Iodine intake in human nutrition: a systematic literature review

The present literature review is a part of the NNR5 project with the aim of reviewing and updating the scientific basis of the 4th edition of the Nordic Nutrition Recommendations (NNR) issued in 2004. The main objective of the review is to assess the influence of different intakes of iodine at different life stages (infants, children, adolescents, adults, elderly, and during pregnancy and lactation) in order to estimate the requirement for adequate growth, development, and maintenance of health. The literature search resulted in 1,504 abstracts. Out of those, 168 papers were identified as potentially relevant. Full paper selection resulted in 40 papers that were quality assessed (A, B, or C). The grade of evidence was classified as convincing, probable, suggestive, and no conclusion. We found suggestive evidence for improved maternal iodine status and thyroid function by iodine supplementation during pregnancy. Suggestive evidence was found for the relationship between improved thyroid function (used as an indicator of iodine status) during pregnancy and cognitive function in the offspring up to 18 months of age. Moderately to severely iodine-deficient children will probably benefit from iodine supplementation or improved iodine status in order to improve their cognitive function, while only one study showed improved cognitive function following iodine supplementation in children from a mildly iodine-deficient area (no conclusion). No conclusions can be drawn related to other outcomes included in our review. There are no new data supporting changes in dietary reference values for children or adults. The rationale for increasing the dietary reference values for pregnant and lactating women in the NNR5 needs to be discussed in a broader perspective, taking iodine status of pregnant women in the Nordic countries into account.

I odine is an essential component of the thyroid hormones, thyroxine (T 4 ) and triiodothyronine (T 3 ), necessary for normal growth, development, and metabolism during pregnancy, infancy and throughout life (1Á3). When the physiological requirements for iodine are not met, a series of functional and developmental abnormalities occur, including thyroid function abnormalities. Severe iodine deficiency results in hypothyroidism, endemic goiter and cretinism, endemic mental retardation, decreased fertility, increased prenatal death, and infant mortality (1Á 4). High iodine intake may also cause disturbances in the thyroid function (1Á4).
In the 4th edition of the Nordic Nutrition Recommendation (NNR) (4) issued in 2004, the recommended daily intake (RDI) of iodine was kept unchanged from the 3rd edition (1996). RDI was set to 90 mg/day for children aged 2Á5 years, 120 mg/day for children aged 6Á9 years, and 150 mg/day for children from 10 years of age, adolescents, and adults. The RDI for iodine presented in NNR 2004 for children, adolescents, and adults is in line with current reference values from different countries and organizations (1,5). In the 4th edition of NNR, an extra 25 mg/day was recommended during pregnancy (RDI set to 175 mg/day) and extra 50 mg/day during lactation (RDI set to 200 mg/day) to provide sufficient iodine in the breast milk (NNR 2004). These reference values were lower than the reference values of 200 mg/day during pregnancy and 250 mg/day during lactation presented by FAO/WHO in 2005 (1). Furthermore, the WHO/UNICEF/ICCIDD recently increased reference values for pregnant women from 200 to 250 mg/day (6).
The recommended indicator for measuring iodine status is based on the population median urinary iodine concentration (UIC) and iodine intake is regarded as adequate when the UIC is 100Á199 mg/L (2,3). Population iodine sufficiency during pregnancy is defined by median UICs of 150 Á249 mg/L (6).
The present literature review is a part of the NNR5 project with the aim of reviewing and updating the scientific basis of the 4th edition of the NNRs (4) issued in (Nord 2004. A number of systematic literature reviews will form the basis for establishment of dietary reference values in the 5th edition of NNR.

Aims
The overall aim was to review recent scientific data on health effects of iodine status (as an indicator of iodine intake). The specific objectives of the review were to assess the influence of different intakes of iodine at different life stages (infants, children, adolescents, adults, elderly, and during pregnancy and lactation), in order to estimate the requirement for adequate growth, development, and maintenance of health. In collaboration with the NNR5 horizontal group on pregnancy and lactation, we added one specific aim, that is, to assess the scientific evidence and special relevance for the Nordic setting by increasing the RDI of iodine during pregnancy and lactation from what was presented in the 4th edition of NNR.
Research/key questions Five research questions were developed: (1) What is the effect of insufficient iodine intake, from diet and supplements, on functional or clinical outcomes in different life stages (pregnancy, infancy, childhood, adulthood, and elderly)? (2) What is the effect of excessive iodine intake, from diet and supplements, on functional or clinical outcomes in different life stages (pregnancy, infancy, childhood, adulthood, and elderly)? (3) What is the association between iodine status (dose response) and clinical and functional or clinical outcomes? (4) What is the effect of iodine intake from different sources on iodine status (UIC)? (5) What are the effects of other nutrients, such as selenium and iron, on iodine status?
The main functional or clinical outcomes of interest were pregnancy outcome, childhood development (including cognitive function and growth), thyroid function (thyroid hormones, thyroid gland size, hyper-and hypothyroidism), metabolism, health, and weight. See Appendix 1 for search terms. Out of the five research questions, only the studies related to the first three are presented in this review, the reason being lack of data related to research questions four and five.

