Flaws of universal salt iodization programmes in nutrition transition contexts: is there a risk of a double burden of inadequate iodine intake and excess adiposity? A case study in Tunisia

Background In the Middle East and North Africa (MENA) region, universal salt iodization (USI) programs defaults were sometimes shown to increase the risk of iodine excess. Also, the nutrition transition which underlies the obesity epidemic in the MENA region is characterized by salt-rich diets, so that there could be a cumulative effect with respect to iodine status. We assess the within-subject co-existence of overweight and inadequate iodine intake, and associated factors. Methods A national cross-sectional study used a stratied, clustered random sample and conducted among Tunisian school-age children aged from 6 to 12 y. (n = 1560). Overweight (Ow) was body mass index (BMI)-for-age ≥ + 1z. Iodine deciency was UIC (Urinary Iodine Content) < 100 µg/L and iodine intake above requirements (IAR) UIC ≥ 200 µg/L. Association of covariables with the within-subject double burden Ow–IAR was assessed by multinomial regression. Results The prevalences of Ow-ID or Obe-ID were marginal, but not so for excess adiposity and IAR as for example prevalence of Ow-IAR was 9.8% (95% CI: [7.7–12.3]). OW and IAR were found to co-occur independently (P = 0.29). Socio-economic patterning of Ow-IAR was mild. Nevertheless, prevalence were the lowest among children of mother with no formal schooling and in the South-East region. Beyond school-age children, we estimated that this double burden of overweight and excess iodine could concern a third of Tunisian adults (all the more for women). Conclusions Among Tunisian children, iodine deciency coupled with excess adiposity was quite marginal. Coexistence of overweight and excess iodine may affect a tenth of these children. More data would be needed to document a possibly even higher rate among adults. Cumulative effects of unhealthy lifestyle due to the nutrition transition interacting with metabolic pathways may be involved in this potential overweight-high iodine intake double burden. In the MENA region, obesity and salt reduction policies should continue to be monitored.


Introduction
Overweight and obesity are nowadays a major global public health problem as more than 1.9 billion adults were overweight and 650 million obese in 2016 worldwide [1]. In the framework of the epidemiological and nutrition transition, overweight, obesity and associated non-communicable diseases have increased especially rapidly in the low-and middle-income countries (LMICs), including the Middle East and North Africa (MENA) region where the prevalence of obesity and diabetes are among the highest worldwide [2]. Nevertheless, the rapid changes in lifestyles underlying the nutrition transition, including towards westernized and more energy rich diets have not always been exclusive of the persistence of micronutrient de ciencies [3]. This has resulted in some contexts, in a double burden of malnutrition resulting from the co-existence of excess adiposity and/or associated Noncommunicable diseases (NCDs) and hypertension [4,5,20,21]. As for control of iodine de ciency, mandatory salt iodization had been implemented in speci c areas since 1984, but the national USI program was adopted in 1995 and launched in 1996 [18,22]. Its evaluation in 2012 showed some success regarding control of iodine de ciency, but also a high proportion of excess iodine intake, partly in relation with defaults in the salt iodization process and its monitoring [22].

Participants
The present study is a based on a secondary analysis of data collected in a previously documented national cross-sectional survey conducted in Tunisia between May and June 2012: 6-12 y. school-children (n = 1560) were surveyed using a random, strati ed, clustered sample [18].

Measurements Anthropometry
Anthropometric assessment was performed according to the World Health Organization (WHO) standards [23]. Height was measured using a wall-mounted stadiometer (Person-check®, Kirchner and Wilhelm, Germany) with a precision of 0.1 cm. Weight was measured using a calibrated scale (Detecto, Webb City, MO, USA. BMI (Body Mass Index = weight/height 2 ) for-age in z-scores was computed from the WHO reference for school-age children. Thinness was de ned as BMI-for-age < − 2 z-scores, overweight as BMI-for-age ≥ + 1 z and obesity as BMI-for-age ≥ + 2 z.

Iodine status
Urine samples were collected according to standardized procedures [24]. The Sandell-Kholthoff method was used to assess urinary iodine concentration (UIC) [16]. Details related to technique precision and validation were previously published [18]. The WHO cut-offs for assessment of population iodine status based on the median UIC (µg/L) were used to classify school-age children as follow [16,25]: UIC < 100 de ned iodine de ciency (ID), UIC ≥ 200 de ned iodine intake above requirements (IAR 200 ) and UIC ≥ 300 de ned excess of iodine status(IE 300 ).

Co-occurrence of inadequate iodine and anthropometric status
Nine different co-occurrences were studied: ID and overweight (or obesity or thinness), IAR 200 and overweight (or obesity or thinness), IE 300 and overweight (or obesity or thinness), (Table 1). Table 1 Prevalence of the co-occurrence of inadequate iodine status and thinness or excess adiposity among 6-12 y. Tunisian school children, by sex. f Thinness: BMI-for-age <-2 z-score, overweight: BMI-for-age ≥ + 1 z-score, obesity: BMI-for-age ≥ + 2 z-score Each double burden was coded as a categorical variable with four categories, e.g. for "iodine intake above requirements (UIC ≥ 200) and overweight": iodine intake above requirements and overweight(IAR 200 &Ow), iodine intake above requirements and not overweight (IAR

Socio-demographic characteristics
A self-administered questionnaire was used to collect information on the parent's occupation, instruction level and age.

