USEO F O R A L I O D I Z E D O I L TO C O N T R O L I O D I N E DEFICIENCY IN I N D O N E S I A

JuliawatiU n t o r o Promotoren: Dr.J . G . A . J . H a u t v a s t Hoogleraar in d e leer van de v o e d i n g en d e v o e d s e l b e r e i d i n g , Lanbouwuniversiteit W a g e n i n g e n

C.E.W e s t , P h D .D S c . Universitair hoofddocent aan de Afdeling Humane Voeding en Epidemiologie, Departement Levensmiddelentechnologie en Voedingswetenschappen, L a n d b o u w u n i v e r s i t e i t W a g e n i n g e n Visiting Professor of International Nutrition, Rollins School of Public H e a l t h , E m o r y U n i v e r s i t y , A t l a n t a G A , U S A

Co-promotor: Dr. I r .J . W . S c h u l t i n k Gastdocent aan de Afdeling Humane Voeding en Epidemiologie, Departement Levensmiddelentechnologie en Voedingswetenschappen, L a n d b o u w u n i v e r s i t e i t W a g e n i n g e n Team Leader German Technical Cooperation (GTZ) at SEAMEO T R O P M E D Regional C e n t e r f o r Community Nutrition, University o f I n d o n e s i a , J a k a r t a , I n d o n e s i a USEO F O R A L I O D I Z E D O I L TO C O N T R O L I O D I N E D E F I C I E N C Y IN I N D O N E S I A

Juliawati Untoro

Proefschrift

ter v e r k r i j g i n g v a n d e g r a a dv a n d o c t o r opg e z a g v a n d e r e c t o r m a g n i f i c u s , van d e L a n d b o u w u n i v e r s i t e i t W a g e n i n g e n , dr. C M . K a r s s e n , in h e t o p e n b a a r t e v e r d e d i g e n opw o e n s d a g 17f e b r u a r i 1 9 9 9 des n a m i d d a g st e v i e r u u r i n d eA u l a

;>. ., jt J Theresearch was carried out withinthe framework of German-Indonesian Technical cooperation through the Deutsche Gesellschaft fur Technische Zusammenarbeit (GTZ)GmbH at the RegionalSouth-East Asian Ministersof Education Organization Centerfor Community Nutrition, at theUniversity of Indonesia, Jakarta.

Financial support for the publication of this thesis by the Wageningen Agricultural Universityand GTZ is gratefully acknowledged.

Use o f o r a l i o d i z e d o i lt o c o n t r o l i o d i n e d e f i c i e n c y in I n d o n e s i a Juliawati U n t o r o

Thesis Landbouwuniversiteit Wageningen. - W i t h ref.- W i t h s u m m a r i e s in Dutch a n d Indonesian. ISBN 9 0 - 5 8 0 8 - 0 2 3 - 4 Subject h e a d i n g s : oral i o d i z e d o i l ,i o d i n e d e f i c i e n c y , s c h o o l c h i l d r e n , Indonesia Cover d e s i g n : Sandra L o h m a n n Printing: Ponsen & L o o i j e n B V , W a g e n i n g e n

©1999J .U n t o r o BIBUOTHEEX !A M D B O U W U N I V E K S I T E I T WAGENINGEN Stellingen (Propositions)

1. The efficacy of iodized peanut oil is greater than that of iodized poppyseed o i l i nc o m b a t i n g i o d i n e d e f i c i e n c y (thist h e s i s ) .

2. Although many indicators have been used to assess whether and to what extent a population is iodine deficient and to monitor the effectiveness of iodine deficiency control programs, urinary iodine concentration a n dt h y r o i d v o l u m e m e a s u r e d b y u l t r a s o u n d a r et h e m o s t suitable ( t h i st h e s i s ) .

3. Iodine d e f i c i e n c y disorders are recognized not only as a p u b l i c health nutrition issue, but also as an obstacle to human development (this thesis).

4. The d e v e l o p m e n t o f c o g n i t i v e p e r f o r m a n c e o f s t u n t e d s c h o o l c h i l d r e n i s lesst h a nt h a t o ft h e i r n o n - s t u n t e d c o u n t e r p a r t s (thist h e s i s ) .

5. Non-iodized s a l t a v a i l a b l e in t h e m a r k e t w h i c h is c h e a p e r t h a n iodized salt, may s u b v e r t the effectiveness of iodized s a l t in c o m b a t i n g iodine deficiency (thist h e s i s ) .

6. Simple g o i t e r ist h e e a s i e s t o f a l l k n o w n d i s e a s e s t o p r e v e n t . It m a y b e excluded from the list of human diseases as soon as society determines t o make t h e effort (D Marine. Prevention and treatmentof simplegoiter, Atl.Med. J. 1923; 26:437-443).

7. When t h e t w e n t i e t h century ends, it w o u l d be s a t i s f y i n g to be able t o look b a c k a n d s a y : " T h a t w a s t h e c e n t u r y w h e n i o d i n e d e f i c i e n c y was eliminated f r o m t h ef a c e o f o u r p l a n e t " .

8. Selling i o d i z e d s a l tt o a p o p u l a t i o n w i t h e n d e m i c i o d i n e d e f i c i e n c y isn o t like m a r k e t i n g ' C o c a - C o l a ' .

9. Cybernet e n a b l e s people to contact others all over the world within seconds, b u t r e d u c e s m e a n i n g f u l c o n t a c t b e t w e e n p e o p l e .

10. S i g n i f i c a n t i s n o t a l w a y s r e l e v a n t .

11. Learning does not end with the completion of formal education. Learning is a lifelong experience for those with an appetite for knowledge. 12. T h e r e i s n o t h i n g w r o n g w i t h h a v i n g d i f f e r e n t o p i n i o n s , b u t i t ' s a b s o l u t e l y wrongt o e n f o r c e o n e ' s o p i n i o n ,n o m a t t e r w h a t t h e r e a s o n .

13. T h e r e is only one way to fight violence with nonviolence: education (DalaiLama).

14. For e v e r y t h i n g we have m i s s e d , w e have g a i n e d s o m e t h i n g else; a n d for everything we gain, we lose something else (Ralph WEmerson. Nature, Addressesand Lectures. HarvardDivinity School, 1849).

ProefschriftJuliawati Untoro Useof oral iodized oil to control iodine deficiency in Indonesia Landbouwuniversiteit Wageningen,17 February 1999 For e v e r y o n e w h o w o r k s t o w a r d s the e r a d i c a t i o n o f iodine d e f i c i e n c y d i s o r d e r s Abstract

Use o f o r a l i o d i z e d o i l t o c o n t r o l i o d i n e d e f i c i e n c y i n I n d o n e s i a

PhDthesis by Juliawati Untoro, Divisionof Human Nutritionand Epidemiology, WageningenAgricultural University, the Netherlands.

Iodine deficiency is a leading cause of preventable mental retardation and universal salt iodization has been adopted as the main strategy for its control. However additional strategies are required where iodized salt cannot be made available in t h e short term or only with difficulty in t h e long term. Oral iodized oil supplementation is useful for this purpose. The aim of the work described in t h i s thesis was t o compare the efficacy of different preparations of oral iodized oil f o r controlling iodine deficiency. In addition, the performance of different outcome indicators of iodine deficiency, the impact of nutritional status and iodine supplementation on cognitive performance, as well as the effectiveness of salt iodization i nt h e p o p u l a t i o n w e r e i n v e s t i g a t e d .T h e s t u d i e s w e r e c a r r i e d o u t i n s c h o o l children a g e d 8 - 1 0y l i v i n g i na n e n d e m i c i o d i n e d e f i c i e n t a r e a i n I n d o n e s i a . A s i n g l e o r a l d o s e o f i o d i z e d o i l p r e p a r e d f r o m p e a n u t o i l w h i c h i s r i c h i n o l e i c acid resulted in three times higher retention of iodine and twice the length of protection than iodized oil prepared from poppyseed oil which has less oleic acid and m o r e l i n o l e i c a c i d .T h u s i o d i z e d o i l s b a s e do n o l e i c a c i d r i c ho i l s s h o u l d b e g i v e n preference t o i o d i z e d p o p p y s e e d o i l i n p r o g r a m s t o c o n t r o l i o d i n e d e f i c i e n c y . Urinary iodine concentration and thyroid volume measured by ultrasound were found to be the most useful indicators for assessing iodine status and measuring t h e impact of iodized oil s u p p l e m e n t a t i o n among iodine d e f i c i e n t school children. H o w e v e r t h y r o i d p a l p a t i o n s t i l l h a s a u s e f u l p l a c e i n a s s e s s i n g i o d i n e s t a t u s because no sophisticated equipment is required. Iodine status as measured by urinary iodine c o n c e n t r a t i o n a t b a s e l i n e a n d s t u n t i n g w e r e f o u n d t o b e r e l a t e d t o t h e improvement of cognitive performance when children were dosed with iodized o i l . The use o f iodized s a l t , w h i c h was c o r r e l a t e d w i t h urinary iodine c o n c e n t r a t i o n and thyroid volume, resulted in improvement of the iodine status of the population studied. Apart from promulgation enabling legislation, much effort needs to be expended t o i n c r e a s e t h e s u c c e s s o f s a l t i o d i z a t i o n f o r c o n t r o l l i n g i o d i n e d e f i c i e n c y . Contents