Methods
Search terms were defined during spring 2010, in collaboration with Sveinn Olafsson, librarian at Landspitali The National University Hospital of Iceland, Reykjavik, Iceland. The search terms are presented in Appendix 1.
The final search was run in September 2010, including all the relevant population groups and clinical outcomes, resulting in 1,516 abstracts. Studies published from January 2000 until September 2010 were included. Abstract screening was conducted in October and November 2010 according to the guide for conducting Systematic Literature Reviews for the 5th edition of the NNRs. Inclusion criteria in the abstract screening process were the following: relevant to iodine nutrition in the Nordic countries, Nordic or English language,]50 subjects, representative samples of the population or specific sub-samples of the population, preferably using UIC (spot samples or 24-h collections) as indicator of iodine status. Other potential indicators of iodine status and thyroid function, such as thyroid volume (TV), thyroid-stimulating hormone (TSH), T3 and T4, were also included. Most cross-sectional studies, only describing iodine status without clinical outcomes of interest for this review, were excluded at this point. Exceptions were studies conducted in one of the Nordic countries or studies with clinical outcomes of interest that might not be covered by data from cohort studies or intervention trials.
The overall aim of the present work was to review and update the scientific basis of the NNRs (NNR 4th edition), issued in (Nord 2004. As a systematic review was not used as basis for the NNR 2004, we decided to order some review papers along with original papers. The reason for this decision was also related to the special aim of the current review to assess the scientific basis for recently increased reference values from WHO/UNICEF/ICCIDD for pregnant women (6), and the relevance for the Nordic setting. All together 276 full papers were ordered, of which 108 papers were immediately excluded and not included in the full paper selection (86 overviews, 19 editorials, commentary, prize lectures, opinions or letters to the editors, and 3 publications that had been withdrawn), leaving 168 publications. Full paper screening was conducted in February 2011, where 128 papers were excluded, leaving 40 papers selected for quality assessment. Reasons for exclusion are provided in Appendix 2. The selected papers were grouped according to clinical outcomes and different age stages into the following categories: pregnancy and lactation, including endpoints such as birth outcome, development, and health of the offspring (n016); children, including endpoints such as cognitive function and development (n09); excessive iodine intake (n04); and adults (n 02). Studies from the Nordic countries (n 013) were assessed separately in order to get an overview of iodine nutrition in the Nordic countries. Many of the Nordic studies only included descriptive information, while others were included in the relevant categories (according to clinical endpoints presented in each paper) at a later stage (n 04, all in the pregnancy and lactation category).
To evaluate the quality of the selected articles (n040), we used the Quality Assessment Tool (QAT) received from the NNR5 secretary. The QAT included questions about study design, recruitment, compliance, dietary assessment, confounders, statistics, outcomes, and so on. The summary of findings from studies graded as A or B according to QAT are presented in summary Tables 1Á6. Detailed information is provided in evidence tables (Appendix 3Á7). Main results of the papers graded C are given in the text, but those studies are not used in the final grading of evidence. The grade of evidence was classified as convincing, probable, suggestive, and no conclusion, in line with criteria introduced in the Systematic literature review (SLR) guide for the 5th edition of NNR.

