The Journal of Nutrition Vol. 128 No. 7 July 1998, pp. 1122-1126

Urinary Iodine Excretion Is the Most Appropriate Outcome Indicator for Iodine Deficiency at Field Conditions at District Level^1,2

Lucia V. H. Pardede^*, Widanto Hardjowasito, Rainer Gross^{**, 3}, Drupadi H. S. Dillon^*, Ongko S. Totoprajogo, Mardhani Yosoprawoto, Lies Waskito, and Juliawati Untoro^*

^*  Regional SEAMEO-TROPMED Center for Community Nutrition, Jakarta 10038, Indonesia,  Medical Faculty, Brawijaya University, Malang, Indonesia and ^** Deutsche Gesellschaft für Technische Zusammenarbeit (GTZ) GmbH, 65726 Eschborn, Germany

	ABSTRACT

Abstract Introduction Methods Results Discussion References

To empower local authorities to plan and evaluate adequate interventions, appropriate iodine deficiency disorders (IDD) indicators need to be identified. The aim of this study was to describe the magnitude and severity of IDD with different outcome indicators and associate them with functional indicators. Schoolchildren (n = 544) aged 8-10 y were assessed in 11 villages within five subdistricts of Malang District, East Java, Indonesia. Outcome indicators of IDD were goiter size as measured by palpation and ultrasonography (USG), urinary iodine excretion (UIE) and serum thyroid stimulating hormone (TSH) concentration in blood as well as functional indicators such as intellectual performance (IQ: Catell's Culture Fair Intelligence Test) and anthropometric indices. The total goiter rate (TGR) measured by palpation and USG were 35.7 and 54.4%, respectively. Based on UIE and TSH, the prevalence of iodine deficiency was 63.7 and 3.4%, respectively. In individuals, goiter, thyroid volume and UIE were associated significantly (r = 0.35; P < 0.001 and r = 0.30; P = 0.02 respectively). Among villages, TGR measured by palpation was significantly correlated with thyroid volume (r = 0.61; P = 0.045) and UIE (r = 0.68; P = 0.021), whereas TSH was not significantly associated with any of the observed indicators in individuals or groups. Multiple regression analysis showed that USG ( = 0.67; P < 0.001) and UIE ( = 4.39; P = 0.008) related significantly with cognitive performance (IQ). The associations between IDD indicators and cognitive performance and height-for-age Z scores suggest that socioeconomically advantaged children had better iodine status. We suggest that UIE is the best indicator for local authorities to assess iodine deficiency.

	INTRODUCTION

Abstract Introduction Methods Results Discussion References

Iodine deficiency is the leading cause of mental impairment and has serious effects on the physical development of children, on young child mortality and on the reproductive performance of women as indicated by increased rates of abortion, stillbirth and congenital abnormalities (Hetzel 1983). The most notable clinical sign of iodine deficiency is goiter.

Indonesia is a country with high prevalence of iodine deficiency disorders (IDD)⁴ (Hetzel 1989). From a national survey conducted among schoolchildren in 1990 that used the palpation method, the national goiter prevalence was estimated to be 27.7% (Kodyat et al. 1991, Ministry of Health 1993a). As shown in a previous study, goiter was associated significantly with school performance in elementary school children from 12 Indonesian provinces (Ministry of Health 1988).

Since 1993 Indonesia has established a national salt iodization program (Ministry of Health 1993a). However, despite increased distribution of iodized salt, groups of people exist with significantly higher prevalence of IDD because of the limited access to iodized salt in villages or districts (Heywood 1995). Consequently, local authorities need to plan and implement additional intervention measures such as the distribution of iodized oil capsules or drinking water. Successfully eliminating such pockets of iodine deficiency will depend on the correctly determining the population's iodine status for accurate program planning and evaluation (WHO/ UNICEF/ICCIDD 1994). Furthermore, reliable collection of valid data is necessary to identify such pockets. This study will compare the validity and appropriateness of IDD outcome indicators within a district under field conditions with locally available staff. For the purpose of validation, functional indicators (intellectual performance and anthropometric indices) were assessed as well as IDD outcome indicators.

