine status [47]. If serum TSH and T 4 are within normal limits, individuals are assumed to be iodine sufficient, since a decrease in T 4 and increase in TSH only occurs when iodine deficiency is severe [48]. The American Thyroid Association states there are 20 million Americans with thyroid disorders and 13 million are undiagnosed with a majority of the diagnosed and undiagnosed population comprised of women, especially women of reproductive age [23]. These assumptions are based on the current evaluation of TSH levels and depending upon a “normal” range of values, and therefore accounts for the significant discrepancy in numbers. Nevertheless, this would mean ~ 20% of our population is at risk for thyroid disorders, a number not unlike the population observed in the Goiter Belt before salt iodization in the 1920s. According to the Mayo Clinic, accurate thyroid function tests are available to diagnose hypothyroidism, and treatment of hypothyroidism with synthetic thyroid hormone is usually simple, safe, and effective [49]. However, iodine deficiency is not a consideration when diagnosing hypothyroidism, even though iodine is essential to produce thyroid hormones, and iodine deficiency is one of the leading causes of hypothyroidism. Conversely, taking in too much iodine can also cause hypothyroidism [23, 49]. Therefore, we have a problem that we do not take in enough iodine because we are fearful of causing thyroid dysfunction, but because of iodine deficiency, we have an epidemic of thyroid disorders that is currently only being treated by taking an over-prescribed drug that eliminates healthy thyroid functioning. It might be simpler to mandate iodization of salt or improve iodine intake from diet or supplements rather than creating a levothyroxine-dependent hypothyroid population.

Dietary Iodine Deficiency

Historically, iodine deficiency in the USA was a matter of geographic location. Iodine is found in varying quantities in the oceans and on land masses. The “Goiter Belt” included states from the Pacific Northwest, the northern Rocky Mountains, to the Midwest, Great Lakes, and Appalachia. Areas prone to flooding and mountainous terrain are consistently iodine depleted. Food sources from these areas lack iodine, and therefore, goiter was prevalent. Severe iodine deficiency manifests as a goiter. In the 1820s, J. F. Coindet, a Swiss physician, recognized iodine for its ability to reduce goiter size. By 1920, David Marine, M. D., from Cleveland, OH, in the Goiter Belt region, brought iodine treatment to the forefront in the USA. Dr. Marine first studied iodine on animals and then on school girls with goiter. Sodium iodide supplementation among adolescent girls reduced thyroid enlargement, a result of iodine deficiency, from 21 to 0.2%. This study is what led to the iodization of salt in the USA. Goiters, a common problem in the early twentieth century and the result of iodine deficiency, became a thing of the past with salt iodization. Salt iodization programs, including bread fortification, began as a result of the work of these men. Due to the iodization of salt in the 1920s, iodine deficiency and the symptoms associated with it were markedly reduced [50].

Iodine deficiency during fetal and infant developmental stages may cause mental retardation, autism, developmental delays, cretinism, goiter, and hypothyroidism in the offspring [2, 23, 24]. Iodine deficiency in the mother may contribute to hypothyroidism, goiter, fibrocystic breast disease, breast cancer, cognitive decline, and fibromyalgia [51]. Overall, iodine deficiency manifests in the thyroid gland as clinical or subclinical hypothyroidism, goiter, myxedema, and cretinism, or it may present as non-specific conditions such as stunted growth, mental retardation, and decreased intelligence [1, 2, 52]. Deficiencies of micronutrients such as vitamin A, selenium, iron, and zinc have also been shown to adversely affect iodine metabolism and thereby thyroid function [53]. The current iodine intake guidelines are the minimum for disease prevention, but not necessarily whole-body health. It is still unknown how much iodine is necessary for iodine sufficiency beyond prevention of goiter. The WHO established population medians do not consider iodine sufficiency of vulnerable groups such as women of reproductive age. All potential factors involved in iodine uptake and excretion must therefore be scrutinized to assess iodine sufficiency of a population.