Pregnancy and lactation
Iodine status and thyroid function Studies relating iodine status during pregnancy to maternal and/or neonatal thyroid function are presented in Table 1 (details are provided in Appendix 3). An Italian trial (7) assessed iodine status and thyroid function in women after supplementation of 200 mg iodine or 50 mg iodine per day during pregnancy and up to 6 months after delivery. Improved iodine status was observed in both groups, but no difference in thyroid function was found between groups. The most relevant studies in the Nordic perspective are those from Denmark (8,9). The study by Nøhr and Laurberg (9) included healthy pregnant women with no previous history of thyroid disease, comparing maternal and neonatal thyroid function between mothers receiving 150 mg iodine as a supplement during pregnancy to those not receiving any supplements. Although small difference in thyroid function was seen between groups, the study suggests that iodine supplementation of the mother will, in general, not improve fetal thyroid function in areas such as Denmark with mild iodine deficiency. A randomized controlled trial was conducted by the same research group among women with thyroid peroxidase antibodies (TPO-Ab), showing that it is unlikely that supplementation of 150 mg/day will have adverse effects in TPO-Ab women living in an area with mild-to-moderate ID (8).
Iodine nutrition of pregnant women from Norway (n 0119) was studied by Brantsaeter (C-study) and colleagues (10). Women using dietary supplements had median iodine intake of 215 mg/day (range 106Á 526) compared with 122 mg/day (range 25Á340) among non-supplement users. The median UIC was also significantly higher in iodine supplement users (190 mg/24 h for FFQ and 220 for FD) than in non-supplement users (110 mg/24 h) (10).

Pregnancy complications and pregnancy outcomes
All studies in this category were evaluated as low-quality studies (C) due to high drop-out rate, or other methodological issues (data not shown). Higher birth weight of infants whose mothers had UIC 50Á99 mg/L compared with those with UICB50 mg/L was reported in a cohort study from Spain (11). Three more studies assessed the association between iodine status and reproductive failure (12) or pregnancy complications (13Á14). Table 2 (details are provided in Appendix 4) describes studies relating prenatal indicators of iodine status to cognitive function in the offspring. In the study by Choudhury and Gorman (15), Chinese infants were stratified into iodine deficiency groups (ID) by cord blood TSH concentration. Lower mental developmental index (MDI) was observed in the group with highest cord blood TSH. The third study in Table 2 describes results from Project Viva (16) where associations between maternal as well as newborn thyroid function and cognitive function were assessed. Higher level of T 4 in newborns was associated with slightly lower scores on the visual recognition memory test at 6 months. However, no association was observed between maternal or newborn thyroid function and cognitive function at 3 years. It should be noted that low number of women had abnormal thyroid function in the study. Other studies in this category were quality graded as C-studies, as the statistical analysis was questioned or potential confounding factors not adjusted for (data not shown). The Berbel study (17) was a non-randomized intervention study where iodine supplementation (200 mg KI/day) was initiated at 4Á6 weeks or 12Á14 weeks of pregnancy or after delivery. The study suggests that delay in maternal iodine supplementation increases the risk of neurocognitive developmental delay of their offspring. Only 11Á12% of the total study population was included in the analysis as the authors established extensive exclusion criteria in order to obtain comparably homogenous groups of children. In a non-randomized intervention study by Velasco and colleagues from 2009, pregnant women were provided with 300 mg iodine in the intervention group, while a control group received no supplementation. Psychomotor development index (PDI, which is one of three scales of the Bayley Scales of Infant Development used in the study) was significantly higher in children of mothers in the intervention group than the control group (18). However, lactation was found to be a confounding factor explaining the variance in the PDI. Other possible TSH Mothers in the 'I group had lower TSH (mU/L), than the no I group. The 'I group of neonates had higher TSH than the no I group.

B
The study suggests that iodine supplementation of the mother will, in general, not improve fetal thyroid function in areas such as Denmark with mild iodine deficiency. A slightly inhibitory effect may be expected, which is probably not of clinical significance. Nøhr et al., 2000 (8) Pregnant women with thyroid peroxidase antibodies (TPO-Ab) n066 150 mg iodine supplement or no iodine supplementation.

Postpartum thyroid dysfunction (PPTD)
TPO-AB level at screening was a good predictor of the PPTD risk. No statistical significant difference in the frequency of PPTD in the three groups, with no significant increase in the prevalence, severity, or duration of PPTD when 150 mg iodine was given to TPO.
A Unlikely that supplementation of 150 mg/day will have adverse effects in TPO-Ab women living in an area with mild to moderate ID.

Ingibjö rg Gunnarsdottir and Lisbeth Dahl
confounding variables were not controlled for and the results should therefore be considered as preliminary. In a study from China, cognitive function was assessed in children (5-go 7-year-old follow up) whose mothers initiated iodine supplementation during different stages of pregnancy (early: 1st, 2nd or late: 3rd trimester) and in a control group of children receiving iodine supplementation from 2 years of age (19). The main results point towards the suggestion that children would benefit from their mothers iodine supplementation during pregnancy in the particular population studied.

