Abstract
Background
The status of iodine nutrition of a population can be determined by measurement of urinary iodine concentrations since it is thought to indicate dietary iodine intake. Normally, these results are compared to population-based criteria, since there are no reference ranges for urinary iodine.
Objective
To determine the percentile ranges for urinary iodide (UI) concentrations in normal individuals in the United States.
Materials and methods
The third National Health and Nutrition Examination Survey (NHANES III) (1988–1994) database of the civilian, non-institutionalized, iodine-sufficient US population was used. The 2.5th to 97.5th percentile ranges for urinary iodine and for urinary iodine per gram creatinine ratio (UI/Cr) (μg/g) were calculated for females and males, 6–89 years of age, each stratified by age groups.
Results and conclusions
We calculated the percentile ranges for urinary iodine. After exclusions of subjects with goiter or thyroid disease, the study sample included 21,530 subjects; 10,439 males and 11,091 females. For women of childbearing age (14–44 years), urinary iodine concentration 2.5th to 97.5th percentiles are 1.8–65 μg/dl or 36–539 μg/g creatinine. For pregnant women, the ranges are 4.2–55 μg/dl or 33–535 μg/g creatinine.
Keywords: Iodine deficiency, diagnosis, epidemiology, environmental, prevention and control, Human, Nutrition surveys, Pregnancy, Public health
1. Introduction
Iodine is an essential micronutrient and an integral component of thyroid hormones. Normal concentrations of thyroid hormones are required for normal metabolism and optimal brain development, especially during gestation and the first 3 years of life. Iodine deficiency during pregnancy may result in neurodevelopmental deficits and in extreme cases in cretinism.
The status of iodine nutrition of a population is determined by measurements of iodine as urinary iodide (UI) concentrations since it is considered an indicator of the adequacy of the iodine intake of that population, when carried out with appropriate technology and sampling [1,2]. UI/Cr is considered a more reliable measure of iodine excretion than random spot concentration measurement since it corrects for hydration status and for body mass. The choice among methods depends on the intended application, reliability and complexity of instrumentation, number of samples, technical capability, safety and cost. Epidemiological field studies are large by default and therefore demand simple, reliable, rapid and cost-effective methods for determining the iodine status of the population.
The criteria for iodine deficiency in a population has been established by the World Health Organization (WHO) stating that the median UI concentration in a population should be >10 μg/dl, and ≤20% of the population should have UI concentrations of < 5 μg/dl [2]. If the UI per gram creatinine ratio is used for iodine evaluation, the ratio should be >50 μg I/g Cr [2].
However, these parameters apply to populations and not to individuals. We used the third National Health and Nutrition Examination Survey (NHANES III) database of the civilian, non-institutionalized, iodine-sufficient US population to calculate the age-related normal urinary iodine concentration ranges (2.5th to 97.5th percentiles) for females and for males, 6–89 years of age, stratified by age groups. Percentile ranges are important to identify the at-risk population. In the case of urinary iodine globally, the lower 2.5% cut-off is of greater clinical relevance. As we were dealing with a normal population, we were able to use the percentile approach to calculate these percentile ranges [3].
2. Methods
NHANES III, a stratified, multistage probability study was conducted between 1988–1994 and represented all the states in the US and the District of Columbia [4]. Urinary iodine testing was performed on children >6 years on carefully selected, non-institutionalized population representing all races across the US. The age ranges were separated as pre-pubertal, reproductive age and post-reproductive age. Up to 13 years, the data was grouped in age ranges consisting of 2–4 years to assess changes in iodine exposure during growth and development. Adequate iodine availability is critical during the reproductive years (as defined by CDC) for fetal development, thus, the large group of ages 14–44 years.
2.1. Study sample
The present study included all subjects 6–89 years of age whose urinary iodide and urinary creatinine concentration measurements were available. Of the 22,088 subjects with both urinary iodine and creatinine concentration measurements, 459 cases of thyroid disease and 99 cases of goiter were excluded (17 subjects reported having both). The present study includes 21,530 subjects including 290 pregnant women (14–44 years) (Table 1).