Chapter 1 General i n t r o d u c t i o n 11

Chapter 2 Efficacy o f o r a l i o d i z e d p e a n u t o i l i s g r e a t e r t h a nt h a t o f 31 iodized p o p p y s e e d o i l a m o n g I n d o n e s i a n s c h o o l c h i l d r e n

Chapter 3 Comparison o f i n d i c a t o r s t o a s s e s s i o d i n e s t a t u s a n d i t s 51 improvement t h r o u g h s u p p l e m e n t a t i o n w i t h i o d i z e d o i l

Chapter 4 Effect o f s t u n t i n g , i o d i n e d e f i c i e n c y a n d o r a l i o d i z e d o i l 69 supplementation o n c o g n i t i v e p e r f o r m a n c e o f s c h o o l children i na ne n d e m i c i o d i n e d e f i c i e n t a r e a o f I n d o n e s i a

Chapter 5 Impact o f s a l t i o d i z a t i o n o n i o d i n e s t a t u s o f I n d o n e s i a n 87 school c h i l d r e n l i v i n g i na m o d e r a t e l y i o d i n e d e f i c i e n t area

Chapter 6 General d i s c u s s i o n 101

Annex 1 Efficacy o f d i f f e r e n t t y p e s o f i o d i s e d o i l 115 Lancet 1998,351:752- 753(Letter to the Editor)

Summary 119 Samenvatting 123 Ringkasan 127 Acknowledgments 131 About t h e a u t h o r 135 Chapter 1

General i n t r o d u c t i o n Chapter 1

IODINE DEFICIENCY: MAGNITUDE OF THE PROBLEM AND ITS CONSEQUENCES Iodine deficiency is the world's leading cause of preventable mental retardation. Up u n t i l t h e b e g i n o f t h e 1990s, i t w a s regarded a s being a s i g n i f i c a n t public health p r o b l e m in 118 c o u n t r i e s w i t h 1600 million people at risk (1). In 1990 the W o r l d S u m m i t f o r C h i l d r e n , a t U n i t e d N a t i o n s H e a d q u a r t e r s in N e w Y o r k , s e t t h e goal f o r t h e e l i m i n a t i o n of i o d i n e d e f i c i e n c y d i s o r d e r s (IDD) by t h e y e a r 2 0 0 0 . S i n c e then, reduction in i o d i n e d e f i c i e n c y is a g l o b a l s u c c e s s story by a n y s t a n d a r d . T h i s achievement involved a c o o r d i n a t e d international effort to change diets in a s u b t l e but important way by the introduction of iodized salt (2). UNICEF estimates that nearly 6 0 p e r c e n t o f a l l e d i b l e s a l t i n t h e w o r l d is n o w i o d i z e d . O f t h e c o u n t r i e s t h a t had i o d i n e d e f i c i e n c y a tt h e b e g i n n i n g o f t h e d e c a d e , 2 6 n o w i o d i z e o v e r 9 0 p e r c e n t of t h e i r e d i b l e s a l t o r i m p o r t t h a t p r o p o r t i o n i f t h e y a r e n o t s a l t p r o d u c e r s . A n o t h e r 14 countries iodize b e t w e e n 7 5 p e r c e n t a n d 9 0 p e r c e n t of t h e i r s a l t . A s l a t e a s 1 9 9 4 , 48 c o u n t r i e s w i t h e s t a b l i s h e d i o d i n e d e f i c i e n c y s t i l l h a d n o p r o g r a m s a t a l l . O ft h e s e , 14 now iodize more t h a n half of t h e i r salt (2). A l t h o u g h iodization of salt has been successful in r e d u c i n g t h e p r e v a l e n c e of iodine d e f i c i e n c y , a d d i t i o n a l s t r a t e g i e s are required t o eradicate iodine deficiency. Probably t h e best alternative is o r a l d o s i n g with i o d i z e d o i lw h i c h i st h e s u b j e c t o ft h i st h e s i s . Although goiter is the most manifest sign, iodine deficiency results in irreversible b r a i n d a m a g e i n t h e f e t u s a n d i n f a n t , r e t a r d e d m e n t a l a n d p s y c h o - m o t o r development i nt h e c h i l d , a n d a l s o i m p a i r e d r e p r o d u c t i v e f u n c t i o n ( 3 - 1 1 ) . I nt h e m o s t severe c a s e s , i t l e a d s t o c r e t i n i s m .T h e c u m u l a t i v e c o n s e q u e n c e s in i o d i n e d e f i c i e n t populations s p e l l d i m i n i s h e d p e r f o r m a n c e f o r t h e e n t i r e e c o n o m y . In I n d o n e s i a , I D D comprise one of t h e most important malnutrition problems with high rates of goiter prevalence being r e p o r t e d ( T a b l e 1 ) . The main cause of IDD is i n a d e q u a c y of iodine intake d u e t o environmental deficiency of this essential element. This interacts with poverty and remoteness when t h e r e is l i t t l e contribution of f o o d f r o m outside an iodine d e f i c i e n t area t o t h e diet, a s i st h e c a s e w i t h m u c h s u b s i s t e n c e a g r i c u l t u r e . Poverty, w i t h poor s a n i t a t i o n and g e n e r a l m a l n u t r i t i o n , m a y w o r s e n t h e e f f e c t s of i o d i n e d e f i c i e n c y . I n a d e q u a c y o f iodine i n t a k e i st h e m a j o r b u t n o tt h e s o l ef a c t o r r e s p o n s i b l e f o r IDD.T h e i m p o r t a n c e of other factors in causing iodine deficiency including goitrogenic substances, protein energy malnutrition (PEM), v i t a m i n A and selenium deficiencies, has been revealed b ys e v e r a l s t u d i e s . 12 Generalintroduction

Table 1 . G e n e r a lo v e r v i e wo f i o d i n es t a t u si nI n d o n e s i a

Periodo fi n v e s t i g a t i o n Indicator

1980-1982(12) Prevalenceo fg o i t e r , 1 1 . 3 - 7 4 . 7 % Peoplea tr i s k ,3 0m i l l i o n Estimatedn u m b e r o fc r e t i n s ,7 5 0 , 0 0 0 1987-1990( 1 2 ) Prevalenceo fg o i t e r ,2 . 8 - 6 2 . 2 % 1983-1984( 1 3 ) Adequately i o d i z e ds a l t ( >3 0p p m ) , 33.0% 1995( 1 4 ) Adequately i o d i z e ds a l t (>3 0 p p m ) , 49.8%