Lactation
The literature search did not result in many papers related to lactation, and only three papers in this area were selected for quality assessment. A Danish study from 2004 (B study according to quality assessment), that was already included in the NNR 4th edition (4, 20), showed that the level of iodine in the breast milk of smokers was 26.0 mg/L (23.2Á29.1 mg/L) and in nonsmokers 53.8 mg/L (49.4Á58.5 mg/L), pB0.001. Significant differences were also found in the infants, as the urinary iodine in infants with smoking mothers was 33.3 mg/L (29.9Á37.2) versus 50.4 mg/L (46.0Á55.1 mg/L) in nonsmokers. Although the main message to breastfeeding mothers would be not to smoke, this study highlights the importance of obtaining enough iodine from the diet or through supplementation. Several methodological issues (such as low participation rate and lack of adjustments for potential confounders) where observed during quality assessment of the other two studies in this category (21Á22). UIC was higher in formula-fed infants than breastfed in a study from New Zealand, although no information was provided on the iodine status of the lactating mothers (21). In an Australian study, a correlation between iodine status of the mothers and iodine content of breast milk was found (22).

Cognitive function
Results of three studies are presented in Table 3 (details are provided in Appendix 5) (23Á25), all suggesting improved cognitive function in 6-to 13-year-old children related to iodine supplementation or improved iodine status. The results from the Gordon study, performed in New Zealand, might be relevant in the Nordic setting since the study includes children from a mildly iodinedeficient area (UIC 63 mg/L at baseline). The study suggests that mildly iodine-deficient children might benefit from iodine supplementation of 150 mg/day, in order to attain their full intellectual potential. However, the two other studies might not be relevant in the Nordic perspective, including children from iodine-deficient area of Albania and North Benin. A cross-sectional study from Spain points in the same direction (26), where an

Ingibjö rg Gunnarsdottir and Lisbeth Dahl
intelligence quotient below the 25th percentile was significantly related to UI below 100 mg/L (OR 1.4, p00.02), adjusted for potential confounding factors (data neither shown in Table 3 nor included in grading of evidence).

Other outcomes
Only cross-sectional studies were retrieved studying the relationship between iodine status or iodine supplementation and outcomes such as hearing (27), body composition (28, 29), growth, and insulin-like-growth factor-I (30). References to these studies are only included in this review for informational purpose as cohort studies or intervention studies were lacking (data not shown). In an intervention study by Zimmerman (graded as B study) iodine-deficient children (UI at baseline 46 mg/L) were supplemented with iodized oil or iodized salt for 5Á6 months. A significant increase was observed in UI in the iodine group (UI 158 mg/L at endpoint), while total and LDL-cholesterol concentration as well as C-peptide decreased (data not shown) (31).

Adults and elderly
The literature search did not result in many studies, including adults and elderly in relation to iodine. Only two publications were selected for quality assessment in this category, both graded as B studies (Table 4, details are provided in Appendix 6). Subjects with the metabolic syndrome were found to have increased TV and nodule prevalence, and insulin resistance was suggested as an independent risk factor for nodule formation in an iodine-deficient environment (32). However, no information was provided on iodine nutrition (neither urine iodine nor iodine intake), making the study less relevant for the purpose of NNR. Prostate cancer incidence according to UIC concentration (7-to 21-year followup) was assessed in the First National Health and Nutrition Examination Survey Epidemiological Followup Study (NHEFS) (33). After adjustments for potential confounding factors, the association found turned out to be non-significant. However, reported history of thyroid disease was associated with greater than two-fold increased risk of prostate cancer.

Excessive intake
Four studies related to excessive iodine intake were a subject to quality assessment by the group. In children, UIC]500 mg/L was found to be associated with increasing Tvol in 6-to 12-year-old children, while UIC 300Á500 mg/L was not (34) ( Table 5, details are provided in Appendix 7). Results of other selected papers in this category should be interpreted with caution due to lack of information, especially related to adjustments for potential confounding factors (35Á37) (data not shown). A prospective community-based survey among 13-year-old Chinese children, examined again 5 years later, found no difference in occurrence of autoimmune hyperthyroidism between communities with median UIC of 88, 214, and 634 mg/L (35). A caseÁcontrol study (36) showing small but significant difference in UIC between women with autoimmune subclinical hypothyroidism and the matched controls (3279113 vs. 274999 mg/L, pB0.01), and a Chinese cohort study by Guan et al. (37) suggested that postpartum thyroiditis (PPT) in pregnant women is triggered by high (defined as UIC!300 mg/L) iodine intake.