Table 1.
Demographics for urinary iodine concentrations (μg/dl) and urinary iodine/creatinine ratio (UI/Cr)(μg/g) data from NHANES III, females and males age 6–89 yearsa,b
| Age groups
|
n
|
||
|---|---|---|---|
| Female | Sample size | % of females | % of total patients |
| 6–9 years | 950 | 8.56 | 4.41 |
| 10–11 years | 520 | 4.69 | 2.41 |
| 12–13 years | 429 | 3.87 | 1.99 |
| 14–44 years | 5522 | 49.79 | 25.65 |
| 45–59 years | 1411 | 12.72 | 6.55 |
| 60–89 years | 2259 | 20.37 | 10.49 |
| Total females | 11,091 | 100 | 51.50 |
| Pregnant womenc | 290 | 2.61 | 1.35 |
| Male | Sample size | % of males | % of total patients |
|---|---|---|---|
| 6–9 years | 1025 | 9.82 | 4.76 |
| 10–11 years | 553 | 5.31 | 2.57 |
| 12–13 years | 390 | 3.73 | 1.81 |
| 14–44 years | 4782 | 45.8 | 22.21 |
| 45–59 years | 1312 | 12.57 | 6.09 |
| 60–89 years | 2377 | 22.77 | 11.04 |
| Total males | 10,439 | 100 | 48.50 |
| Total individuals | 21,530 | 100 |
Based on NHANES III (1988–1994) laboratory sample.
Excluding patients with goiter and thyroid disease.
Pregnant women are already included in the group of 14–44-year-old females.
2.2. Laboratory methods
2.2.1. Urinary iodine
UI concentrations were determined using the Sandell–Koltoff reaction [5]. The limit of detection (LOD) was 0.2 μg/dl. The UI concentrations were determined at the Iodine Research Laboratory, the University of Massachusetts Medical Center, Worcester, MA. Iodine standards were prepared from analytical grade potassium iodate (KIO3) and consisted of four concentrations of KIO3 ranging from 0 to 0.3 μg/ml iodine. The samples were analyzed in duplicate with every 10 urine samples. UI concentrations were calculated from the slope of the y-intercept of the standard curve. A quality control sample was digested and analyzed with every 10 urine samples. Samples were repeated for values < 0.1 μg/ml by using a larger sample size and for those above the highest standard by diluting the sample. The coefficient of variance for UI determination ranged from 2.7% to 7.0%.
2.2.2. Urinary creatinine
NHANES III creatinine was measured by the Jaffé alkaline picrate method. The LOD was 1 mg/dl. Creatinine concentration standards (50–300 mg/dl) were analyzed in duplicates with every 60 urine samples. Urinary creatinine concentrations were calculated from the slope y-intercept of the standard curve. Quality control sample was analyzed with every 20 urine samples. Samples were repeated for values < 10 and >300 mg/dl. The coefficient of variance for urinary creatinine determination ranged from 1.5% to 7.7% [4].
2.2.3. Statistical analysis
Statistical analysis was performed using SPSS, version 10, from SPSS, Chicago, IL, 2001. In all analyses, sampling weights were used to adjust for unequal probabilities of selection and to account for non-response. Variance estimates that account for the complex survey design were calculated. The data was divided to males and female subjects and stratified by age. Urinary iodide geometric means and S.E.M. were calculated (Table 2). The 2.5th to 97.5th percentile ranges for females and for males were stratified by age groups (Table 3).
Table 2.