	MATERIALS AND METHODS

Abstract Introduction Methods Results Discussion References

This study was designed as a cross-sectional study to measure selected outcome and functional indicators among Indonesian schoolchildren in district level. The study covered 11 villages in five subdistricts in Malang district, East Java province. Selection of the 11 villages were based on the prevalence of IDD from a previous study (Ministry of Health 1993b), indicated by VGR: five villages with higher visible goiter rate (VGR; moderate or severe IDD) and six villages with lower VGR (normal or mild IDD). All of the selected villages have never been introduced to iodination programs. From each village, at least one public elementary school was identified as a survey site.

Based on the recommendation of WHO/UNICEF/ICCIDD (1994), schoolchildren aged 8-10 y were selected as the study population. In younger children, the thyroid is more difficult to examine, whereas in older children, stage of puberty might be an additional variable.

According to Dunn and van der Haar (1990), 40 subjects were needed to determine the median concentration of urinary iodine in a region. Accordingly, a sample size of 50 subjects per village was selected, in anticipation of a 20% drop-out rate. Schoolchildren were recruited (n = 511) from the third and fourth grades of elementary school in the selected villages; written parental consent was obtained from all participants.

Goiter size.  Goiter size was assessed with two methods, palpation and ultrasonography (USG). Each child was palpated and the size graded by either of two experienced observers: one medical doctor and one nutritionist. Before beginning the trial, both examiners agreed on a standardized palpation technique. The palpated goiter size was classified as grade 0, I and II (WHO/UNICEF/ICCIDD 1994).

The USG measurements were conducted by six experienced radiologists and the first author. Before the thyroid volumes were assessed, measurement procedures were standardized under supervision of a consultant from Program Against Micronutrients Malnutrition (PAMM, Atlanta, GA). Ultrasound equipped with a transducer of 7.5 MHz was used for this study (Phillips SDR 1480, Eindhoven, Netherlands). The selection of transducer 7.5 MHz is recommended by WHO/UNICEF/ICCIDD (1994) to obtain adequate resolution of the thyroid of the schoolchildren aged 8-10 y.

Thyroid volume measured by USG, was calculated based on the width (W), depth (D) and length (L) of left and right side of the thyroid gland using the following formula: where 1 = left gland and 2 = right gland.

Results of USG from the studied population were compared with normative thyroid volume data from populations with sufficient iodine intake. Goiter was identified as thyroid volume was >97th percentile (WHO/UNICEF/ICCIDD 1994).

Urinary iodine excretion.  Measurement of urinary iodine excretion (UIE) was based on the iodine concentration in urine samples that were collected during the morning of the school visit. Urine was collected in a plastic container that already contained ~1 g thymol. Urine sample collection was organized by the nurses/midwives from the health centers. After sample collection, the containers were sealed and identified with labels containing the identification code of the subject as well as that of the village and subdistrict. All urine samples were sent promptly to and analyzed in the authorized IDD laboratory in Semarang. Acid digestion method was used for urinary iodine analysis (Dunn et al. 1993). The urinary iodine concentration was expressed in µmol iodine/L urine as recommended by Dunn et al. (1993).

Serum thyroid stimulating hormone concentration.  Blood sample spots were collected in duplicate using filter paper (Schleicher & Schuell, Keene, NH). All blood samples were sent to the PAMM Laboratory in Atlanta, which is affiliated with the center for Environmental Health and Laboratory Sciences at the CDC (Center for Disease Control, Atlanta, GA). As recommended by WHO/UNICEF/ICCIDD (1994), the microenzyme-linked immunosorbant assays technique was used to determine serum thyroid stimulating hormone (TSH) concentrations. On the basis of WHO criteria, a TSH concentration >5 mU/L is considered as elevated TSH, indicative of a hypothyroid state.