Iodine nutrition in the Nordic countries
The majority of the studies in the area of iodine nutrition from the Nordic countries are from Denmark. In total, 13 studies from Nordic countries were selected for quality assessment. Results of four of them have already been presented in the section on pregnancy and lactation (8Á10, 20). Main results of the studies from the Nordic countries are presented in Tables 6 and 7.

The effect of iodization of salt on iodine status in Denmark
The Danish Investigation of Iodine Intake and Thyroid Disease (DanThyr) is the official clinical monitoring of  Smokers have lager thyroid volume than non-smokers; however, the difference in thyroid volume was reduced after iodization. The effect of smoking on TSH and free T 4 was unchanged after iodization.

B
The effect of smoking on thyroid volume seems to be dependent on iodine intake.

TSH and prevalence of thyroid dysfunction
Higher TSH level after iodization in both regions and across age groups. Lower prevalence of mild hyperthyroidism and increased prevalence of hypothyroidism related to a higher iodine intake.

B
Increased iodine intake after mandatory iodization change the pattern of thyroid dysfunction in the population.

Ingibjö rg Gunnarsdottir and Lisbeth Dahl
the Danish iodine supplementation program, which prospectively measure the incidence rates of hyper-and hypothyroidism in the cities of Aalborg and Copenhagen.
In the first examination in 1997Á98, the Aalborg area was found to be in the range of moderate iodine deficiency, whereas the area around Copenhagen had mild iodine deficiency (38). The difference in iodine intake in these two areas can mainly be explained by the difference in iodine content in drinking water (5 mg/L in Aalborg and 18 mg/L in Copenhagen) (39). In 2000, it became mandatory to fortify all salts used in bread and household with iodine at a level of 13 mg/g. In 2004Á2005, the urinary iodine excretion had increased significantly in all age groups compared with before mandatory iodine fortification in both areas. For instance, the medianestimated 24-h urinary iodine excretion in both areas was 78 mg/day before iodization and 140 mg/day after iodization among non-supplement users. The corresponding median UIC in both areas increased from 61 mg/L in 1997Á1999 to 101 mg/L in 2004Á2005 (39). However, the iodine intake in the youngest age groups in both cities and in women aged 40Á45 years in the Aalborg area was still below the recommendation after the mandatory iodization of salt (39). Milk, water, and salt intake were determinants of iodine intake in 2004Á2005, whereas bread and fish intake were not related with iodine intake (39).

Associations between iodine status and thyroid function
The studies from Denmark based on the DanThyr programme shows marked differences in pattern of thyroid dysfunction with different iodine intakes (40, 41) and the optimal level of iodine intake to prevent thyroid disease may be a relatively narrow range around the recommended daily iodine intake of 150 mg (42). In general, mild and moderate iodine deficiency is associated with more hyperthyroidism and less hypothyroidism than high iodine intake (42). In 1997Á1998, the incidence rate of hyperthyroidism was higher in the Aalborg area with moderate iodine deficiency (with UI of 45 mg/L) compared with the Copenhagen area with higher iodine intake (mild iodine deficiency) (with UIC of 61 mg/L) (38). Further, hyper-and hypothyroidism were more common in females than in males in both areas, and the incidence rates of both hyper-and hypothyroidism increased with age. In the Copenhagen area, a higher incidence rate of hypothyroidism was found compared with the Aalborg area. Even the small differences in UIC from mild (61 mg/L) and moderate (45 mg/L) iodine deficiency areas in Denmark showed marked differences in the prevalence of goiter with 9.8% goiter in the mild iodine deficiency area (Copenhagen) and 14.6% goiter in the moderate iodine deficiency area (Aalborg) (43, 44).
A lower TV was seen in all age groups independent of sex after iodization and the decline was largest in the Aalborg area with former moderate iodine deficiency (40). The level of TSH was also found to increase from 1.30 mUI/L to 1.51 mUI/L in both regions and across age groups after the introduction of iodization of salt (41). The increase was expected as populations with iodine sufficiency in general have a higher level of TSH than populations with iodine deficiency (41). The effect of smoking on hormonal levels of TSH and free T 4 were unchanged after the iodization, however, increased iodine intake had an effect on the TV of smokers, as the difference in TV between heavy smokers and nonsmokers was reduced after iodization of salt (45).
Iodine status: studies from other Nordic countries A cross-sectional study of Swedish national data on UIC of children aged 6Á12 years indicated adequate iodine nutrition, and there were no gender or age differences in median UIC of the children (46). This study provides evidence that the voluntary addition of iodine to salt since 1,936 at a level of 40Á70 mg/kg is sufficient to ensure adequate iodine nutrition in the Swedish population (46). Iodized table salt remains the main dietary source of iodine in the diet and among adults it is estimated to provide more than 50% of the iodine intake in Sweden (46). In another Swedish cross-sectional study among small groups of children, teenagers, and adults, the median UIC suggested adequate iodine nutrition (47).
A cross-sectional study including adolescent girls from Iceland found optimal iodine status; however, the result should be used with cation, as only 39% completed the study. Still the results are good estimates of the iodine nutrition of adolescent girls from Iceland (48).
Results from a representative study in Norway suggest that the dietary iodine intake is in the range considered to be sufficient among adults and children; however, it decreased among adolescents, especially among girls (49). Regular intake of milk, dairy products, and seafood are of importance to secure adequate iodine intake in Norway as the iodization of salt (only table salt) is very low (5 mg/g). This was clearly shown in the study including subjects with a variable intake of fish and dairy products, which indicated mild iodine deficiency among subjects having low intake of these two food groups (50).