Goitrogenic substance s play a r o l e i n t h e e t i o l o g y of IDD i n h u m a n s (15-17). Natural goitrogens were first found in vegetables of the genus Brassica (the Cruciferae family). Their anti-thyroid action is related to the presence of thioglucosides, w h i c h a f t e r digestion release t h i o c y a n a t e (SCN) and isothiocyanate (18).T h e s e c o m p o u n d s a r e p o w e r f u l g o i t r o g e n i c a g e n t s t h a t a c t b y i n h i b i t i n g t h y r o i d iodide t r a n s p o r t a n d a t h i g h d o s e s , c o m p e t e w i t h i o d i d e i nt h e o r g a n i f i c a t i o n p r o c e s s (15). A n o t h e r important group of natural goitrogens is t h e cyanoglycosides, which are f o u n d i n s e v e r a l s t a p l e s (cassava, m a i z e , b a m b o o s h o o t s , s w e e t p o t a t o e s ) (19). After ingestion, these glycosides release cyanide (CN) which is detoxified by conversion t o t h i o c y a n a t e . A c a s s a v a - b a s e d d i e t c o m b i n e d w i t h a l o w i o d i n e s u p p l y produces marked differences in the prevalence of goiter, such differences are determined by t h e balance between iodide and t h i o c y a n a te concentrations in t h e blood r e a c h i n g t h et h y r o i d a n d i nt h et h y r o i d i t s e l f ( 1 9 ) . Severe P E Ma f f e c t s t h y r o i d f u n c t i o n a n dt h e m e t a b o l i s m o ft h y r o i d h o r m o n e s . Iodine malabsorption may be a s s o c i a t e d with PEM a n d t h u s contribute t o endemic goiter, p a r t i c u l a r l y w h e r e i o d i n e i n t a k e i s l i m i t e d ( 2 0 - 2 2 ) . Selenium h a s b e e n s h o w n t o b e a n e s s e n t i a l c o m p o n e n t of i o d o t h y r o n i n e 5 ' - deiodinase t y p e I , I Ia n d I I I ( 2 3 , 2 4 ) .T h y r o x i n e (T 4),t h e m a j o r h o r m o n e p r o d u c t o f t h e thyroid gland, is converted to the more biologically active hormone 3,5,3'- triiodothyronine by t y p e I a n d t y p e II i o d o t h y r o n i n e 5'-deiodinase (25). T h e t y p e III iodothyronine deiodinase converts T4 and T3 into inactive reverse-T3 and diiodothyronine respectively, by catalyzing the inner ring deiodination (26,27). Therefore, selenium-deficient subjects have low tissue deiodinase activities and abnormal t h y r o i d h o r m o n e m e t a b o l i s m ( 2 3 , 2 8 ) . The role of v i t a m i n A in IDD w a s studied by Horvart and Maver (29) on t h e 13 Chapter 1

island o f K r k , Y u g o s l a v i a . T h e p r e v a l e n c e o f g o i t e r i na g r o u p o f s c h o o l c h i l d r e n w a s decreased by 45% in those who received 3,000 lU/d vitamin A supplementation while i t r e m a i n e d t h e s a m e i n a c o n t r o l g r o u p w h i c h w a s n o t s u p p l e m e n t e d . A s t u d y by Ingenbleek and de Visscher (30) has also shown that vitamin A affects iodine metabolism. They found that the concentration of transthyretin, retinol-binding protein a n d r e t i n o l l e v e l s d e c r e a s e d progressively with increase in g o i t e r size w h i l e serum albumin levels and urinary iodine concentration were low in the goitrous subjects in S e n e g a l . W o l d e - G e b r i e l et a l . (31) showed t h a t Ethiopian children with goiter grade IB and II had lower serum retinol and retinol-binding protein levels compared w i t ht h o s e w i t h n o g o i t e r o r g r a d e IA g o i t e r .

IODINE M E T A B O L I S M Most o ft h e i o d i n e i nt h e h u m a n b o d y e n t e r s t h e c i r c u l a t i o n a s i o d i d e ,w h e r e i t becomes p a r t o f t h e i o d i n e p o o l ( 3 2 ) .T h e h e a l t h y a d u l t h u m a n b o d y c o n t a i n s 15-20 mg o f i o d i n e o f w h i c h a b o u t 7 0 - 8 0 % i s i nt h e t h y r o i d g l a n d w h i c h w e i g h s o n l y 1 5 - 2 5 g. T h u s ,t h e p o o l o f i o d i n e i s c o n c e n t r a t e d m a i n l y i nt h e t h y r o i d .T h e r e m a i n d e r is i n tissues o r i nt h e c i r c u l a t i o n e i t h e r a sf r e e i o d i n e o r p r o t e i n - b o u n d i o d i n e . The n o r m a l i n t a k e a n d r e q u i r e m e n t f o r c h i l d r e n a n da d u l t s a r e 1 0 0 - 1 5 0 n gp e r day. Excess iodide is readily excreted by the kidney. The level of excretion correlates w e l l w i t h t h e level of i n t a ke s o t h a t it c a n be u s e d t o a s s e s s t h e level o f iodine i n t a k e (33). T h e t h y r o i d h a s t o t r a p a b o u t 6 0 ^ g o f i o d i n e p e r d a y t o m a i n t a i n an a d e q u a t e s u p p l y o f T 4.T h i s i s p o s s i b l e b e c a u s e o f t h e v e r y a c t i v e i o d i d e t r a p p i n g mechanism w h i c h e n a b l e s t h e t h y r o i d t o m a i n t a i n c o n c e n t r a t i o n gradient s f o r iodide (thyroid/plasma concentration ratios) of about 100 (34). In iodine deficiency, this gradient m a y e x c e e d 4 0 0 i n o r d e r t o m a i n t a i n t h e o u t p u t o f T 4.T h e a m o u n t o f i o d i n e in t h e g l a n d is c l o s e l y related t o i o d i n e i n t a k e a n d t h e c o n t e n t may d r o p t o 1 m g o r less i nt h e i o d i n ed e f i c i e n t t h y r o i d g l a n d ( 3 5 ) . About half of t h e i o d i n e in t h e d i e t , a b s o r b e d f r o m t h e intestine as inorganic iodide, is n o r m a l l y t a k e n up b y t h e t h y r o i d gland (the rest is e x c r e t e d in u r i n e ) and there i n c o r p o r a t e d i n t o p r o t e i n ( t h y r o g l o b u l i n ,T g ) t of o r m m o n o -a n d d i - i o d o t h y r o s i n e

(MIT a n d D I T ) , p r e c u r s o r s o f t e t r a i o d o t h y r o n i n e (T4) a n d t r i i o d o t h y r o n i n e (T3). T h e s e hormones are then released into the blood, often over quite long periods, in response to various stimuli controlled by thyroid stimulating hormone (TSH). T S H which is secreted by the anterior pituitary, is the principal active regulator and 14 General introduction accelerates iodoprotein synthesis. T h e release of T S H is s t i m u l a t e d by t h y r o t r o p i n releasing hormone (TRH), w h i c h is p r o d u c e d by t h e hypothalamus. Both T R H a n d TSH secretion are t r i g g e r ed by a decline in blood thyroid hormone levels, so the system m a i n t a i n s t h e s e b l o o d c o n c e n t r a t i o n s at f u n c t i o n a l l e v e l s o v e r a w i d e r a n g e of iodine s t a t u s ( 3 4 ) .

