Background and review question
Many people around the world do not consume enough iodine. This is a problem because iodine is important for normal childhood growth and brain development, and for ensuring a healthy adult population. Inadequate intake of iodine can lead to health problems, such as intellectual disability and goitre (enlargement of the thyroid gland). Currently, the main strategy to increase the amount of iodine consumed in populations recommended by the World Health Organization is adding iodine to salt. However, in some areas where salt is not the major condiment, adding iodine to other foods has also been explored. The aim of our study was to examine the effect of adding iodine to foods, beverages, condiments, or seasonings, other than salt, on iodine nutrition status and health-related outcomes in all populations.
We searched for articles from different sources including published research papers, unpublished reports, and through direct communication with experts and organisations working to address iodine and micronutrient deficiency. We last searched the databases in January 2018.
Eleven studies, which captured data on 4317 participants (3636 children, 648 women of reproductive age, and 33 infants), met our inclusion criteria. The type of foods used as vehicle to deliver iodine differed between the studies, and included biscuits, milk, fish sauce, drinking water, yoghourt, fruit beverage, seasoning powder, and infant formula milk. The amount of iodine provided to participants ranged from 35 µg/day to 220 µg/day, and study duration ranged from 11 days to 48 weeks. Of the 11 studies included, five examined the effect of adding iodine alone to foods compared to either no intervention or the same foods without iodine; while six evaluated the effect of adding iodine plus other micronutrients to foods compared to the same foods without iodine, but with different levels of other micronutrients.
No study evaluated the effect of adding iodine to foods on death, mental development, cognitive function, cretinism (a condition characterized by impaired control of physical movement and intellectual disability), hypothyroidism (underactive thyroid), thyroid-stimulating hormone concentration, or serum thyroglobulin concentration (these are biological markers that indicate the presence of iodine deficiency when concentration in the blood is high).
Two studies reported on the effect of the intervention on goitre, one study assessed five physical development measures (weight, height, weight-for-age, height-for-age, and weight-for-height scores), and one examined adverse effects. All studies assessed urinary iodine concentration (the concentration of iodine secreted in the urine, which indicates the presence of iodine deficiency when concentration is low in a population group, rather than in an individual). We combined the data that met our requirements in these studies in a meta-analysis.
We are uncertain of the effects of iodine fortification on the proportion of participants with goitre, or on any of the five physical development measures. One study reported narratively that no adverse effects were observed during the trial. We found a significant increase of 38.32 µg/L in urinary iodine concentration after adding iodine to foods, compared to the groups that did not have iodine added, from studies of higher quality.
Quality of the evidence
Using GRADE, we rated the quality of the evidence as very low for goitre and physical development measures, due to study limitations (risk of bias) and imprecise results, and low for adverse events due to indirectness and imprecise results. We rated the quality of the evidence for urinary iodine concentration, from studies in which participants were allocated to treatment groups at random (gold standard design for clinical research), as moderate. On the other hand, quality of the evidence for urinary iodine concentration from studies without this random element was rated as very low, due to study limitations and imprecise results.
Overall, there is no clear evidence on the effect of the intervention on reducing the proportion of people with goitre, improving physical growth, or adverse events. However, our results show that adding iodine to foods likely increases urinary iodine concentration. Additional studies to better quantify the effect of the intervention on these outcomes, as well as other outcomes, are needed.
The evidence on the effect of iodine fortification of foods, beverages, condiments, or seasonings other than salt on reducing goitre, improving physical development measures, and any adverse effects is uncertain. However, our findings suggest that the intervention likely increases urinary iodine concentration. Additional, adequately powered, high-quality studies on the effects of iodine fortification of foods on these, and other important outcomes, as well as its efficacy and safety, are required.
Iodine deficiency disorders (IDD) affect close to 1.9 billion people worldwide, and are a major public health concern in many countries. Among children, iodine deficiency is the main cause of potentially preventable deficits of central nervous system development and impairment of cognitive function, as well as goitre and hypothyroidism in people of all ages. Salt iodisation is the preferred strategy for IDD prevention and control, however, in some instances where salt is not the major condiment, alternate vehicles for iodine fortification have been considered.
To assess the effects of fortifying foods, beverages, condiments, or seasonings other than salt with iodine alone or in conjunction with other micronutrients, on iodine status and health-related outcomes in all populations.
