Assessment of the Impact of Salt Iodisation Programmes on Urinary Iodine Concentrations and Goitre Rates: A Systematic Review

Introduction Two main strategies are currently recommended for the prevention and control of iodine deficiency in the world: implementation of universal salt iodisation programmes and permanent monitoring of iodine consumption by the population. Although iodine intake and coverage iodised salt have increased in the world population, iodine deficiency disorders (IDDs) may still be a public health problem in a few countries or communities. Objective To assess the impact of salt iodisation programmes on urinary iodine concentrations and goitre rates in the world population. Methodology. A systematic review based on the PRISMA method. We obtained articles from Scopus, Science Direct, MEDLINE databases, and other sources between March and April 2020, without limitation of dates. “Iodisation” AND “urinary iodine concentrations” AND “goitre” in English, Portuguese, and Spanish without filters and clinical trial, case-control, and cross-sectional studies were included in this review. Results Of 479 abstracts, twenty-three were eligible. Coverage on iodised salt was in the range of 16 to 98%, and 11 studies had been sufficient, whilst eight studies had adequate iodine concentration in salt and three excess. 81.8% of studies that had an adequate median of UIC had a good impact in their respective salt iodisation programmes. Conclusion After 18 years of salt iodisation programme implementation in the 13 countries, the majority achieved sustaining elimination of IDD whilst all had adequate median UIC; however, more detailed studies are still needed to confirm that all communities are equally protected of IDD.


Introduction
Iodine is a micronutrient utilised for the synthesis of thyroid hormones and necessary for neurological development. Iodine deficiency (ID) causes damage to health, such as goitres, hypothyroidism, hyperthyroidism, neuropsychomotor retardation, and cretinism [1]. International organisations suggest two strategies for the prevention and control of ID: implementation of a universal salt iodisation (USI) programme and monitoring iodine consumption by the population through urinary iodine concentration (UIC) assessment. e impact of salt iodisation programmes is assessed by process and impact indicators. Process indicators are associated with the concentration of iodine in salt and how much of the population has access to iodised salt [1]. Impact indicators assess UIC [1], also considering the thyroid volume (Tvol) and the total goitre prevalence rate (TGR). High iodine intake reduces both thyroid volume and TGR, and both of these measures are reported to be more sensitive to long-term iodine intake assessment; hence, they are good indicators [2,3].
Salt iodisation is a safe, effective, and low-cost strategy, and its implementation is mandatory in 128 of the 196 countries of the world. Of note, the particular programmes vary depending on the conditions in each country [4]. Based on the proportion of cases with a median UIC <100 μg/L, the World Health Organization (WHO) has estimated that 1.9 billion people, corresponding to 31% of the world population, are affected by insufficient iodine intake across 47 countries, where iodine deficiency disorders (IDDs) still remain a health public problem [1]. To achieve sustainable IDD control, global experience has demonstrated that salt iodisation programmes are the most equitable, effective, and sustainable strategy to ensure adequate iodine status for all population groups [3]. It is important to note that the indicator is a median UIC <100 µg/L and not the proportion of cases below that value.
Currently, the global coverage of iodised salt in families is 86%. is has resulted in the number of countries with IDDs being reduced from 113 (1993) to 24 (2017) [3]. Nevertheless, ID may remain in some countries, and the effect of salt iodisation programmes on ID and IDDs in the world population is unclear. erefore, the objective of this review was to assess the impact of salt iodisation programmes on urinary iodine concentrations and goitre rates in the world population.