Iodine exists in the blood as T4, T 3 and as inorganic iodine. The level of inorganic iodine f a l l s in i o d i n e deficiency and rises w i t h increased intake. T 4 is t h e major f o r m o f t h y r o i d h o r m o n e s e c r e t e d b y t h e t h y r o i d : i t i s c o n v e r t e d t o e i t h e r T 3 o r reverse T 3 (rT 3). T h e T 4 a n d T 3 a r e mainly (>99%) bound t o t h r e e plasma proteins i.e.: t h y r o x i n e binding g l o b u l i n , t h y r o x i n e binding prealbumin and a l b u m i n , a n d o n l y about 0.5 percent is f r e e in human serum. In t h e bound state, T 4 a n d T 3 are not biologically a c t i v e . I t i st h e c o n c e n t r a t i o n of u n b o u n d h o r m o n e w h i c h d e t e r m i n e s t h e level to which the target cells are exposed (34). Thus the level of free T4 is an important determinant of t i s s u e levels of t h y r o i d hormone and is necessary for t h e brain. Determination of the level of free T4 in serum is the optimum method for assessment of thyroid status and for the diagnosis of hypothyroidism and hyperthyroidism (36). A s t u d y in iodine d e f i c i e n t rats s h o w e d t h a t low f e t a l b r a i n T 3 increased t h e a c t i v i t y o f 5 ' d e i o d i n a s e II a c t i v i t y (37),t h i s m e a n s t h a t t h e d e v e l o p i n g fetal brain is highly dependent on a supply of T 4 because it is converte d to T 3 by intracellular d e i o d i n a t i o n ( 3 8 ) . The synthesis and availability of the thyroid hormone is reduced in iodine deficiency. H e n c e b l o o d l e v e l s o f T 4a n d F T 4 a s w e l l a s o fT S H a n dT g , c a n b e u s e d for assessing thyroid status. Although much of the basic physiology of thyroid hormones a n d e f f e c t s of d e f i c i e n c y of t h y r o i d h o r m o n es a r e r e a s o n a b l y understood and well-described, the mechanism of action of the hormones, and hence the pathological e f f e c t s o f d e f i c i e n c y , r e m a i nt o b ef u l l y w o r k e d o u t ( 3 6 ) .

INDICATORS FOR A S S E S S I N G T H E E X T E N T O F I D D I N P O P U L A T I O N S Indicators a r e e s s e n t i a l f o r m e a s u r i n g t h e e x t e n t o f i o d i n e d e f i c i e n c y , w h e t h e r and w h i c h i n t e r v e n t i o n is n e c e s s a r y a n d f o r e v a l u a t i n g p r o g r a m implementation a n d impact. I n d i c a t o r s c a n b e c l a s s i f i e d a s : o u t c o m e i n d i c a t o r s w h i c h p r o v i d e a m e a s u r e of i o d i n e s t a t u s , a n d p r o c e s s i n d i c a t o r s w h i c h m e a s u r e p r o g r e s s i n i m p l e m e n t i n g a n IDD c o n t r o l p r o g r a m . T h e o u t c o m e indicators can b e f u r t h e r classified according t o whether the assessment is clinical or biochemical. WHO/UNICEF/ICCIDD (39) 15 Chapter 1

generally recommends that at least two indicators should be used. No single parameter reflects the entire IDD picture and resulting changes in t h e thyroid. In cases o f s e v e r e d e f i c i e n c y , initial e m p h a s i s may be o n l o w e r i n g r a t es of g o i t e r and cretinism. E v e n t h o u g h s e v e r a l i n d i c a t o r s t o e v a l u a t e t h e e x t e n t o f i o d i n e d e f i c i e n c y are established, further study on specificity and sensitivity of outcome indicators among i o d i ne d e f i c i e n t p o p u l a t i o n a r e s t i l l n e e d e d .T h e r e f o r e in t h i s t h e s i s outcome indicators f o r d e t e r m i n i n g i o d i n e s t a t u s a r ee x a m i n e d .

Outcome i n d i c a t o r s :c l i n i c a l . ThyroidSize. T h e s i z e of t h e t h y r o i d g l a n d c h a n g e s inversely in r e s p o n s e t o alterations in iodine intake. Thyroid size can be determined by palpation and ultrasonography. T h e p r e f e r r e d t a r g e t g r o u p i s c h i l d r e n a g e d 8 - 1 0 y e a r s but c a n b e extended to children aged 6-12 years old. There is a practical reason for not measuring v e r y y o u n g a g e g r o u p s : t h e s m a l l e r t h e c h i l d , t h e s m a l l e r t h e t h y r o i d a n d the m o r e d i f f i c u l t it i s t o p e r f o r m p a l p a t i o n , and t h e c o n s i d e r a t i o n f o r not measuring the o l d e r g r o u p i st h e p u b e r t y p e r i o d .T h e c l a s s i f i c a t i o n of g o i t e r c u r r e n t l y u s e d i s a s follows ( 3 9 ) : Grade 0 :N o p a l p a b l e o r v i s i b l e g o i t e r . Grade 1 : A mass in t h e neck that is c o n s i s t e n t with an e n l a r g e d t h y r o i d t h a t is palpable but not visible w h e n the neck is in the normal position. It moves upward in the neck as the subject swallows. Nodular alteration(s) can occur even when the thyroid is n o t visibly enlarged. Previously g r a d e 1g o i t e r w a s d i v i d e d i n t o IA ( p a l p a b l e ) and IB ( v i s i b l e with n e c k e x t e n d e d ) . Grade 2 : A s w e l l i n g in t h e neck t h a t is v i s i b l e when the neck is in the normal position and is consistent with an enlarged thyroid when t h e neck is palpated. Previously g r a d e 2 g o i t e r w a s d i v i d e d into II (visible a t c l o s e range with head in normal position) and III (visible at distance with head i n n o r m a l p o s i t i o n ) . Palpation is q u a n t i t a t i v e only in t h e crude s e n s e . T o t a l goiter rate describes the proportion of total goiter grade 1 and 2 in the population. Specificity and sensitivity of palpation are low in grades 0 and 1 due to a high inter-observer variation, misclassification c a n be a s h i g h a s 4 0 % , e s p e c i a l l y but not e x c l u s i v e l y in the a s s e s s m e n t of s m a l l e r enlargements of t h e t h y r o i d . L o w g o i t e r rates, e s p e c i a l l y when f o u n d f o l l o w i n g a s u s t a i n e d intervention, s h o u l d be c o n f i r m e d by u l t r a s o u n d , 16 General introduction which p r o v i d e s a m o r e o b j e c t i v e m e a s u r e o ft h y r o i d s i z e ( 3 9 - 4 3 ) . H o w e v e r , t h e r e a r e several a d v a n t a g e s of p a l p a t i o n a s a m e t h o d o f m e a s u r e m e n t . It i s a t e c h n i q u e t h a t requires n o i n s t r u m e n t a t i o n , c a n r e a c h l a r g e n u m b e r s i na s h o r t p e r i o d o ft i m e , i sn o t invasive and makes relatively limited demands on the skills of the observer. Nevertheless, t h e ease w i t h which accurate palpation can be c o n d u c t e d has been seriously overestimated in s o m e instances as i n a d e q u a t e l y t r a i n e d o b s e r v e rs have been u s e d ( 4 4 ) . Ultrasonography is a means of obtaining an image of the thyroid and can provide a m o r e a c c u r a t e a s s e s s m e n t of t h y r o i d s i z e . T h i s a s s e s s m e n t a l s o r e q u i r e s a t r a i n e d o p e r a t o r , e x p e n s i v e e q u i p m e n t , a n d i s n o t o f t e n p r a c t i c a l f o r r o u t i n e u s e i n surveys. Ultrasonograph y provides a m o r e precise measurement of t h y r o i d v o l u m e than palpation and this becomes especially significant when the prevalence of visible goiter is small, and in monitoring iodine control programs where thyroid volumes a r e e x p e c t e d t o d e c r e a s e over t i m e (43). T h e t h y r o i d v o l u m e is c a l c u l a t e d based on t h e length, w i d t h , and t h i c k n e s s of both lobes using an ellipsoid model (45). The calculated volume should be compared to the normative standard of a population with sufficient iodine intake (46). In iodine replete populations, the expected prevalence of t h y r o i d v o l u m e s greater t h a n t h e 9 7 th c e n t i l e w o u l d be 3 % , and this figure can be compared with the observed prevalence. In addition, the median ( 5 0 lhc e n t i l e ) t h y r o i d v o l u m e m a y b eu s e f u l . Cretinism. Endemic cretinism, w h i ch is t h e most dramatic consequence of iodine deficiency, is caused by thyroid hormone deficiency during development of the c e n t r a l n e r v o u s s y s t e m d u r i n g t h e p r e n a t a l p e r i o d .T h e m a n i f e s t a t i o n o f e n d e m i c cretinism include mental retardation, severe growth retardation, squinting of eyes andd e a f n e s s .