Anthropometric measurements.  Anthropometric measurements for weight and height were performed according the recommendations of Gibson (1990). Weight was measured using electronic weighing scales (SECA, Hamburg, Germany). All electronic scales were calibrated for accuracy. The schoolchildren were barefoot with minimum clothing and stood in the center of the scale with the body weight evenly distributed between both feet. Then the subject was asked to look straight ahead, still and relaxed. The weight was measured to the nearest 0.1 kg.

Height measurement was taken using a microtoise (UNICEF, Copenhagen, Denmark) and measured to the nearest 0.1 cm. The microtoise was hung on the wall in such a way as to ensure a vertical position (Gibson 1990). The anthropometric measurements were conducted by the first author.

Intelligence quotient.  The intelligence quotient (IQ) of the schoolchildren was measured using the Catell's culture fair intelligence test (CFIT) by a team of psychologists. This method had been used to analyze the association between intellectual performance and iodine deficient subjects in Spain (Bleichrodt et al. 1980). The CFIT had been standardized and used in Indonesia to determine general intelligence level; the CFIT consists of four subtests: substitution, mazes, vocabulary and figure comparison (Hartono and Djokomoeljanto 1993).

Statistics.  Variables with values recorded in either frequency or ranking categories and nonnormally distributed data were analyzed with a nonparametric test (Spearman's rank correlation test). Confounding factors were controlled with multiple regression analysis. Data were analyzed statistically according Snedecor and Cochran (1980) and using the software of SPSS/PC 4.0 (SPSS Inc., Chicago, IL).

Anthropometric data were analyzed using Epi Info software version 6.0, and the data were presented as indices of Z scores of height-for-age (HAZ), weight-for-age (WAZ) and weight-for-height (WHZ). These indices were compared with reference data of the National Center of Health Statistics (WHO 1993) to judge whether the subjects were underweight, stunted or wasted using cut-off point of 2 SD. The differences were considered significant at probability level (P) of 0.05.

Ethical considerations.  Ethical considerations followed all the guidelines of the CIOMS (1991) for human research. The study protocol was approved by the human ethics committee, SEAMEO-TROPMED Regional Center for Community Nutrition at the University of Indonesia.

	RESULTS

Abstract Introduction Methods Results Discussion References

Among a total of 544 schoolchildren of which 44% were boys and 56% were girls. The group's breakdown by age was 28.1, 48.0 and 23.9% for 8-, 9- and 10-year olds, respectively. Nearly one half of the children (48%) were stunted, 3% were wasted, and one third (34%) were underweight. There were no significant differences in the gender distribution within each age group. Chi-square analysis did not reveal a significant relationship between prevalence of goiter (measured by USG and palpation) and gender or age.

Table 1 shows the distribution of IDD prevalence at the villages level using four different indicators separately and in combination. The total goiter rate (TGR) measured by palpation and USG alone was 35.7 and 54.4%, respectively. The proportion of subjects with a UIE <0.79 µmol/L was 63.7%, median, 0.51 µmol/L. Only 3.4% of the schoolchildren showed elevated TSH concentrations (>5 mU/L), and in four villages (Ngadireso, Tambak Asri, Sumber Agung and Karangsari) no cases of elevated TSH were found.

The prevalence of IDD also was influenced by the method used to identify goiter. For example, in the village of Pringgodani, all children were identified with goiter (using USG), whereas in Karangsari, no signs of thyroid enlargement were found. However, when the same children were assessed by palpation, the prevalence of goiter in the two villages was nearly the same.

Additionally, the prevalence of children with two, three and four abnormal IDD indicators in the 11 villages was measured. By increasing number of the abnormal IDD indicators, the overall prevalence of IDD of the 11 villages decreased drastically from 63.7 to 0.4%. The ranking of the prevalence found in the villages differed not only between the single indicators but also if two, three or four indicators were used for IDD assessment.