Materials and Methods
is systematic review was based on the Preferred Reporting Items for Systematic Reviews (PRISMA) [5]. e guiding question was what is the impact of salt iodisation programmes on iodine deficiency and iodine deficiency disorder of the worldwide population between 1999 and 2020? e search occurred in March and April 2020, using MEDLINE (PubMed), Science Direct, and Scopus databases; the Iodine Global Network; the Food Fortification Initiative; the Cochrane library; and the Portuguese Medical Association without limitation of dates. We used the descriptors: "iodisation" and "urinary iodine concentrations" and "goitre", provided by Health Science Descriptors (DeCS) in English, Portuguese, and Spanish, without filters.
As inclusion criteria, all articles had to have been published between 1999 and 2020, which corresponds to the period during which salt iodisation programmes have been intensely promoted and available in many countries. e studies also had to address the effect of the salt iodisation programmes, detailing the indicator utilised, mean-± standard deviation (SD)/median iodine content in salt, and UIC. Systematic reviews, manuscripts, and articles that assessed iodine content but were not associated with iodised salt consumption and that addressed the iodine nutritional status or TGR of the population prior to the implementation of the salt iodisation programme were excluded.
PICOS was defined as follows: population-people in populations before and after introduction of USI; intervention-USI introduced (iodised salt used, iodised salt coverage, adequate iodised salt used); comparator-historical control period before USI or before intervention; and outcomes-TGR and median UIC after an intervention.
All articles were recorded in a spreadsheet in Microsoft Excel® after completing searches and eliminating duplicates for each database and between databases. ree researchers selected the articles independently. In the case of divergence, the researchers discussed the article and reached an agreement.
is review used randomised clinical trials and longitudinal case-control and repeated cross-sectional studies. e impact of salt iodisation programmes was assessed using the criteria for the elimination of IDDs established by the WHO: (i) the proportion of 8-to 10-year-old children with a median UIC < 100 μg/L, (ii) the TGR of 8to 10-year-old children is <5%, and (iii) at least 95% of the population has access to iodised salt and >90% of that salt is adequately iodised. e iodine status was classified as mild for a median UIC < 100 μg/L or adequate for a median UIC between 100 and 199 μg/L. For schoolchildren, the risk of adequate iodine intake was between 200 and 299 μg/L or ≥300 μg/L for risk of adverse health consequences.
Iodine intake in pregnant women was classified as insufficient for a median UIC < 150 μg/L, adequate for a median UIC between 150 and 249 μg/L, above requirements for a median UIC between 250 and 499 μg/L, and excessive for a median UIC ≥ 500 μg/L. For lactating women, a median UIC < 100 and >100 μg/L was considered insufficient and adequate, respectively.
UIC is a biomarker of iodine status in schoolchildren and adults and an indicator of the iodine intake in schoolchildren, adults, and pregnant and lactating women. Of note, it is also an indicator of the impact of and can represent ID. In addition, TGR represents IDDs and represents thyroid function [8].
e salt iodisation programme was classified as unsuccessful when ID was observed in the population and the median UIC was inadequate. It was classified as inequitable when UIC was adequate but IDDs were present. It was classified as effective when UIC was adequate and IDDs were absent. It was classified as sustainable when the goal of IDD elimination had been achieved [3].
is review followed a method proposed by Downs and Black [9] to assess the quality of the studies. It comprises four categories: report of the study (clarity), external validity (representativeness), internal validity (biases and confounding factors), and statistical power of the study. Only 17 questions of the scale were used because 10 are applicable to experimental studies. e responses score was "1" (when the criterion assessed was present) or "0" (when the criterion assessed was absent).

Results
e search resulted in 479 articles, 403 from the databases and 66 from the other resources. After eliminating duplicates and reading titles, abstracts, and complete articles, we included 20 studies. After a citation search, we included three additional articles, for a total of 23 ( Figure 1).
Of the 23 studies assessed, 100% reported changes in the investigated population's median UIC and 68.2% presented changes in TGR (Table 1, continuation I, II, III, IV, and V). e studies provided data from an assessment period from 1999 to 2020 and were conducted in North America, the Eastern Mediterranean region, Africa, South, Southwest and East Asia, and the Western Pacific with infants, school Articles written in a language other than portuguese, english, and spanish: 1      e first limitation of studies was low coverage iodised salt in the household of these women and in many cases the women not given sufficient sample salt in collection data. In contrast, in the countries with higher sample sizes, the median UICs were adequate and the TGR decreases.
In studies, the TGR was low in iodised salt consumers (7, 6%) compared with nonconsumers (33%). e UIC was higher in infants with mother consumers of the iodised salt.
e UIC was higher in urban people compared to rural, higher in soil iodine concentration areas compared to other areas without, and higher in newborns or teenage girls compared to pregnant women and lactating women, and in pregnancy, the UIC decreased from the first to the third trimester.
Regarding the assessment of the methodological quality of the studies, the lowest score was 10 and the highest was 17, indicating good quality and reliability of the results. e bestassessed criteria were objectives/hypothesis clearly described, random variability of data for outcomes, sample representativeness, equal follow-up time for the whole sample, valid and reliable outcome measures, individuals recruited in the same population, and individuals recruited within the same time period. However, only five studies described power.