Since an individual’s iodine status is dependent on iodine consumption and excretion, it would be ideal to use dietary intake to measure iodine consumption. Although adequate dietary iodine intake is important in human development, few studies have reported estimates of dietary exposure to iodine in the USA [54,55,56]. The leading sources of dietary iodine are dairy products, eggs, fish, and seaweed [57, 58]. The U.S. Department of Agriculture (USDA) proposed a percentage daily value (% DV) set at 150 μg (100% DV) for iodine among US adults to help individuals estimate the iodine content of diet [59, 60]. The % DV of iodine in commonly consumed US foods is as follows: one cup of reduced-fat milk, 56 μg iodine (37% DV); low-fat plain yogurt, 75 μg iodine (50% DV); one large egg, 24 μg iodine (16% DV); three ounces of fish sticks, 54 μg iodine (36% DV); baked cod, 99 μg iodine (66% DV) [57, 58]. Seaweed is the richest source of iodine because marine plants and animals concentrate iodine from seawater. One gram of dried or powdered seaweed, such as nori, wakame, kelp, or kombu, may contain iodine in the ranges of 16 μg (11% DV) to 2984 μg (1989% DV) [57]. Another major dietary source of iodine is iodized table, which was introduced in the 1920s and proven to be effective in combating iodine deficiency in the US salt [61]. Many salts sold in the USA follow the current recommendations for iodine fortification levels as a form of potassium iodate and potassium iodide [6, 10, 62]. Salt-iodization in the USA is voluntary and not mandatory unlike in many other countries, and consumers can still purchase either iodized or non-iodized salt. Although the Iodine Global Network estimates that the proportion of US households with access to iodized salt now exceeds 90%, data regarding actual usage is limited, and the contribution of iodized salt to the overall iodine sufficiency of the US population is uncertain [10, 62]. The Salt Institute has estimated that about 70% of the table salt in the USA is iodized, whereas table salt accounts for only 15% of total daily intake of salt [62]. Although iodized table salt is still an important source of iodine in the USA, adequate iodine intake may not be fully achieved with iodized salt only. A recent analysis of US iodized salt sales identified that only 53% of table salt sold at the retail level in the USA is iodized [63]. To make matters worse in the USA, processed foods or restaurant foods tend to use non-iodized salt due to the alleged adverse effect on the quality and taste of food [64, 65]. The USDA also does not mandate the listing of iodine content on food packaging. It is assumed that the majority of salt consumption in the USA comes from processed foods, which primarily uses non-iodized salt during production [57]. The vast majority of sodium intake is estimated to come from packaged and restaurant foods. It is estimated that only 11–12% comes from salt added to the table or salt added during home cooking. Also, the USDA food database for iodine is incomplete and reliance on dietary recall will not provide accurate results [57, 58].

A high degree of variability also exists in the iodine content of various dietary sources of iodine. The diets of cattle and chickens are often supplemented with kelp, iodine-rich seaweed, which results in variable amounts of iodine in meats, milk, and eggs [37]. Another source of iodine has been the use of iodophors in the dairy industry; iodophors are cleaning agents containing iodine used to sanitize the machinery in dairy operations and clean cow teats [66]. They are used unevenly, and some of the iodine from teat dips is absorbed and found in milk and meat [67]. There is little information whether iodophors are still widely used as there are other options for sanitizers including some that contain chlorine, an endocrine disruptor, and competitor of iodine. In the late 1950s, some bakeries were adding iodate to commercial bread mix as a dough conditioner or bread stabilizer [68], which provided a significant source of iodine in the average American diet. However, bread makers stopped using this iodide additive in the 1980s, possibly due to pressure exerted by health policymakers and the preference of brominated flour [69].

Many individuals in the USA consume restricted diets for various reasons and may have eliminated iodine-rich foods from their diets. Dairy, especially milk consumption, by adults and children, has declined in the USA. Consuming dairy products was the principal indicator of iodine status for both men and women [34, 37]. Milk has been limited or eliminated in many diets for reasons such as lactose intolerance, allergies, or believing it is a high-fat, high-calorie food. Eggs have been restricted from many people’s diets due to the high cholesterol levels in egg yolk and its relationship to heart disease. Just a few decades ago, sodium was implicated as the cause of hypertension; doctors and dietitians were instructing patients to avoid using table salt leading to the elimination of salt from the diets of many Americans. The recent change in the dietary guidelines for reduction of salt intake from 3500 to 2300 mg/day further exacerbates the issue of reduced iodine intake.