Table 2 shows correlations between the four IDD indicators in schoolchildren on individual and village levels. In individuals, strongest relationships were found between palpated goiter and thyroid volume measured by USG (r = 0.35; P < 0.001) and UIE (r = 0.33; P < 0.01). At the village level, significant relationships were found between thyroid volume and UIE with palpated goiter (r = 0.63 and 0.61, respectively; P < 0.05) and between USG and UIE (r = 0.53; P < 0.05). However, no association was found between TSH and other outcome indicators.

Table 3 shows the multiple regression between the observed continuous IDD indicators and functional indicators in the schoolchildren. Because almost half of the children (48%) were stunted, HAZ of the children could be an indirect indicator of their socioeconomic status and, at the same time, a functional outcome indicator. Therefore this index was used in the analysis as both dependent and independent variable. All IDD indicators were associated with HAZ (P < 0.001). Furthermore, UIE and USG were correlated with cognitive performance (R² = 0.32; P < 0.001). None of the functional indicators were significantly associated with TSH. HAZ as a proxi-indicator of socioeconomic status was correlated significantly with IQ ( = 2.83; P = 0.001).

	DISCUSSION

Abstract Introduction Methods Results Discussion References

On the basis of TGR criteria suggested by WHO/UNICEF/ICCIDD (1994) and measured by USG and palpation, the population in this overall area was categorized as severe endemic IDD (TGR of 35.7 and 54.4%, respectively). However, the prevalence of children with two, three or four abnormal indicators of IDD reduced drastically from 51.7 to 0.4%. This decrease can be explained by the low prevalence of increased TSH levels and the inconsistency of abnormal single indicators.

According to the results shown in Table 1, TGR determined by USG was nearly 50% higher than determined by palpation. However, a lower prevalence of goiter measured by USG compared with palpation was found in three villages, especially in which subjects had smaller goiter sizes. This finding confirms the statement of WHO/UNICEF/ICCIDD (1994) that palpation, though crude, may be easier to assess in larger goiters. Using USG requires more experience and training for a standardized thyroid volume measurement, particularly in cases where several persons assess the goiter status and interobserver variation is high.

Also Berghout et al. (1988) found that thyroid size as estimated by inspection and palpation (grade 0 to III according to Stanbury et al. 1974) was poorly related to thyroid volume as measured by USG. They suggested that the application of thyroid volume may prevent overestimation of goiter prevalence in epidemiological surveys. Another finding by Wachter et al. (1987) showed that palpation among Tanzanian schoolchildren aged 6-17 y overestimated the prevalence of goiter compared with that found by USG.

Despite the high prevalence of goiter observed in this study, only very few schoolchildren (3.4%) showed elevated TSH levels (>5 mU/L). In West Sumatra, Indonesia, TSH levels in mothers did not reveal the presence of IDD despite a high prevalence of goiter (Oenzil 1993). Results of the present study also showed that there was no association between TSH and any other IDD indicators. This finding confirmed the previous study by Wachter et al. (1987) that also found no correlation between TSH level and UIE or thyroid volumes. Furthermore, there was no association between TSH and functional indicators such as anthropometric indices and intellectual performance.

The prevalence of goiter, assessed by USG, was associated with intellectual impairment of schoolchildren in this study, this corresponds to the findings of Grant et al. (1992). Taking into consideration that UIE reflects the current situation of the iodine supply and that goiter volume indicates the longer term iodine status in the children, the findings suggest that cognitive performance of the schoolchildren had a direct relationship with iodine status. However, many factors besides IDD may be interfering with children's intellectual development.