Statistical analysis
Data management and statistical analyses were carried out with Stata software (version 14·0; StataCorp, College Station, USA). The type I error risk was set at 0·05 for all analyses. All estimates, standard errors, P-values and con dence intervals take into account the complex sampling plan (svy pre x in Stata).
Descriptive results are expressed as means for interval variables, and as proportions for categorical variables. For each of the nine combinations of iodine x anthropometric status, the null hypothesis of independence between the iodine and anthropometric status binary variables was assessed using chi-square tests. Associations between the double burdens in four categories and socio-demographic factors were quanti ed by relative prevalence ratios (RPR) estimated within multinomial logistic regression models using the mlogit Stata command [26]: the response reference category was that of both not inadequate iodine and no excess adiposity (e.g. for the "Iodine Above Requirements and Overweight" double burden, this was the Ow category).This analysis, using double burdens coded as 4 category response variables, enabled to estimate associations with co-variates of single and double burdens from the same model (v. the same response reference category i.e. subjects with none). For each covariable (milieu, region, sex, age, mother's and father's level of education and professional activity), crude associations were estimated in univariate models featuring one covariate at a time. Adjusted associations were derived from a multivariate model including all covariables.
Descriptive analyses were rst performed separately for girls v. boys. But as we did not observe meaningful differences, multivariate analyses were ultimately ran and presented for girls and boys together.

Sample characteristics
The population characteristics have been previously published [18]: 1560 school children were included in the study, and their mean age was 9.3 ± 0.04 y.

Co-occurrence of inadequate iodine and anthropometric status
There was no difference in prevalence between girls and boys, whatever the co-occurrence of inadequate iodine and anthropometric status considered ( Table 1). The highest overall prevalence of double burden was observed for the co-occurrence of IAR 200 & Ow at 9.7% (95%: 7.7-14.3). Also, 5.0% (95%: 3.7-6.7) of the children featured both IE 300 & Ow. Other types of inadequate iodine and anthropometric status double burdens were rare. Our data did not provide any evidence at the 0.05 alpha level against the null hypothesis of independence between inadequate iodine an anthropometric status, whatever the combination considered (P-value for chi-square tests ranging from 0.29 to 0.74).

Association of the double burden with socio-demographic factors
The reported results are relative only to the study of the iodine intake above requirements (UIC ≥ 200) -overweight double burden due to the low rate of the other forms (Table 2).