Iodine deficiency may also be caused by substances called goitrogens which inhibit or block iodine uptake into the thyroid [1, 2]. Iodine is part of the halide group along with bromine, chlorine, and fluorine. These halides act as goitrogens and compete with iodine uptake into the thyroid, especially under iodine deficiency conditions. The thyroid requires iodine to produce thyroid hormones; however, if the other halides are dominant, then iodine may not be utilized for thyroid hormone production [70]. If goitrogens subvert iodine uptake, it may be lost by excretion in the urine. It is not known if this could induce a falsely high urinary iodine excretion. Goitrogenic factors may have some role in declining iodine measurement; however, their role may be underestimated. In the USA, the impact of iodine-disrupting elements on the iodine status of the population, especially on women of reproductive age, is not known. Goitrogens found in cruciferous vegetables and lima beans are commonly consumed in the USA. Bromine as potassium bromate replaced iodate in bread in the 1970s over concern of excessive iodine consumption. Potassium bromate is a renal carcinogen and increases iodine excretion [71, 72]. Other goitrogens hurting iodine status are perchlorate, bisphenol A, oral contraceptives, amiodarone, flavonoids, and polyphenols [73]. Perchlorate has been discovered in contaminated groundwater and has also been detected in vegetables and dairy products. Perchlorate blocks iodine intake via the sodium iodide symporter (NIS), which is a membrane protein that transports iodide into the thyroid or into milk of mammals. For this reason, perchlorate has a strong goitrogenic effect [74,75,76]. An analysis of the NHANES 2007–2008 dataset determined that perchlorate along with thiocyanate and low iodine reduce thyroid function exhibited as decreased circulating T 4 [77]. Another highly toxic substance affecting thyroid hormones during low iodine status is serum perfluoroalkyl acids (PFAS). These chemicals are found in stain, carpet, food packaging, paints, and stains. When iodine levels are low, and TPO antibodies are present, PFAS may disrupt thyroid function and alter thyroid hormone levels [73, 77]. Flavonoids, primarily from soy and millets, may become goitrogenic if consumed excessively. Vegetables, fruit, and supplements contain flavonoids, such as quercetin, in significant amounts. Flavonoids are healthy substances possessing antioxidant, antiviral, apoptotic, and anti-inflammatory qualities. However, excessive consumption coupled with iodine-deficient conditions may disrupt thyroid function. Similarly, resveratrol found in grapes and berries is a polyphenol with health-promoting properties, but overconsumption may inhibit the NIS gene expression thus blocking iodine uptake [78].

The American Thyroid Association (ATA) recommends that women of reproductive age, planning to become pregnant, and pregnant and lactating women consume between 220 and 290 μg/day of iodine, to compensate for fetal and maternal requirement and losses [6, 24]. Iodine levels below these guidelines may lead to iodine deficiency disorders (IDD) in the mother and offspring. Women of childbearing age, 15–44 years, are at the highest risk for iodine deficiency. A Boston study reported that 49% of pregnant and lactating women were consuming iodine below the RDA of 150 μg/day [79]. Educating women of reproductive age is crucial to create greater awareness of the importance of adherence to WHO and ATA recommendations for iodine nutrition. Iodine supplementation may need to be started well in advance of pregnancy for maximum benefit. An observational study by Moleti et al. [80] demonstrated that consumption of iodized salt for more than 2 years before pregnancy was associated with lower TSH and lower rates of gestational hypothyroidism than supplementation which commenced only in pregnancy. Prolonged use of iodized salt is associated with better maternal thyroid function, probably due to greater intra-thyroidal iodine stores to utilize during pregnancy. A further study by the same group reported higher TSH concentrations in women who took iodine supplements from early gestation compared to women who consumed iodized salt alone from 2 years before conception or those who took no supplements at all [81]. Similar comparison studies in the US population of women of reproductive age are lacking.

We have hypothesized that the lack of mandatory salt iodization programs in the USA, changes in dietary patterns leading to a reduction in iodine intake, the decline in bread fortification, increased consumption of processed foods that lack iodine, consumption of goitrogens, reduced salt guidelines, and certain geographic and socioeconomic factors may have an impact on iodine nutrition status of women of reproductive age in the USA resulting in iodine deficiency in this vulnerable population. In addition to these factors, awareness of the importance of adequate iodine nutrition, particularly during preconception, pregnancy, and lactation, among the US populace is lacking indicating cause for a significant public health concern that needs to be addressed. It is possible that all the above-discussed factors could be contributing to the reemergence of iodine deficiency in the US population, with women of reproductive age being the most vulnerable to the effects of decreased iodine intake.

Limitations and Directions for Future Research

The strengths of this review are as follows: this scoping review synthesizes evidence on the emerging topic of iodine deficiency in women of reproductive age in the USA, the search strategy included multiple electronic bibliographic databases, the reference list of 12 different articles, internet search engines, the websites of relevant organizations, citations, and articles were reviewed by two independent reviewers who met in regular intervals to discuss results to ensure that all citations and articles were properly accounted for during the process, and an updated search was also performed in April 2018 to enhance the timeliness of this review. For this reason, this review provides a broad overview of evidence of emerging iodine deficiency among the vulnerable population subset of women of reproductive age in the USA. The limitations of this scoping review are the following: this review may have missed some relevant studies due to the English language restriction, and the selection process being limited to peer-reviewed journal articles. It is possible that searching other databases, including gray literature in the search, and the inclusion of studies published outside of the USA may have identified additional relevant studies. However, since the scope of the review was to assess the articles published in the USA and analyzing the iodine status data for the US population subset of women of reproductive age, we believe that these limitations are insignificant. Directions for future research should include conducting a more extensive systematic review and/or a meta-analysis to assess the magnitude of iodine deficiency in women of reproductive age in the USA, including studies that may have evaluated thyroid hormone status markers to assess iodine nutrition status of women of reproductive age in the USA, and conducting a more exhaustive search of gray area literature to include all possible resources of iodine nutrition in the USA.