Discussion
Iodine deficiency remains a major threat to the health and development of populations around the world, and it is claimed that much of Europe is iodine deficient (51). The iodine status in all the Nordic countries is not well documented; however, based on UIC, the iodine nutrition status in Denmark, Iceland, Finland, and Sweden is sufficient and it is deficient in Norway according to WHO data (51). The overall aim was to review recent scientific data on health effects of iodine status (as an indicator of iodine intake) in order to update current Nordic dietary reference values and to assess the scientific evidence and special relevance for the Nordic setting by increasing the RDI of iodine during pregnancy and lactation from what was presented in the 4th edition of NNR.
Grading of evidence is presented in Table 8. It should be emphasized that the grading of evidence is only based on studies from 2000Á2010 and in some cases inclusion of earlier studies might have resulted in different grading. Evidence supporting that iodine supplementation during pregnancy is associated with maternal iodine status and thyroid function is suggestive (7, 9). One A study and one B study showed improved cognitive function of infants and children up to 18 months with potential indicators of improved iodine status of the mother (15, 16), while the evidence for improved cognitive function in older children is limited. It should be noted that no direct measurements of iodine intake where used in these studies (15,16), and the conclusions are therefore based on the association between thyroid function (as an indicator of iodine status) and cognitive function of the offspring. The relevance of these studies to be used to set recommendations on iodine intake might therefore be questioned. Moderately to severely iodine-deficient children (6Á13 years) will probably benefit from iodine supplementation or improved iodine status in order to improve cognitive function (23Á 25, 31), while only one study showed improved cognitive function with iodine supplementation in children from a mildly iodine-deficient area (23). No conclusions can be drawn related to other outcomes included in our search. A second literature search (using the same search string as previously) was conducted in March 2012, including Iodine status is related to risk of prostate cancer.
No conclusion One B study Hoption Cann et al., 2007 (33) Excessive intake of iodine (UIC 300Á500 or !500 mcg/ L) is associated with adverse effects in children.
No conclusion One B study Zimmermann et al., 2005 (34) *Using the criteria for assigning grade of evidence presented in the WCRF cancer report, introduced in the SLR guide for the 5th edition of NNR.
studies published in the period October 2010 to February 2012. No additional studies were included in this review, as it would not modify the conclusions drawn from the studies included. Surprisingly, dietary data was only included in a very low number of studies. Furthermore, in many cases the exposure was thyroid function rather than estimate of iodine intake (i.e. UIC). Definitions of severe, moderate, and mild iodine deficiency also vary between studies. It is therefore challenging to use information from the studies included in this review in order to set dietary reference values.

Conclusions
There are no new data supporting changes in dietary reference values for children or adults. Although the WHO/UNICEF/ICCIDD has increased the RDI for iodine from 200 to 250 mg/day in pregnancy and in lactating women (6), they emphasized the need for more data on the level of iodine intake that ensures maternal and newborn euthyroidism. The iodine requirement during pregnancy is increased because the mother synthesizes Â50% more iodine-containing thyroid hormones to maintain maternal euthyroidism and to transfer thyroid hormones to the fetus and because the mother has increased renal losses of iodine (3). The rationale for increasing the dietary reference values for pregnant and lactating women in the 5th edition of NNR needs to be discussed in a broad perspective taking into account iodine status of pregnant women in the Nordic countries. Nordic studies retrieved have mainly described the thyroid function rather than the intake and sources of iodine in the diet. Further studies are required, especially among the most vulnerable groups, but also studies which assess possible adverse effects of high intake of iodine.