At the village level, UIE was associated significantly with the prevalence of goiter as determined by palpation and USG (P < 0.05). UIE concentration also was related significantly to the HAZ of the schoolchildren, with stunted children having a lower UIE concentration than normal children. Furthermore, there was a significant relationship between UIE and IQ points. As a result, UIE values were more strongly associated with the two functional indicators of intellectual performance and linear growth than the prevalence of goiter. These associations were significant despite the employment of several surveyors working under field conditions.

HAZ related significantly with UIE and cognitive performance. Because in this study group chronic iodine deficiency was not associated significantly with the age-related height of the children, it seems more likely that the association mainly can be explained by the fact that HAZ is functioning more as a socioeconomic factor; e.g., children who show higher iodine content in their urine live in better socioeconomic situations. The use of HAZ as a proxy for the socioeconomic situation is supported by the fact that almost half of the surveyed children (48%) were stunted. This is further supported by the fact that HAZ is related to IQ.

Under the field conditions of this survey, that the prevalence of IDD in the villages as assessed by different indicators was inconsistent. There may be several reasons for this inconsistency. First, TSH is widely used and accepted for measuring IDD in the neonate but seems to be invalid as an appropriate indicator of IDD of school-aged children. Second, UIE reflects current iodine concentrations, and goiter indicates a chronic situation of iodine deficiency. Therefore, the prevalence of IDD as determined by the two indicators does not necessarily need to be consistent (Hetzel 1993). At the time of the survey, iodized salt did not reach the households of the study area. Therefore this factor should not lead to a larger discrepancy. Third, despite training and standardizing the assessment procedures, the accuracy of measurement under field conditions may differ between methods. This aspect must be acknowledged when assessment methods are recommended, especially if interventions are decentralized and local health staff are empowered to plan and implement actions. In larger populations in particular, the reliability of assessment by palpation and USG, but not UIE, depends on the measurement accuracy of several surveyors. In addition assessment methods that may be successful in research and at the national level might not be applicable at the local level, particularly in developing countries. For this reason, it is necessary to identify appropriate methods for fieldworkers in impoverished areas.

Table 4 shows the findings of this study on selected outcome indicators based on the technical feasibility and reliability. UIE measurement seems to be the best IDD indicator because the collection of urine is relatively simple and does not require working with sophisticated equipment in the field. However, using UIE as an IDD indicator is only applicable if a reliable laboratory is available for the chemical analysis of urinary iodine. Otherwise, palpation seems to be the best method, in particular for targeting, due to its low cost and ease of implementation.

	FOOTNOTES

Manuscript received 30 October 1996. Initial reviews completed 30 January 1997. Revision accepted 7 January 1998.

	ACKNOWLEDGMENTS

The authors thank Robin Houston, PAMM, for the training and the loan of an ultrasound apparatus and to Warwick May, PAMM, for the TSH analysis.