Discussion
e WHO has defined process indicators for assessing and monitoring fulfilment of salt iodisation programmes as the iodine concentration in salt (ICS) and salt coverage or consumption (SC). e impact indicators to identify the achievement of goals established for the elimination of IDDs are UIC and TGR [1,34].

ICS and SC.
e coverage of iodised salt in the population ranged from 16% to 98%, although in 10 studies, it was sufficient (>90%). However, in the present findings, the ICS varied from 2% to more than 153% of the value recommended by the WHO. Of the 14 studies that assessed ICS, 11 reported an adequate ICS based on the countries' legislation. Of those, eight were within the WHO recommendations (15-40 mg of iodine/kg of salt) and three were in excess. Countries localised in the Eastern Mediterranean and Southwest Asia had less access to iodised salt compared with countries in Africa, North America, and East Asia. However, all the regions were considered to be iodine-deficient areas in 2011 [4]. is review evidenced fulfilment of salt iodisation legislation. Among countries that had reached the goal of iodised salt coverage, there had been a gradual reduction in the iodination range and salt consumption [16,18,28,30].
Regarding outcomes, many studies did not find a difference in the ICS and SC between rural and urban areas. In 2001, in Sparta [27], western Turkey, SC was greater in urban compared with rural areas. However, some regions had excess iodine intake because of high iodine concentrations in drinking water. On the other hand, high iodine intake was observed due to consuming other food sources of iodine such as bread, milk, and dairy products. Consequently, even though people in urban areas showed reduced iodised SC, they still consumed adequate amounts of iodine. One study reported that dairy products and bread contribute 13%-64% of the daily adult iodine intake requirement in high-income countries when consumed more than twice a day per person [35], because, in these countries, a reduction in salt intake has been prioritised to reduce the risk of noncommunicable diseases [36]. ese iodine food sources are important as supplements but not as salt substitutes.
Inadequate salt storage and washing salt with water before seasoning foods are some of the practices observed in the home environment that can compromise the amount of iodine available in salt. ese are in contrast to the use of crystal salt, which contributes to an adequate ICS. erefore, it is necessary to maintain the salt iodisation programmes, even with some industries claiming high costs in the production of iodised salt. Governments should provide legislation to ensure that salt iodisation programmes continue and manufacturers comply [37,38].

UIC.
e adoption of universal salt iodisation has been positive for an adequate median UIC in 17 (73.9%) of the 23 studies included in this review [10, 11, 13-26, 30, 31]. Among the six (26.1%) other studies that represent countries with ID, two [27,28] were assessed in schoolchildren and the other four [29,[31][32][33] were in pregnant and lactating women; the authors reported insufficient UIC and a moderate level of IDDs. Based on the studies, a 16.9%-166% increase in UIC (R 2 � 0,143; P � 0.005) (Supplemental Figure 1) in a population with ID and IDDs within 3-18 years after a salt iodisation programme had been implemented is relevant because it classifies the salt iodisation programmes as promising [39]. In this case, three studies showed good scenarios. A randomised clinical trial showed an 81% increase in UIC levels in iodine-deficient pregnant women and adequate intake 3 years after the salt iodisation programme had been implemented [11]. In the two studies that examined schoolchildren, both started the salt iodisation programmes in 1999. In one, the UIC level had increased 162% 16 years after the implementation and was adequate [14]. On the other hand, the increase was 166%. Five years after implementation (1999)(2000)(2001)(2002)(2003)(2004)(2005), such a level was adequate, but in the subsequent 12 years (2006-2017), it represented an excess [25]. ese outcomes also evidence that even with the recommended ICS, ID can still occur in pregnant women. Furthermore, lactating women lose iodine to breast milk to ensure that their newborns have adequate iodine. Hence, the recommended iodine concentration in salt recommended to the overall population [40] is not necessarily sufficient for pregnant and lactating women.