Discussion
In a nutrition transition context, where excess adiposity but also inadequate iodine intake is of concern among children, our original study assessed the prevalence and the associated factors of the different forms of the within-subject double burden of excess of adiposity and inadequate iodine status among Tunisian 6-12 y. children. We showed that the most prevalent form of such a double burden was the co-occurrence of IAR (UIC ≥ 200) with overweight, which concerned one child out of ten. We also underlined that excess adiposity and the different types of inadequate iodine (ID, IAR and IE) status co-occurred independently.
As this study is to our knowledge the rst to tackle that issue, comparisons are di cult. This prevalence is coherent with the observed signi cant prevalences of both iodine intake above requirements (one child out of two) and overweight (two children out of ten). Nevertheless, how the prevalence of the double burden derives from the prevalences of each single burden depends on whether their co-occurrence is synergistic (e.g. the probability of iodine intake above requirements increases if the child is overweight or vice versa), antagonistic (e.g. the probability of iodine intake above requirements decreases if the child is overweight and vice versa) or independent. In the present study, whatever the type of iodine inadequate status (i.e. de ciency or excess), our data were in accordance with the hypothesis of its independent co-existence with overweight. Beyond the observed prevalences, this also is consistent with the observed associations of the excess iodine and overweight double burden with the area of residence and socio-demographic characteristics: indeed in the case of probabilistic independence it can be shown that the measure of associations (RPR) of the double burden IAR 200 &Ow with the co-factors should be identical  [15]. Nevertheless, there are several hypotheses that could be in favour of a non-independent co-occurrence of inadequate iodine status and overweight either at the physiological and environmental level.
Theoretically, the slowdown of thyroid activity (hypothyroidism) is believed to cause low metabolic rate, reduced gluconeogenesis, reduced liposis and hence promoting weight gain [50,51]. This hypothesis was consistent with the reported negative association between body mass index and thyroid hormones level [28,[30][31][32]52].
More than adequate iodine intake may increase subclinical hypothyroidism [53]. In fact, a recent research conducted by Shan and al. [54] reported that subclinical hypothyroidism prevalence was signi cantly higher among population having more than adequate iodine (22.6% vs. 12.7% for adequate iodine intake, P < 0.01). A meta-analysis reported a signi cant risk of hypothyroidism pertaining to iodine excess [55]. In the other hand, it is thought that hypothyroidism could be a consequence of obesity [56,57]. In fact, low chronic in ammation grade, typically observed in obese subjects, has been proposed to depress thyroid function [11,32,58]. The link seems to be ensured by the leptin and pro-in ammatory cytokines [59]. There are clear association between thyroid hypofunction and hyperleptinemia [33,60]. This raise of hyperleptinemia is showing to increase the secretion of the pro-in ammatory cytokines. The different links between thyroid function, leptin and obesity have been extensively reviewed by Duntas and colleagues [33]. Iodine appeared to be an important link in a loop con guration characterizing the association between thyroid gland and fat tissue accumulation.
Beyond the physiological pathways discussed above, in the context of the nutrition transition that countries of the MENA region are experiencing, there are also external factors e.g. linked to the food environment that could increase the risk of both inadequate iodine status and excess adiposity at subject level.
Generally, the nutrition transition is characterized by an increased intake of foods with a high sugar, fat and salt content, and Tunisia is no exception [10,17,61]. Indeed, several studies reported a very high salt consumption, from 11 to 14 g/day vs. the 5 g/day recommended. [62,63]. Also, as part of a worldwide strategy to tackle iodine de ciency disorders [16], Tunisia has implemented a USI program since 1995 [18]. Failure in the program monitoring and control has resulted in inadequately iodized salt (as a quarter of the commercialized salt is excessively iodized) [22]. In a such a context subjects with diets with high sugar, fat and salt content which would make them more prone to excess adiposity, would also be more at risk of excess iodine (as a cumulative effect of high salt intake and inadequate salt iodization). So that would be in favour of a synergetic rather than independent co-occurrence. There could be also interactions with the metabolic pathways above, e.g. in relation with the interactions between thyroid function and adipose tissue.
Compared with all the elements in favour of a synergistic co-occurrence explained above, our observations (which are in accordance with the independence hypothesis) may be due to methodological limitations. As for measurements, urine spot measurements have known limitations for the assessment of iodine status at individual level and especially long-term high iodine intake [64]. Also, no data was available about thyroid function biomarkers (free thyroxin and thyroid stimulating hormone). We did not either estimate iodine intake e.g. by measuring dietary intake. More importantly, it could be that the metabolic pathways pertaining to the non-independent co-occurrence of iodine excess and excess adiposity (and/or their interactions with environmental factors) get fully activated only in the long term. So that they would not manifest themselves fully in this population of 6-12 y. children. Testing that hypothesis would require the same kind of data on the same subjects when they reach adulthood or at a least on a comparable sample of adults. So that the 6-12 y. age-class is a limitation of our study. Nevertheless, this is by recommendation of the WHO, as school age children are the target age class for assessment of iodine status [25].
Beyond assessing the nature of the co-occurrence of iodine status and excess adiposity (i.e. synergistic, antagonistic or independent), the study population of school-age children also has limitations regarding the assessment of the magnitude of the double burden in the whole population. Nevertheless, WHO also considers that iodine status of school-age children can be used as an approximative estimate of iodine status of the whole population [16]. Based on the assumption that iodine status and excess adiposity are co-occurring independently, one can then infer a rough estimate of the double burden by the product of our observed prevalence of iodine intake above requirements (about a half) and that of overweight among Tunisian adults (about two thirds) [61,65]: so that about a third of Tunisian adults would be at risk of both iodine intake above requirements and overweight (and all the more for adult women which are much more prone to excess adiposity in this context). From the same reasoning one can infer that about one woman out of ten would also be affected by the cooccurrence of overweight and iodine de ciency. These estimates would be a lower bound if one takes into account that the co-occurrence of inadequate iodine status and excess adiposity is likely more synergistic than independent in older subjects (vs. our studied age-class for which our data was compatible with the independence hypothesis). But this estimated prevalence of subject-level co-occurrence of overweight and inadequate iodine intake are nevertheless signi cant from a public health point of view, especially with regards to intergenerational effects on risk of both chronic diseases and mental development [66] as we underlined they are higher among women which are much more prone to excess adiposity in the context.

Conclusion
In the MENA region, lifestyles which underly the increase in excess adiposity and associated NCDs include diets with possibly increased salt content. This may result in excess iodine intake, which may cluster with excess adiposity both due to these shared environmental factors and synergistic metabolic pathways. In this study of Tunisian children, this hypothesis was not shown to be true. While obesity and excess iodine intake were documented, little overlap was detected.
As the nutritional transition proceeds in the MENA region it would be useful to monitor the prevalent double burden of excess iodine intake and excess adiposity. Availability of supporting data: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

List Of Abbreviations
Competing interests: The authors declare no con icts of interest.
Funding: The work was supported by the Tunisian National Institute of Nutrition and Food Technology of the Tunisian Ministry of Health and by grants from UNICEF Tunisia.
The manuscript was drafted while RD was visiting research fellow at NUTRIPASS Unit, IRD (French National Research Institute for Sustainable Development), Montpellier, France, in 2018 (grant IRD "Mobilité Sud-Nord").