Means and percentiles for urinary iodine concentrations (μg/dl) and UI/Cr (μg/g) ratios for females and males 6–89 yearsa,b and for pregnant women
| Subgroup | N | GMc ± S.E.M. (95% confidence intervals)
|
Percentile
|
||||
|---|---|---|---|---|---|---|---|
| Urinary iodine (μg/dl) UI/creatinine ratio (UI/Cr) | 10th | 25th | 50th | 75th | 90th | ||
| Female | 11,091 | ||||||
| 6–9 years | 950 | 20.32 ±0.52 (19.30–21.39) | 7.4 | 13 | 22 | 32.8 | 48.8 |
| 258 ±6 (247–270) | 113 | 168 | 263 | 393 | 540 | ||
| 10–11 years | 520 | 17.83 ±0.55 (16.75–18.97) | 7.2 | 11.5 | 18.5 | 26 | 42.5 |
| 187 ±6 (176–198) | 84 | 122 | 171 | 304 | 483 | ||
| 12–13 years | 429 | 16.66 ±0.59 (15.51–17.89) | 6.6 | 10.5 | 17 | 26 | 40.5 |
| 140 ±4 (132–149) | 67 | 88 | 144 | 207 | 295 | ||
| 14–44 years | 5522 | 12.20 ±0.14 (11.91–12.50) | 3.8 | 7 | 13 | 21.2 | 33.5 |
| 120 ±1 (117–122) | 53 | 74 | 113 | 177 | 292 | ||
| 45–59 years | 1411 | 9.72 ±0.25 (9.24–10.23) | 2.9 | 5 | 10 | 17.8 | 30.2 |
| 143 ±3 (138–149) | 61 | 89 | 134 | 221 | 355 | ||
| 60–89 years | 2259 | 11.62 ±0.22 (11.19–12.07) | 4 | 6.4 | 11.8 | 19.2 | 32.8 |
| 173 ±3 (168–180) | 72 | 106 | 161 | 270 | 414 | ||
| Childbearing age (14– 44 years) | |||||||
| Pregnant | 290 | 15.40 ±0.66 (14.14–16.77) | 6.2 | 9.2 | 14.8 | 25.3 | 41 |
| 155 ±6 (143–169) | 69 | 97 | 145 | 286 | 390 | ||
| Not pregnant | 5232 | 12.06 ±0.15 (11.77–12.38) | 3.7 | 6.9 | 13 | 21 | 33.3 |
| 118 ±1 (116–121) | 53 | 73 | 112 | 174 | 285 | ||
| All female | 5522 | 12.20 ±0.14 (11.91–12.50) | 3.8 | 7 | 13 | 21.2 | 33.5 |
| 120 ±1 (117–122) | 53 | 74 | 113 | 177 | 292 | ||
| Male | 10,439 | ||||||
| 6–9 years | 1025 | 25.20 ±0.56 (24.10–26.34) | 10.8 | 16.2 | 26.8 | 39.5 | 58 |
| 290 ±5.7 (279–302) | 133 | 203 | 282 | 435 | 629 | ||
| 10–11 years | 553 | 26.45 ±0.83 (24.85–28.16) | 10.5 | 16.5 | 28.7 | 42.5 | 62 |
| 249 ±7.2 (235–264) | 112 | 158 | 259 | 360 | 575 | ||
| 12–13 years | 390 | 20.28 ±0.93 (18.50–22.24) | 8.5 | 12.5 | 19.3 | 29.2 | 46.5 |
| 177 ±8.2 (161–194) | 68 | 106 | 157 | 266 | 453 | ||
| 14–44 years | 4782 | 14.72 ±0.17 (14.39–15.07) | 5.5 | 9.5 | 15.5 | 24 | 37.5 |
| 104 ±1 (102–106) | 46 | 65 | 99 | 157 | 245 | ||
| 45–59 years | 1312 | 13.44 ±0.32 (12.81–14.09) | 4.2 | 7.9 | 13.8 | 22 | 38.5 |
| 120 ±2.3 (115–125) | 52 | 76 | 113 | 179 | 289 | ||
| 60–89 years | 2377 | 15.46 ±0.28 (14.91–16.02) | 5.5 | 9.2 | 15.2 | 25.8 | 41.5 |
| 148 ±2.4 (144–153) | 63 | 90 | 136 | 224 | 365 | ||
Based on NHANES III (1988–1994) laboratory sample, weighted to national population.
Excluding patients with thyroid disease and goiter.