TGR.
IDDs were indicated in 15 (65.2%) studies, showing goitre reductions from 1.2% to 62.3% (R 2 � � 0,328; P � 0.001) (Supplemental Figure 2) between 16 and 18 years after the intervention had commenced. Goitres are still prevalent in the regions where chronic ID has been identified, and this represents an indicator of nutritional status over a long period [34,41]. us, TGR reduction in a population is expected when the intervention is combined with an increased ICS, more of the population has access to iodised salt, and there is regular monitoring of ID in the population. e change in the TGR pattern from severe to mild and from mild to eliminated IDDs in the 18-year period of intervention with iodised salt indicates the adequacy of UIC levels [10,11,[14][15][16][17][18][19][20].
Regions where IDDs had been eliminated showed a reduction in the iodine concentration in salt over time [20].
is phenomenon was observed in the Eastern Mediterranean region, which was previously classified as an area with ID, and, curiously, sub-Saharan Africa in 1999, when the USI programme was recommended by the WHO. Recent studies have reported excess UIC and have recommended readjusting the ICS [42,43]. is phenomenon may be present in populations with ID and sufficiency iodine intake. e consumption of iodised salt is crucial for the prevention and control of IDDs. Countries should examine their iodine policies to ensure that iodine-deficient areas have greater access to iodised salt. e data confirmed that pregnant women represent a unique group when assessing UIC in the adult population. Specifically, IDDs occur more in women than in men, and they are 10 times more likely to occur in young than old women, especially in pregnant women living in areas with insufficient iodine levels [44,45]. However, the occurrence of IDDs in women is associated with impaired brain development in their children [6]. e outcomes showed adequate UIC in schoolchildren, but goitres were present in areas with iodine deficiency as well as adequacy, with a higher incidence in those groups that did not consume iodised salt. Hence, monitoring the nutritional status and nutritional intake of the population is crucial [1].
Some regions of the countries with IDDs in the population presented higher iodine content in the water because these people previously had iodine deficiency [46].

Salt Iodisation Programmes in Different Regions.
e recent recommendations from UNICEF for salt iodisation programmes differ within the same country (rural and urban areas) across time (number and time of the monitoring programme) and depending on the iodine concentration in salt or soil, the iodine deficient population (children or women of reproductive age), socioeconomic status, and regions (south, north, east, and west) [3].

Eastern Mediterranean, South, Southwest Asia, and
Africa. In Iran, salt iodisation programmes became sustainable for schoolchildren 11 years after implementation, based on the increased iodised salt coverage. After two years in northwest Iran with 20-40 mg iodine/kg salt, there was ID in rural areas but excessive iodine in urban areas; however, in the northern part of the country, salt iodisation programmes were achieved sustainable in 2015. In the southern part of the country, there was insufficient UIC in pregnant and lactating women, although newborns were iodine adequate.
e iodisation programmes were classified as sustainable because the SC was increasing even though the ICS was 63% of the recommended value, a discrepancy that underlies why ID is still observed in the country.
Other findings showed achievements a short time after the intervention had been introduced. In Ethiopia, the salt iodisation programme was sustainable after 3 years, based on the increased iodised SC and ICS. Since 2010, the ICS has been readjusted. Indeed, since 2013, the ICS has been set at > 15 mg iodine/kg salt for rural areas in the northern part of the country, and the salt iodisation programme has been sustained [33]. Ethiopian children whose mothers consumed iodised salt had adequate iodine concentration [11]. In 2014, some villages in the north had been exposed to 20-40 mg iodine/kg salt, and this was inadequate: ID and IDDs appeared in pregnant women. However, the country has achieved sustainable elimination of IDDs in the population. In a 2018 study from China, there had been sustainable elimination of IDDs through salt iodisation in children [20]. Studies from 2017 in Aira, in rural areas in western Ethiopia, showed 34% and 80% of mild ID in 73 schoolchildren and 40 pregnant women surveyed [47]. In this case, the salt iodisation programme could not be sustained in this country. Whilst this study was not representative of the country, it provides directions for the need to monitor the iodisation programme over time.
In India, the salt iodisation programme, with 20-40 mg of iodine/kg salt, was inequitable 1 year after it began for adult women in the north [26]. However, pregnant women in the centre of the country with >15 mg iodine/kg salt had ID, although there had been greater salt coverage and more than half the adequate ICS. is was the only case where pregnant women had an elevated risk of ID still with adequate ICS. is risk is likely due to the low ICS in rural regions and low consumption of iodised salt [27,29,30]. e ICS for this group has been readjusted in some countries, including China, because this group requires more iodine compared to the rest of the population [48].