Outcome i n d i c a t o r s : b i o c h e m i c a l Serum thyroidhormones. Measurement of t h y r o i d hormones in b l o o d m i g h t provide the ultimate tools for measuring IDD. Laboratory methods, usually radioimmunoassay t e c h n i q u e s , e x i s t f o r measuring b l o o d l e v e l s o f t h e m a j o r t h y r o i d hormones, T 4, FT4, T 3, T g and T S H . W h i l e providing some important information, they have the disadvantages of being expensive, being generally unavailable in many d e v e l o p i n g c o u n t r i e s , a n d r e q u i r i n g t h e c o l l e c t i o n o f b l o o d s a m p l e s . Urinary iodine concentration. Almost all iodine in the body is eventually excreted in t h e urine. T h u s measurement of iodine in t h e urine provides a good 17 Chapter 1 index of the iodine ingested. However, since an individual's level of urinary iodine varies daily and even during a given day, data can be used only for making a population-based estimate. The iodine concentration in early morning urine specimens (child o r a d u l t ) provides a n a d e q u a t e a s s e s s m e n t of a p o p u l a t i o n ' s iodine status; 24-hour samples are not necessary. Urinary iodine concentration is preferably expressed per liter of urine (100 u.g/L i s e q u i v a l e n t t o 0.79 |imol/l_) rather than per gram of creatinine (47). Furnee et al. (47) f o u n d that the iodine-creatinine ratio in c a s u a l u r i n e s a m p l e s is a n u n s u i t a b l e indicator f o r e v a l u a t i n g iodine s t a t u s in areas where large inter and intra individual variations in urinary creatinine concentration exist. A m o d e l f o r d e s c r i b i n g u r i n a r y i o d i ne a f t e r o r a l d o s i n g of iodized oil was developed by Furnee et al. (48), which reflects the mutual effects of the physiological m e c h a n i s m involved i n t h e r e t e n t i o n a n d e l i m i n a t i o n o f i o d i n e .

Epidemiological c r i t e r i a f o r a s s e s s i n g t h e s e v e r i t y of I D D A summary of c u t - o f f points a n d prevalence t h a t a r e considered indicative of a s i g n i f i c a n t p u b l i c h e a l t h p r o b l e m f o r IDD i s p r e s e n t e d in T a b l e 2 .

Table 2. Summary of IDD prevalence indicators (outcome indicators) and criteria for a significant p u b l i c h e a l t h p r o b l e ma

Indicator Target p o p u l a t i o n Severity o f p u b l i c h e a l t h p r o b l e m

Mild Moderate Severe

Total g o i t e r ( b y p a l p a t i o n , % ) o r School a g e c h i l d r e n , 5.0-19.9 20.0-29.9 >30.0 thyroid v o l u m e > 9 7 th c e n t i l e b y 6-12y ultrasound3 (%)

Median u r i n a r y i o d i n e l e v e l School a g e c h i l d r e n , 50-99 20-49 <2 0 (ng/L)b 6-12y

TSH > 5 m U / Lw h o l e b l o o d (%) Neonates, 4 - 3 0 d a y s 3.0-19.9 20.0-39.9 > 4 0 . 0

Median T g ( n g / m Ls e r u m ) c Children a n d a d u l t s , 10.0-19.9 20.0-39.9 > 4 00 >1y

Based o nW H O / U N I C E F / I C C I D D ( 3 9 ) m o d i f i e d b yW H O / I C C I D D ( 4 6 ) . Conversion f a c t o r : 100 n g / L = 0 . 7 9 ( i m o l / L No international standards are yet available for this assay so criteria need to be established i n e a c h l a b o r a t o r y ( 4 9 ) .

18 General introduction

With the epidemiological criteria for establishing IDD severity, it should be understood t h a t " m i l d " i s a r e l a t i v e t e r m ; i t d o e s n o t i m p l y t h a t t h i s c a t e g o r y o f I D Di s of l i t t l e c o n s e q u e n c e . W i t h r e s p e c t t o g o i t e r , a t o t a l g o i t e r rate (goiter grades 1 a n d 2) o f 5 % o r m o r e i n p r i m a r y s c h o o l c h i l d r e n (age r a n g e a p p r o x i m a t e l y 6 t o 12 y e a r s ) signals t h e presence of a p u b l i c health problem. T h i s is based on t h e observation that in a n o r m a l iodine-replete population, t h e p r e v a l e n c e of goiter should be q u i t e low. T h e c u t - o f f of 5% a l l o w s s o m e m a r g i n o f i n a c c u r a c y of g o i t e r assessment and for goiter that may occur in iodine-replete population due t o other causes such as goitrogens and autoimmune thyroid diseases. The previously recommended 10% cut-off level has been revised downwards since it has been shown that goiter prevalence rates between 5% and 10% may be associated with a range of abnormalities, including inadequate urinary iodine concentration and/or abnormal levels o fT S H a m o n g a d u l t s , c h i l d r e n a n d n e o n a t e s ( 3 9 ) . With r e s p e c t t o u r i n a r y i o d i n e c o n c e n t r a t i o n ,f r e q u e n c y d i s t r i b u t i o n c u r v e s a r e necessary for full interpretation, since values from populations are usually not normally d i s t r i b u t e d , a n d t h e r e f o r e t h e median v a l u e is u s e d r a t h e r t h a n t h e m e a n . Iodine deficiency is indicated when the median value for iodine concentration in urine is l e s s t h a n 0 . 7 9 |amol/L, i . e . w h e n 5 0 % o f t h e s a m p l e s have v a l u e s less t h a n 0.79 n m o l / L The specificity of TSH for IDD screening has not been clearly quantified. Individuals with mild elevations of TSH can now be detected by using t he newer sensitive whole-blood TSH assay. IDD screening programs are not designed to follow u p i n d i v i d u a l s b u t t o d i r e c t p o p u l a t i o n - b a s e d interventions. R e f e r e n c e d a t a f o r TSH a r e a v a i l a b l e a m o n g neonates because t h e y a r e routinely collected a s p a r t o f neonate congenital hypothyroid screening programs. TSH values are currently in whole blood units or serum units. A T S H cut-off point of 20-25 mU/L w h o l e blood (approximately 40-50 mU/L serum) is commonly used to screen for congenital hypothyroidism. IDD may present with TSH levels which are only mildly elevated. While further study of iodine-replete populations is n e e d e d , a cut-off of 5 mU/L in whole blood is regarded as appropriate for epidemiological studies of IDD in neonates. Individuals (children and adults) with sufficient iodine intake show a median Tg s e r u m l e v e l of 10 n g / m l a n d a n o r m a l upper limit, f o r individuals, of 20 n g / ml i n most a s s a y t e c h n i q u e s . T h e r e s u l t s o b t a i n e d f r o m a s u r v e y s h o u l d b e e x p r e s s e d a s a m e d i a n a n d a st h e p e r c e n t a g e o fT g l e v e l s a b o v e 2 0 n g / m l ( 3 9 ) . H o w e v e r i t s h o u l d 19 Chapter 1

be n o t e d t h a t no international standards are y e t a v a i l a b l e for this assay so criteria needt o b ee s t a b l i s h e d i ne a c h l a b o r a t o r y ( 4 9 ) .