GM—Geometric means. Weighted geometric mean ± standard error of the mean (S.E.M.) and 95% confidence interval.
Table 3.
2.5th to 97.5th Percentile ranges for urinary iodine concentrations (μg/dl)a and urinary iodine per gram creatinine (UI/Cr) (μg/g) ratios for males, females (6–89 years)a,b,c and pregnant women
| Subgroup | N | 2.5th to 97.5th percentiles
|
|
|---|---|---|---|
| Urinary iodine concentration (μg/dl) | UI/creatinine ratio (UI/Cr) (μg/g) | ||
| Female | 11,091 | ||
| 6–9 years | 950 | 3.6–74.0 | 68–947 |
| 10–11 years | 520 | 4.1–80.0 | 57–744 |
| 12–13 years | 429 | 3.6–75.0 | 42–564 |
| 14–44 years | 5522 | 1.8–65.0 | 36–539 |
| 45–59 years | 1411 | 1.7–67.0 | 39–743 |
| 60–89 years | 2259 | 2.2–62.0 | 47–723 |
| Childbearing age (14– 44 years) | |||
| Pregnant | 290 | 4.2–55.0 | 33–535 |
| Not pregnant | 5232 | 1.8–65.0 | 36–541 |
| All female | 5522 | 1.8–65.0 | 36–539 |
| Male | 10,439 | ||
| 6–9 years | 1025 | 5.4–85.0 | 80–940 |
| 10–11 years | 553 | 6.0–98.0 | 62–820 |
| 12–13 years | 390 | 4.5–74.0 | 51–840 |
| 14–44 years | 4782 | 2.4–66.0 | 34–420 |
| 45–59 years | 1312 | 2.6–70.0 | 39–527 |
| 60–89 years | 2377 | 2.6–86.0 | 41–769 |
UI conversion factor from μg/l to nmol/l = × 7.90.
Based on NHANES III (1988–1994) laboratory sample, weighted to national population.
Excluding patients with thyroid disease and goiter.
3. Results
After exclusions of subjects with goiter or any thyroid disease, the study sample included 21,530 subjects (Table 1), ranging from 6 to 89 years of age representing over 220 million US children and adults. Females comprised 51.5% of the total sample survey and 2.61% of the females were pregnant.
The female and male populations were stratified by age. All females of childbearing age were calculated together (14–44 years), with and without the group of pregnant women (n = 290). In Table 2, the geometric means, standard error of the means and confidence intervals, medians and other percentiles have been calculated for urinary iodine concentrations of each of the age groups, together with the UI/Cr ratios. The 2.5th to 97.5th percentile ranges for each of the age groups are presented in Table 3.
3.1. Demographic characteristics
After exclusions of subjects who had goiter and/or thyroid disease, the study sample included 21,530 subjects; 10,439 males and 11,091 females of ages ranging from 6 years of age to their 90th birthday. NHANES III urinary iodine testing was performed on children 6 years and older. Females comprised 51.5% of the total sample survey and 2.61% of the females were pregnant.
4. Discussion
Dietary iodine is ingested in a variety of forms and most of it is reduced in the gut to iodide, and is rapidly absorbed [6]. Most of the iodide is transported into the thyroid and incorporated into thyroid hormones. The extrathyroidal inorganic iodine pool consists of iodide derived from the diet and from peripheral catabolism of thyroid hormones and iodothyronines by deiodination and is in dynamic equilibrium with the thyroid gland and with the kidneys. Urinary iodine concentration is currently the most practical biochemical marker for determining the iodine nutrition of populations at the time of measurement [2]. The NHANES data represents casual spot urine samples, reflecting the findings of a population at a point in time, known to include wide variations both in regional and in individual UI concentrations [7]. Some of the variation was overcome by measurements of urinary creatinine to correct for urinary dilution that could affect urinary iodine concentrations.