	LITERATURE CITED

Abstract Introduction Methods Results Discussion References

• Berghout A., Wiersinga W. M., Smits N. J., Touber J. L. The value of thyroid volume measured by ultrasonography in the diagnosis of goitre. Clin. Endocrinol. 1988; 28:409-414[Medline]
• Bleichrodt N., Drenth P.J.D., Querido A. Effects on iodine deficiency on mental and psychomotor abilities. Am. J. Phys. Anthropol. 1980; 53:55-67[Medline]
• CIOMS. (1991) International Guidelines for Ethical Review of Epidemiological Studies. Council for International Organizations of Medical Sciences, Geneva, Switzerland.
• Dunn, J. T., Crutchfield, H. E., Gutekunst, R. & Dunn, A. D. (1993) Methods for Measuring Iodine in Urine. UNICEF/WHO/ICCIDD, The Netherlands.
• Dunn, J. T. & van der Haar, F. (1990) A Practical Guide to the Correction of Iodine Deficiency. International Council for Control of Iodine Deficiency Disorders. Technical Manual No. 3. UNICEF/WHO/ICCIDD, The Netherlands.
• Gibson, R. S. (1990) Anthropometric assessment of growth. In: Principles of Nutritional Assessment (Gibson, R. S., ed.), pp. 163-183. Oxford University Press, New York, N.Y.
• Grant, D. B., Fuggle, P. & Tokar, S. (1992) Psychomotor development in infants with congenital hypothyroidism diagnosed by neonatal screening. Acta Med. Austriaca 19 (suppl. 1): 54-56.
• Hartono, B. & Djokomoeljanto, R. (1993) Spektrum disfungsi perkembangan Hemisfer otak di daerah defisiensi iodium. In: Kumpulan Naskah Lengkap Simposium GAKI. Kongres Nasional III Perkumpulan Endokrinologi Indonesia (PERKENI). Badan Penerbit Universitas Diponegoro, Semarang, Indonesia.
• Hetzel B. S. Iodine deficiency disorders and their eradication. Lancet 1983; 12:1126-1129
• Hetzel, B. S. (1989) The Story of Iodine Deficiency: An International Challenge in Nutrition. Oxford University Press, New Delhi, India.
• Hetzel, B. S. (1993) The Prevention and Control of Iodine Deficiency Disorders. Nutrition Policy Discussion Paper No. 3. ACC/SCN, FAO, Rome.
• Heywood, P. (1995) Iodine deficiency disorders control program: issues and recommendations. World Bank, Washington, D.C.
• Kodyat, B. A., Djokomoeljanto, R., Karyadi, D., Tarwotjo, Muhilal, Husaini & Sukaton, A. (1991) Micronutrients Malnutrition Intervention Program: An Indonesia Experience. Directorate General of Community Health, Ministry of Health R.I., Jakarta, Indonesia.
• Ministry of Health. (1988) Impact Evaluation on IDD Control Program in Indonesia. Directorate of Community Nutrition, Ministry of Health, Jakarta, Indonesia.
• Ministry of Health. (1993a) Hasil Survey Prevalensi Gondok Endemik di Kabupaten Dati II Malang. Dinas Kesehatan, Malang, Indonesia.
• Ministry of Health. (1993b) Program Penanggulangan Gangguan Akibat Kekurangan Iodium pada Repelita VI dan PJP II. Direktur Jenderal Pembinaan Kesehatan Masyarakat, Departmen Kesehatan Republik Indonesia. In: Kumpulan Naskah Lengkap Simposium GAKI. Kongres Nasional III Perkumpulan Endokrinologi Indonesia (PERKENI). Badan Penerbit Universitas Diponegoro, Semarang, Indonesia.
• Oenzil, F. (1993) Penelitian Data Dasar Dalam Rangka Evaluasi Efektifitas Distribusi Kapsul Minyak Beriodium di Sumatera Barat. Fakultas Kedokteran Universitas Andalas, Padang, Indonesia.
• Snedecor, W. G. & Cochran, W. G. (1980) Statistical Methods, 7th ed. Iowa State University Press. Ames, IA.
• Stanbury, J. B., Ermans, A. M., Hetzel, B. S., Pretell, E. A. & Querido, A. (1974) Endemic goitre and cretinisim: public health significance and prevention. WHO Chronicle, 28: 220-228.
• Wachter, W., Pickardt, C. R., Gutekunst, R., Horn, K., Konig, A., Kavishe, F. P. & Scriba, P. C. (1987) Use of ultrasonography for goiter assessment in IDD: studies in Tanzania. In: The Prevention and Control of Iodine Deficiency Disorders (Hetzel, B. S., Dunn, J. T., and Stanbury, J. B., eds.), pp. 95-125. Elsevier Publishers B.V., Amsterdam, The Netherlands.
• WHO. (1993) Measuring Change in Nutritional Status. WHO, Geneva, Switzerland.
• WHO/UNICEF/ICCIDD. (1994) Indicators for assessing iodine deficiency disorders and their control through salt iodination. WHO/NUT/94.6, Geneva, Switzerland.

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