Studies were identified through systematic searches of the following databases from their start date to January 2018: Cochrane Public Health Group Specialised Register; CENTRAL; MEDLINE; MEDLINE in Process; Embase; Web of Science; CINAHL; POPLINE; AGRICOLA; BIOSIS; Food Science and Technology Abstracts; OpenGrey; Bibliomap and TRoPHI; AGRIS; IBECS; Scielo; Global Index Medicus-AFRO and EMRO; LILACS; PAHO; WHOLIS; WPRO; IMSEAR; IndMED; and Native Health Research Database. We also searched reference list of relevant articles, conference proceedings, and databases of ongoing trials, and contacted experts and relevant organisations to identify any unpublished work. We applied no language or date restrictions.
Studies were eligible if they were randomised or quasi-randomised controlled trials (RCT) with randomisation at either the individual or cluster level (including cross-over trials), non-randomised RCTs, or prospective observational studies with a control group, such as cohort studies, controlled before-and-after studies, and interrupted time series. We included studies that examined the effects of fortification of food, beverage, condiment, or seasoning with iodine alone, or in combination with other micronutrients versus the same unfortified food, or no intervention. We considered the following measures: death (all-cause), goitre, physical development, mental development, cognitive function and motor skill development, cretinism, hypothyroidism, adverse effects (any reported by trialists), urinary iodine concentration, thyroid-stimulating hormone (TSH) concentration, and serum thyroglobulin concentration. We included all populations, including pregnant women, from any country.
Two review authors independently assessed study eligibility, extracted data, and assessed risk of bias of included studies.
We used random-effects meta-analyses to combine data and generate an overall estimate of treatment effect, when more than one study examined the same outcome measure. The overall effect estimate was calculated as the mean difference (MD) or standardised mean difference (SMD) between the intervention group and the comparison group for continuous outcomes, and as odds ratio (OR) for dichotomous outcomes. We assessed the level of heterogeneity through the I² statistic. We conducted post-hoc subgroup analyses to explore possible sources of heterogeneity, and sensitivity analyses to check the robustness of the findings from the primary analyses. We assessed the quality of the evidence for each outcome using the GRADE framework.
Where it was not possible to pool the results in a meta-analysis, we provided a narrative summary of the outcomes.
Eleven studies met the criteria, providing 14 comparisons, and capturing data on 4317 participants. Seven studies were RCTs, three were cluster non-RCTs, and one was a randomised cross-over design. Seven studies were carried out among school children (N = 3636), three among women of reproductive age (N = 648), and one among infants (N = 33). The studies used diverse types of food as vehicle for iodine delivery: biscuits, milk, fish sauce, drinking water, yoghourt, fruit beverage, seasoning powder, and infant formula milk. Daily amounts of iodine provided ranged from 35 µg/day to 220 µg/day; trial duration ranged from 11 days to 48 weeks. Five studies examined the effect of iodine fortification alone, two against the same unfortified food, and three against no intervention. Six studies evaluated the effect of cofortification of iodine with other micronutrients versus the same food without iodine but with different levels of other micronutrients. We assessed one study to be at low risk of bias for all bias domains, three at low risk of bias for all domains apart from selective reporting, and seven at an overall rating of high risk of bias.
No study assessed the primary outcomes of death, mental development, cognitive function, cretinism, or hypothyroidism, or secondary outcomes of TSH or serum thyroglobulin concentration. Two studies reported the effects on goitre, one on physical development measures, and one on adverse effects. All studies assessed urinary iodine concentration.
The effects of iodine fortification compared to control on goitre prevalence (OR 1.60, 95% CI 0.60 to 4.31; 1 non-RCT, 83 participants; very low-quality evidence), and five physical development measures were uncertain (1 non-RCT, 83 participants; very low-quality evidence): weight (MD 0.23 kg, 95% CI -6.30 to 6.77); height (MD -0.66 cm, 95% CI -4.64 to 3.33); weight-for-age (MD 0.05, 95% CI -0.59 to 0.69); height-for-age (MD -0.30, 95% CI -0.75 to 0.15); and weight-for-height (MD -0.21, 95% CI -0.51 to 0.10). One study reported that there were no adverse events observed during the cross-over trial (low-quality evidence).
Pooled results from RCTs showed that urinary iodine concentration significantly increased following iodine fortification (SMD 0.59, 95% CI 0.37 to 0.81; 6 RCTs, 2032 participants; moderate-quality evidence). This is equivalent to an increase of 38.32 µg/L (95% CI 24.03 to 52.61 µg/L). This effect was not observed in the meta-analysis of non-RCTs (SMD 0.25, 95% CI -0.16 to 0.66; 3 non-RCTs, 262 participants; very low-quality evidence). Sensitivity analyses did not change the effect observed in the primary analyses.