The Total Diet Study of the Food and Drug Administration (FDA), a yearly program that measures the amounts of minerals in foods and estimates their intakes in representative diets of specific age–sex categories, indicated that the average intake of iodine in the US was adequate (1982–1991) [8]. The NHANES III survey also reported that the US population is iodine sufficient according to WHO criteria [9]. NHANES III database of the civilian, non-institutionalized, iodine-sufficient US population was used here to calculate the percentile ranges for urinary iodine concentrations for individuals for females and males stratified by age groups.
NHANES III indicates that UI concentrations were higher for males of all ages than for females of the same age group (beside the group of pregnant women) probably because of a higher iodine intake (Table 2). UI concentrations were highest in the 6–9-year age group (GM = 20.32 μg/dl) for females, and in the 10–11-year age group (GM = 26.45 μg/dl) for males. Iodine values were lowest in the 45–59-year age group for both females (GM = 9.72 μg/dl) and males (GM = 13.44 μg/dl). The geometric means for UI/Cr were higher for males up to age 14 years than for females of the same age group. However, from age 14 years, the UI/Cr ratios were higher for the females. The UI/Cr concentrations were highest at the 6–9-year age group for both females (GM = 258 μg/g) and males (GM = 290 μg/g). They were lowest at the 14–44-year age group for both females (GM = 120 μg/g) and males (GM =104 μg/g).
The Total Diet Study of iodine intake survey indicated that during 1982–1991, the iodine intake for 2-year-olds was higher than the Recommended Dietary Allowances (RDA) suggested by the National Research Council (NRC) and National Academy of Sciences. The higher iodine intake of the younger age groups relative to the intake of the older >age groups may explain in part the higher UI concentrations of the younger age groups in the NHANES III data.
Pregnancy is accompanied by alterations in the requirements for iodine. Because of the susceptibility of the developing fetus to iodine deficiency, women of childbearing age are at a particularly sensitive stage and need to make sure their iodine intake is sufficient. Of the 5522 females of childbearing age (ages ranging from 14 to 44.99 years), 290 women were pregnant. UI geometric means for the pregnant women were higher (15.4 F0.66 μg/dl) than those of non-pregnant women of childbearing age (12.06 F 0.15 μg/dl). Renal iodide clearance depends principally on glomerular filtration rate (GFR) [10]. It is normal for the GFR to be higher (as much as 50% higher) during pregnancy, leading to a higher renal iodide loss beginning in the early weeks of gestation through the pregnancy, and to a wide variability in plasma and UI concentrations [11]. UI concentrations increased during pregnancy in iodine-replete areas [12–14] and in borderline-sufficient areas [12,15] increasing during the course of pregnancy. [12,16].
It is reported that iodine intake from food of healthy adults in the United States is within the daily requirements for both women and men (1991–1997) [17]. When maternal iodine consumption during early pregnancy and during the second trimester is insufficient, low nutritional iodine status may lead to spontaneous abortion, stillbirth and neurodevelopmental consequences. The transfer of iodide from the maternal circulation to the developing fetus for fetal thyroid hormone production during the second half of gestation further compromises the mother when she is iodine deficient. UI concentrations are higher in pregnant women in comparison to non-pregnant women (this is not due to an increase in dietary I intake) indicating they may not be a true reflection of their iodine status during pregnancy, which may in fact be lower.
Acknowledgments
Presented in part at the Thyroid Hormone and Brain Development: Translating Molecular Mechanisms to Population Risk International Conference, September 23–25, 2002, National Institute of Environmental Health Sciences, Research Triangle Park, NC. The authors wish to thank Drs. JG Hollowell, S Andersen and RW Tyl for reading the manuscript and for their helpful comments. This work was self-funded.