Process i n d i c a t o r s o f I D Dc o n t r o l p r o g r a m s As programs are implemented for the control of IDD in a country, it is important to establish mechanisms for monitoring and evaluating these activities. Included in such monitoring protocols will be both indicators associated with the process of t h e programs, as well as indicators of the impact realized through the implementation of t h e c o n t r o l a c t i v i t i e s . Depending upon t h e s p e c i f i c characteristics of the IDD control programs, distinct indicators will need to be considered and different t e c h n i q u e s e m p l o y e d int h e i r m o n i t o r i n g . A l t h o u g h m o s t c o u n t r i e s w i l l h a v e iodized s a l t a s t h e p r i m a r y c o n t r o l a c t i v i t y , o t h e r programs, w h e r e implemented, w i l l need to be monitored, even if they are used as short-term measures while salt iodization i sb e i n g e s t a b l i s h e d . Salt iodization programs. All countries with a significant public health IDD problem s h o u l d u n d e r t a k e a s i t u a t i o n a n a l y s i s o f s a l t a v a i l a b l e f o r h u m a n a n d a n i m a l consumption,f r o m p o i n t s o f p r o d u c t i o n (or i m p o r t a t i o n ) t h r o u g h d i s t r i b u t i o n c h a n n e l s to t h e c o n s u m p t i o n level. S u c h s a l t is r e f e r r e d t o a s foodgrade salt,w h i c h includes crude salt for direct edible use by people, and for livestock; and refined salt for edible u s ea n df o r u s e i n m o s t p r o c e s s e d f o o d s ( 5 0 ) . The i o d i z a t i o n o f s a l t i n v o l v e s t h e a d d i t i o n o f a s m a l l q u a n t i t y o f i o d i n e (30 t o 100 mg of iodine per kg salt, or parts per million - ppm), usually in the form of potassium iodide or potassium iodate. The j o i n t FAO/WHO Expert Committee on Food A d d i t i v e s noted in 1 9 9 1 t h a t "potassium i o d a t e h a s b e e n s h o w n t o b e a m o r e suitable substance for fortifying salt than potassium iodide, because of its greater stability, p a r t i c u l a r l y i nw a r m ,d a m p o rt r o p i c a l c l i m a t e s " ( 5 1 ) . Iodized oil programs.T h e program evaluation should permit a monitoring of periodic recording of distribution of the oral iodized oil capsules and assess an output e . g .n u m b e r o f p e o p l e a t r i s k o f i o d i n e d e f i c i e n c y r e c e i v i n g t h e c a p s u l e s .

INDONESIAN I D DC O N T R O L P R O G R A M S The Government of Indonesia has endorsed the goals of the 1990 World Summit f o r C h i l d r e n a n d t h e r e c o m m e n d a t i o n s of t h e 1991 W o r l d Health A s s e m b l y for t h e e l i m i n a t i o n o f IDD b y t h e y e a r 2 0 0 0 .T o a t t a i n t h e g o a lt h a t by t h e y e a r 2 0 0 0 20 General introduction

no cretinious baby will be born, the IDD National Program in Indonesia has established t h ef o l l o w i n g s t r a t e g i e s ( 5 2 ) . Iodizedsalt forhuman consumption.T o s t r e n g t h e n t h e iodized s a l t p r o g r a m , the government issued a joint decree of four Ministries (Industry, Health, Trade and Home A f f a i r s ) , that all salt for human consumption in Indonesia

should be i o d i z e d t o 4 0 - 5 0 ppm w i t h p o t a s s i u m iodate (KI0 3). Indonesia h a s had a l a w m a n d a t i n g t h e f o r t i f i c a t i o n o f s a l t w i t h i o d a t e s i n c e 1994; t h e l o w e r limit has been s e t at 3 0 ppm I. Results of t h e national survey in 1996 (14) found t h a t half of t h e s a l t c o n s u m e d in 2 0 0 , 0 0 0 households was adequately iodized.

Iodizedinjectable and orallyadministered oil in severelyendemic areas. T h e iodized oil s u p p l e m e n t a t i o n program has been operating since 1974. S o f a r 11 million people have received iodized oil injections. Starting from 1993, injected oil supplementation has been replaced by iodized oil through oral administration ( 1 2 , 5 3 ) .

The program of iodized oil has shown good results in many endemic areas andt h e a p p r o a c h o f s a l t i o d i z a t i o n , h a s s h o w n p r o g r e s s i n I n d o n e s i a . A d m i n i s t r a t i o n of iodized oil by oral may become a more w i d e ly used method in t h e future. T h e major advantages of iodized oil administration are that it can be implemented immediately, and does not involve t h e complexities of altering salt production and trade. T h u s , t h e usual places for iodized oil are f o r the areas of significant iodine deficiency where iodized salt is unlikely t o be successfully implemented soon and correction is n e e d e d promptly. In m a n y such a r e a s , t h e iodized oil program w i l l be necessary for at least several years, and for some remote areas it may be s e m i - permanent ( 5 4 ) .

USE O FO R A L I O D I Z E D O I L F O R C O N T R O L L I N G I O D I N E D E F I C I E N C Y There is evidence from several studies in A l g e r i a (55), Bolivia (56), Malawi (47) a n d Z a i r e ( 5 7 ) ,t h a t o r a l a d m i n i s t r a t i o n o f a s i n g l e d o s e o f i o d i z e d o i l i s e f f e c t i v e for s e v e r a l y e a r s i n p r o t e c t i n g a g a i n s t i o d i n e d e f i c i e n c y . E x p e r i e n c e w i t h o r a l i o d i z e d oil is m o r e l i m i t e d t h a n t h a t w i t h t h e injected m a t e r i a l , a n d p r e c i s e g u i d e l i n e s f o r its optimal d o s e a n dd u r a t i o n o f e f f e c t i v e n e s s a r e n o ta v a i l a b l e . 21 Chapter 1

At p r e s e n t it i s s u g g e s t e d t h a t a s i n g l e o r a l d o s e o f 1m l _( 4 8 0 m g i o d i n e ) w i l l provide a d e q u a t e iodine f o r o n e t o t w o y e a r s a f t e r a d m i n i s t r a t i o n . A p r e v i o u s study in Zaire suggests that smaller doses may be equally effective, at least for a year (57). A s t u d y by Furnee et al. (47) showed that a single dose of an iodized oil in which t h e i o d i z e d f a t t y a c i d sf r o m p o p p y s e e d o i l a r e p r e s e n t a s t r i a c y l g l y c e r o l e s t e r s (675 mg iodine) maintained urinary iodine concentration above 0.40 nmol/L for approximately o n e y e a r w h e r e a s t h e d u r a t i o n o f e f f e c t i v e n e s s of i o d i z e d o i l ( 4 9 0 m g iodine) w h i c h c o n s i s t o f a m i x t u r e o f e t h y l e s t e r s o f i o d i z e d f a t t y a c i d s , l a s t e d o n l y 3 - 4 months. While effectiveness is s h o r t e r than t h a t of injection, o r a l administration avoids the need for syringes, needles, and sterile techniques, and can be administered by responsible persons without medical t r a i n i n g . C a p s u l es of iodized oil c o n t a i n i n g approximately 200 mg iodine are availabl e and c an be administered directly ( 5 8 ) . Iodized oil is based on either triacylglycerol esters or ethyl esters of unsaturated f a t t y a c i d s (59). W h e n t h e u n s a t u r a t e d f a t t y a c i d s react w i t h potassium iodide, s a t u r a t i o n of t h e d o u b l e b o u n d t a k e s p l a c e w i t h t h e a d d i t i o n o f i o d i n e t o o n e of the carbon atoms involved (35). Up until now, the most widely available preparations have been based on poppyseed oil a n d have been manufactured by Guerbert Laboratories, France. Preparations containing triacylglycerol ester were marketed under t h e b r a n d name of O r i o d o l ® while t h o s e c o n t a i n i n g ethyl e s t e r are marketed u n d e r t h e n a m e o f L i p i o d o l ® UF.T h e f a t t y a c i d c o m p o s i t i o n of p o p p y s e e d oil on a weight basis is: linolenic acid (C18:2, n-6), 73%; o l e i c acid (C18:1, n-9), 14%;s t e a r i c a c i d ( C 1 8 : 0 ) ,3 % ; a n d p a l m i t i c a c i d ( C 1 6 : 0 ) ,9 % ( 6 0 ) . AS t u d y b yV a n d e r H e i d e e t a l . (61) i n b o t h m a n a n d r a t s ,s h o w e d t h a t i o d i n e was r e t a i n e d longer f r o m a p r e p a r a t i o n prepared f r o m e t h y l o l e a t e c o m p a r e d w i t h a preparation prepared from ethyl linoleate or from ethyl esters derived from poppyseed o i l .W h i l e t h e w o r k d e s c r i b e d int h i s t h e s i s w a s u n d e r w a y , I n g e n b l e e k e t al. (62) reported on t h e effectiveness of iodized rapeseed oil compared to iodized poppyseed o i l .T h e s e a u t h o r s found t h a t iodized r a p e s e e d s u p p l y i n g 7 5 2 m g I g a v e longer protection in moderate iodine deficient adults (30 wk) compared to iodized poppyseed s u p p l y i n g 7 2 9 m g ( 1 7 w k ) w h e n a n i o d i n e c o n c e n t r a t i o n in u r i n e o f 0.79 iamol/Lw a s t a k e n a s t h e c u t - o f f point. Most o f i o d i n e in t h e r a p e s e e d o i l p r e p a r a t i o n was b o u n dt o o l e i c a c i d a n d i n p o p p y s e e d o i l p r e p a r a t i o n t o l i n o l e i c a c i d ( 6 2 ) .