East Asia and Europe.
In the four studies concerning China and Turkey, there had been a change from ID in the population between 2006 and 2008 [27,28] to adequate iodine between 2015 and 2018 [14,19]. In China, the salt iodisation programme had become sustainable for the entire population by 20 years after intervention. It began in 1990 and the iodine concentration has been adjusted seven times during the intervention [16,[18][19][20]. is readjustment started with 40-60 mg iodine/kg salt when the country had ID [28] and was then adjusted to 15-40 mg iodine/kg salt in 2010. e programme has achieved sustainable IDD elimination in 32 provinces. From 2011 to 2018, the ICS was readjusted again by reducing iodine concentration in salt, and adequate iodine was achieved again in all provinces in 2014. In 2017, it was effective for pregnant women and, in 2018, sustainable for the iodine concentration in areas near water. However, stopping salt iodisation programmes in areas with water that has a high iodine concentration can be a big problem. However, stopping salt iodisation programmes in areas with higher iodine concentration in water and soil may not be the solution, but if in these areas readjusted iodine in all sources including salt may correct iodine, it has bad consequences. ese findings show one experience of the good progress of the salt iodisation programme based on reduced iodine in salt as part of the USI strategy. is evidence is supported by other authors; for example, in Morocco in 1995, the authorities recommended a level of iodisation of the 80 ppm when the level of TGR in the country was higher, in 2009, this was reduced to 15-40 ppm, and now, the country people have adequacy, other countries are with Qatar since 1996, the country has adequate UIC in population, and now the country pulls out all the stops to reduce iodine concentration in salt. United Arab Emirates, Kuwait, Oman, Bahrain, and Palestine archived adequacy UIC in people since 1996, and they have the initiative to reduce iodine in salt [42].
In Turkey, the salt iodisation programme became sustainable for the population 14 years after the intervention began in the urban areas in the south, based on increased adequate iodised salt coverage. Since 2001, it has never been readjusted [14]. In 2001, urban areas in the west, with 20-40 mg iodine/kg salt, had ID and IDDs, and the iodised SC was >68% [27]. After 4 years with the same iodine concentration in salt, in urban areas in the south, the iodised salt coverage was >90% and the programme was sustainable.
e salt iodisation programmes in Turkey and China have shown remarkable success. Although the countries have used different strategies-China has reduced the ICS over time whilst Turkey has maintained the ICS-in both countries, the ICS was adequate [42,43].
Of note, IDDs also occur in countries with higher consumption of other food sources of iodine, such as milk, dairy products, and water. It is necessary to readjust the salt iodisation polices that may be underlying these aspects. e monitory of UIC and SIC is recommended does three and three years, but in every ten years of the implemented salt iodisation programmes, the UICs in the population are adequate (median UIC based on scholar children), but the people with excess iodine intake increased, or TGR is >5% because it occurs also in the situation of iodine excess intake, or because of their consequences with thyroid dysfunction in population or increased iodine deficiency in some groups with pregnant women and lactating women. Salt iodisation is necessarily readjusted and assesses other contributed factors of iodine variation in diet.

Limitations.
e limitations of this review are the limited number of representative studies; few studies for the Americas and Europe and different methodologies were used to calibrate the iodine content in salt, resulting in different iodine quantifications. However, five of the 13 countries had been assessed more than one time, and some in different regions of the same country. According to UNICEF recommendations, the inclusion of many scenarios to assess ID in people is necessary.

Conclusions
is review shows that UIC levels have increased from 16.9% to 166% and also TGR has reduced by 1.2% to 62.3% within 18 years in populations with ID. Hence, salt iodisation programmes have had good impacts on health. e outcomes confirm that 18 years after the implementation of salt iodisation programmes in the 13 countries examined in the included reviews, most had achieved sustainable elimination of IDDs with an adequate UIC. Nevertheless, more detailed studies are still needed to confirm that all communities are equally protected against IDDs. erefore, over time monitoring of impact indicators is relevant. Eliminating IDDs throughout the entire world is the next stage. For this endeavour, the iodine concentration in salt must be adequate according to legislations and coverage iodised salt increased in the household, as well as monitoring all sources of iodine intake in the diet is required to provide a better prediction of the iodine deficiency whilst avoiding excess iodine intake. However, iodised salt still remains the first source of iodine in diet able to be adequate in iodine and reduces TGR. In addition, pregnant and lactating women must be especially considered because they are in great need of iodine by susceptibility to iodine losses.

Data Availability
No data were used to support this study.

Conflicts of Interest
e authors declare no conflicts of interest.