References
- 1.World Health Organization Nutrition Unit. Indicators for assessing iodine deficiency disorders (IDD) and their control through salt iodization. Geneva: WHO; 1994. p. 36. [Google Scholar]
- 2.WHO, UNICEF, ICCIDD. A guide for programme managers. 2. WHO; 2001. Assessment of iodine deficiency disorders and monitoring their elimination; pp. 1–107. WHO/NHD/01.1. [Google Scholar]
- 3.Soldin SJ, Brugnara C, Hicks JM. Pediatric reference ranges. 3. Washington, DC: AACC; 1999. [Google Scholar]
- 4.Gunter EW, Lewis BL, Konchikowski SM. Laboratory methods used for the Third National Health and Nutrition Examination Survey (NHANES III), 1988 – 1994. Hyattsville: Centers for Disease Control and Prevention; 1996. [Google Scholar]
- 5.Benotti J, Benotti N, Pino S, Gardyna H. Determination of the total iodine in urine, stool, diets, and tissue. Clin Chem. 1965;11:932–6. [PubMed] [Google Scholar]
- 6.Nath SK, Moinier B, Thuillier F, Rongier M, Desjeux JF. Urinary excretion of iodide and fluoride from supplemented food grade salt. Int J Vitam Nutr Res. 1992;62(1):66–72. [PubMed] [Google Scholar]
- 7.Soldin OP. Controversies in urinary iodine determinations. Clin Biochem. 2002;35(8):575–79. doi: 10.1016/s0009-9120(02)00406-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Pennington JA. Intakes of minerals from diets and foods: is there a need for concern? J Nutr. 1996;126(Suppl 9):2304S– 8S. doi: 10.1093/jn/126.suppl_9.2304S. [DOI] [PubMed] [Google Scholar]
- 9.Hollowell JG, Staehling NW, Hannon WH, et al. Iodine nutrition in the United States. Trends and public health implications: iodine excretion data from National Health and Nutrition Examination Surveys I and III (1971–1974 and 1988–1994) J Clin Endocrinol Metab. 1998;83(10):3401–8. doi: 10.1210/jcem.83.10.5168. [DOI] [PubMed] [Google Scholar]
- 10.Perry WF, Hughes JFS. The urinary excretion and thyroid uptake of iodine in renal disease. J Clin Invest. 1952;31:457–62. doi: 10.1172/JCI102630. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Liberman CS, Pino SC, Fang SL, Braverman LE, Emerson CH. Circulating iodide concentrations during and after pregnancy. J Clin Endocrinol Metab. 1998;83(10):3545–9. doi: 10.1210/jcem.83.10.5163. [DOI] [PubMed] [Google Scholar]
- 12.Smyth PP, Hetherton AM, Smith DF, Radcliff M, O’Herlihy C. Maternal iodine status and thyroid volume during pregnancy: correlation with neonatal iodine intake. J Clin Endocrinol Metab. 1997;82(9):2840–3. doi: 10.1210/jcem.82.9.4203. [DOI] [PubMed] [Google Scholar]
- 13.Silva JE, Silva S. Interrelationships among serum thyroxine, triiodothyronine, reverse triiodothyronine, and thyroid-stimulating hormone in iodine-deficient pregnant women and their offspring: effects of iodine supplementation. J Clin Endocrinol Metab. 1981;52(4):671–7. doi: 10.1210/jcem-52-4-671. [DOI] [PubMed] [Google Scholar]
- 14.Glinoer D, Delange F, Laboureur I, et al. Maternal and neonatal thyroid function at birth in an area of marginally low iodine intake. J Clin Endocrinol Metab. 1992;75(3):800–5. doi: 10.1210/jcem.75.3.1517370. [DOI] [PubMed] [Google Scholar]
- 15.Chinyanga EA, Dako DY. Profile of thyroid function and urinary iodine excretion of pregnant women attending Harare Central Hospital antenatal clinic. Cent Afr J Med. 1989;35(5):396–400. [PubMed] [Google Scholar]
- 16.Kung AW, Lao TT, Chau MT, Tam SC, Low LC. Goitrogenesis during pregnancy and neonatal hypothyroxinaemia in a borderline iodine sufficient area. Clin Endocrinol (Oxford) 2000;53(6):725–31. doi: 10.1046/j.1365-2265.2000.01156.x. [DOI] [PubMed] [Google Scholar]
- 17.Iodine. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. 8–1. The National Academy of Sciences Press; 2002. pp. 258–89. [PubMed] [Google Scholar]