22 General introduction

Useo f o r a l i o d i z e d o i l i n I n d o n e s i a The iodized oil capsule supplementation program started in Indonesia in 1992/1993. The iodized oil supplement is distributed in moderate and severely endemic areas w h i c h w e r e indicated by p r e v a l e n c e of t o t a l g o i t e r rate 2 0 - 2 9 % a n d 30% a n d a b o v e r e s p e c t i v e l y . T h et a r g e t g r o u p o ft h i s p r o g r a m i sa l l m a l e s a g e d 0 - 2 0 years and females aged 0-35 years, including pregnant and lactating women in moderate a n d s e v e r e e n d e m i c a r e a s (63). I n g e n e r a l , i o d i z e d o i l s h o u l d b e a v o i d e d over t h e a g e of 4 5 y e a r s because of t h e p o s s i b i l i t y of precipitating hyperthyroidism (63). Pregnancy is not regarded as a c o n t r a - i n d i c a t i o n . It is d e s i r a b l e for t h e male population to be included in a n iodized oil program even t h o u g h t h e other groups already mentioned are more at risk. T h e experiences of males of t h e benefits will include greater productivity and quality of life which are important to community acceptance ( 6 3 ) . An Indonesian pharmaceutical f i r m has introduced Yodiol® into t h e market. Yodiol® is prepared by iodization of peanut oil w h i c h has about t h r e e times more oleic a c i d a n d half t h e a m o u n t of linoleic acid c o m p a r e d w i t h t h e e s t a b l i s h e d orally administered iodized oil which is prepared from poppyseed oil. Therefore, we decided t o c o m p a r e t h e e f f i c a c y o f a p r e p a r a t i o n o f i o d i z e d p e a n u t o i lw i t ht h a t o ft h e iodized p o p p y s e e d o i lp r e p a r a t i o n .

OBJECTIVES A N D H Y P O T H E S E S O FT H E S T U D Y The o b j e c t i v e s a n d h y p o t h e s e s ( w r i t t en i nitalics) o ft h i s s t u d y a r e a sf o l l o w s :

Main o b j e c t i v e s a n d h y p o t h e s e s (1). To i n v e s t i g a t e a n d c o m p a r e t h e e f f i c a c y of o r a l l y a d m i n i s t e r e d iodized p e a n u t oil containing a high proportion of monounsaturated f a t t y acids and iodized poppyseed oil containing a high proportion of polyunsaturated fatty acids among Indonesian school children aged 8-10 years living in an endemic iodine d e f i c i e n t a r e a . Theefficacy of iodizedpeanut oil is higherthan that of iodizedpoppyseed oil among Indonesian school children aged 8-10 years living in an endemic iodinedeficient area.

23 Chapter 1

(2). To e v a l u a t e d i f f e r e n t outcome indicators of IDD s t a t u s : c a s u a l urinary iodine concentration, goiter size (measured by palpation and by ultrasound) and

blood levels of FT4 and TSH at baseline and after oral iodized peanut oil supplementation in Indonesian school children aged 8-10 years living in a n endemic i o d i n e d e f i c i e n t a r e a . Urinary iodine concentration, goiter size (measured by palpation and by

ultrasound) andblood levels of FT 4 and TSH at baselineand after oral iodized oil supplementation, indicated the same level of severity of iodinedeficiency in Indonesian school children aged 8-10 years living in an endemic iodine deficientarea.

Secondary o b j e c t i v e s a n d h y p o t h e s e s (3). To i n v e s t i g a t e t h e e f f e c t of iodine s u p p l e m e n t a t i o n on c o g n i t i v e performance of Indonesian school children aged 8-10 years living in an endemic iodine deficient a r e a . Iodine supplementation improves the cognitive performance of Indonesian schoolchildren aged8-10 years living in an endemic iodine deficient area.

(4). To investigate the relationship between nutritional status and cognitive performance of Indonesian school children aged 8-10 years living in an endemic i o d i n e d e f i c i e n t a r e a . School children living in an endemic iodine deficient area with adequate nutritional status, have better cognitive performance than malnourished schoolchildren.

Tertiary o b j e c t i v e a n d h y p o t h e s i s (5). To investigate the relationship between iodized salt consumption and the iodine status of Indonesian school children aged 8-10 years living in an endemic i o d i n e d e f i c i e n t a r e a . Loweriodine intake from iodized salt is associated withlower status ofiodine in Indonesian school children aged 8-10years living in an endemic iodine deficientarea.

24 General introduction

OUTLINE O FT H E T H E S I S The research d e s c r i b e d in t h i s t h e s i s w a s c o n d u c t e d between October 1996 and December 1997 i n a n e n d e m i c iodine d e f i c i e n t area in C i l a c a p d i s t r i c t , Central Java, I n d o n e s i a . Chapter2 describes the efficacy of different oral preparations of iodized oil among s c h o o l c h i l d r e n l i v i n g i na n e n d e m i c i o d i n e d e f i c i e n t a r e a ( O b j e c t i v e 1 ) . Chapter3 d e s c r i b e s t h e c o m p a r i s o n o f i n d i c a t o r s f o r m e a s u r i n g i o d i n e s t a t u s in p o p u l a t i o n a n d t h e impact of i o d i z e d o i l s u p p l e m e n t a t i o n in s c h o o l c h i l d r e n living in a n e n d e m i c i o d i n e d e f i c i e n t a r e a ( O b j e c t i v e 2 ) . Chapter4 describes the effects of oral iodized oil and nutritional status on cognitive performance in s c h o o l c h i l d r e n living i n a n e n d e m i c iodine d e f i c i e n t a r e a (Objectives 3 ,4 ) . Chapter 5 describes the impact of compulsory salt iodization on t h e iodine status of Indonesian school children living in a n endemic iodine deficient area, a s indicated by urinary iodine concentration, thyroid palpation and thyroid volume measured b y u l t r a s o u n d ,a n d b l o o d l e v e l s o f F T 4a n dT S H ( O b j e c t i v e 5 ) . Chapter6 d i s c u s s e s t h e m o s t i m p o r t a n t f i n d i n g s of t h e r e s e a r c h d e s c r i b e d i n thist h e s i s .

25 Chapter 1

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26 Generalintroduction

endemic g o i t e r (author's t r a n s l ) ] . Ann E n d o c r i n o l P a r i s 1 9 8 1 ; 4 2 : 4 3 5 - 8 . 19. Delange F, Iteke FB, Ermans AM. Nutritional factors involved in the goitrogenic action o f c a s s a v a . O t t a w a : I n t e r n a t i o n a l D e v e l o p m e n t R e s e a r c h C e n t r e , 1 9 8 2 . 20. Osman A , Khalid B, T a n T T , Wu LL, Ng M.L. Protein energy malnutrition, thyroid hormones a n d g o i t e r a m o n g M a l a y s i a n A b o r i g i n e s a n d M a l a y s . Asia P a c J C l i n N u t r 1992;1:13-20. 21. Grantham MS, Powell C, Fletcher P. Stunting, severe malnutrition and mental development i ny o u n g c h i l d r e n . Eur J C l i n N u t r 1 9 8 9 ; 4 3 : 4 0 3 - 9 . 22. Grantham MS. A review of studies of the effect of severe malnutrition on mental development. J N u t r 1 9 9 5 ; 1 2 5 : 2 2 3 3 S - 8 S . 23. Arthur JR, Nicol F, Beckett GJ. Selenium deficiency, thyroid hormone metabolism, andt h y r o i d h o r m o n e d e i o d i n a s e s . Am J C l i n N u t r 1 9 9 3 ; 5 7 :2 3 6 S - 9 S . 24. Arthur JR. The role of selenium in thyroid hormone metabolism. Can J Physiol Pharmacol 1 9 9 1 ; 6 9 : 1 6 4 8 - 5 2 . 25. Leonard J L , V i s s e r T J . B i o c h e m i s t r y of d e i o d i n a t i o n . In: Hennemann G , e d . T h y r o i d hormone m e t a b o l i s m . N e w Y o r k : M a r c e l D e k k e r , 1 9 8 6 : 1 8 9 - 2 2 2 . 26. Ramauge M, Pallud S, Esfandiari A, et al. Evidence that type III iodothyronine deiodinase i n r a ta s t r o c y t e i s a s e l e n o p r o t e i n . E n d o c r i n o l o g y 1996;137:3021-5. 27. Schoenmakers C H , P i g m a n s IG, Kaptein E, Darras V M , V i s s e r T J . R e a c t i o n o f t h e type III iodothyronine deiodinase with the affinity label N-bromoacetyl- triiodothyronine. FEBS L e t t 1 9 9 3 ; 3 3 5 : 1 0 4 - 8 . 28. Arthur J R , Nicol F, Beckett G J . T h e r o l e of s e l e n i u m in t h y r o i d h o r m o n e metabolism and e f f e c t s of s e l e n i u m deficiency on t h y r o i d hormone and iodin e m e t a b o l i s m . Biol Trace E l e m R e s 1 9 9 2 ; 3 4 : 3 2 1 - 5 . 29. Horvart A , Maver H. T h e role of v i t a m i n A in t h e occurence of goiter on t h e island Krk,Y u g o s l a v i a . J N u t r 1 9 5 8 ; 6 6 : 1 8 9 - 2 0 3 . 30. Ingenbleek Y , De V i s s c h e r M. H o r m o n a l a n d n u t r i t i o n a l s t a t u s : c r i t i c a l c o n d i t i o n s f o r endemic g o i t e r e p i d e m i o l o g y ? Metabolism 1979;28:9-19. 31. Wolde-Gebriel Z, West CE, Gebru H, et al. Interrelationship between vitamin A, iodine a n d i r o n s t a t u s in s c h o o l c h i l d r e n in S h o a r e g i o n , C e n t r a l Eithiopia. Br J Nutr 1993;70:593-607. 32. Underwood EJ. T h e i n c i d e n c e of t r a c e e l e m e n t deficiency diseases. Philos T r a n s R Soc L o n d B B i o l S c i 1 9 8 1 ; 2 9 4 : 3 - 8 . 33. Bourdoux P, Delange F, Vanderlinden L, Ermans AM. [Pathogenesis of endemic goiter: e v i d e n c e of a d i e t a r y f a c t o r d i f f e r e n t f r o m iodine d e f i c i e n c y (author's t r a n s l ) ] . Ann E n d o c r i n o l P a r i s 1 9 7 8 ; 3 9 : 1 5 3 - 4 . 34. Wartofsky L. Endocrinology and Metabolism. In: Isselbacher KJ, Braunwald E, Wilson JD, Martin JB, Fauci A S , Kasper DL, eds. Harrison's Principles of Internal Medicine. 13th e d .N e w Y o r k , N . Y . : M c G r a w - H i l l , I n c , 1 9 9 4 : 1 9 3 0 - 5 2 . 35. Hetzel B S . T h e s t o r y o f i o d i n e d e f i c i e n c y : a n i n t e r n a t i o n a l c h a l l e n g e in n u t r i t i o n . N e w York, N . Y . : O x f o r d U n i v e r s i t y P r e s s , 1 9 8 9 . 36. Hetzel BS. T h e prevention and control of iodine deficiency disorders. Rome, Italy: ACC/SCN, F A O , 1 9 9 3 . 37. Moreale d e E s c o b a r G , C a l v o R , E s c o b a r d e l R e y F , O b r e g o n M J .T h y r o i d h o r m o n e s int i s s u e s f r o m f e t a l a n d a d u l t r a t s . Endocrinology 1994;134:2410-5. 38. Moreale de Escobar G, Obregon MJ, Calvo R, Escobar del Rey F. Hormone nurturing of t h e d e v e l o p i n g brain: t h e rat m o d e l . In: Stanbury J B , e d . T h e damaged brain of iodine deficiency. New York: Cognizant Communication Corporation, 1993:103-22.

27 Chapter 1

39. WHO/UNICEF/ICCIDD. I n d i c a t o r s f o r a s s e s s i n g i o d i n e d e f i c i e n c y d i s o r d e r s a n d t h e i r control p r o g r a m s . G e n e v a : W H O , 1 9 9 4 . 40. Gutekunst R, Chaouki ML, Dunn JT, Benmiloud M. Field assessment of goiter: comparison of palpation, s u r f a c e outline and ultrasonography. Int Symp on Iodine andt h e T h y r o i d 1 9 9 0 ; ( a b s t ) 41. Gutekunst R, Smolarek H, Hasenpusch U, et al. Goitre epidemiology: thyroid volume, iodine excretion, t h y r o g l o b u l i n and thyrotropin in Germany and Sweden. Acta E n d o c r i n o l C o p e n h 1 9 8 6 ;1 1 2 : 4 9 4 - 5 0 1 . 42. Berghout A, Wiersinga WM, Smits NJ, Touber JL The value of thyroid volume measured by ultrasonography in the diagnosis of goitre. Clin Endocrinol Oxf 1988;28:409-14. 43. Vitti P, Martino E, Aghini LF, et a l . T h y r o i d volume measurement by ultrasound in children as a t o o l for the assessment of mild iodine deficiency. J Clin Endocrinol Metab 1 9 9 4 ; 7 9 : 6 0 0 - 3 . 44. Stanbury JB, Pinchera A. Measurements of iodine deficiency disorders. In: Hetzel BS, P a n d a v C S , e d s . S . O . S . f o r a b i l l i o n . N e w D e l h i , I n d i a : O x f o r d U n i v e r s i ty Press, 1994:73-88. 45. Delange F, B e n k e r G , C a r o n P, e t a l .T h y r o i d v o l u m e a n d u r i n a r y i o d i n e i n E u r o p e a n schoolchildren: s t a n d a r d i z a t i o n of v a l u e s f o r a s s e s s m e n t of i o d i n e d e f i c i e n c y . Eur J Endocrinol 1 9 9 7 ; 1 3 6 : 1 8 0 - 7 . 46. WHO, I C C I D D . R e c o m m e n d e d normative v a l u e s f o r t h y r o i d v o l u m e in c h i l d r e n a g e d 6-15y e a r s . BullW o r l d H e a l t h O r g a n 1 9 9 7 ; 7 5 : 9 5 - 7 . 47. Furnee CA, v a n der Haar F, W e s t CE, H a u t v a s t J G A J . A c r i t i c a l a p p r a i s a l of goiter assessment a n d t h e r a t i o o f u r i n a r y i o d i n e t o c r e a t i n i n e f o r e v a l u a t i n g iodine s t a t u s . Am J C l i n N u t r 1 9 9 4 ; 5 9 : 1 4 1 5 - 7 . 48. Furnee C A , P f a n n G A , W e s t C E , v a n d e r Haar F, v a n d e r Heide D., Hautvast J G A J . New m o d e l f o r d e s c r i b i n g u r i n a r y i o d i n e e x c r e t i o n : i t s u s e f o r c o m p a r i n g d i f f e r e n t o r a l preparations o f i o d i z e d o i l . Am J C l i n N u t r 1995; 6 1 : 1257-62. 49. Feldt RU, P r o f i l i s C, C o l i n e t E, e t a l . H u m a n t h y r o g l o b u l i n reference material (CRM 457); 1 s t p a r t : A s s e s s m e n t of h o m o g e n e i t y , s t a b i l i t y a n d i m m u n o r e a c t i v i t y ; 2 n d p a r t : Physicochemical c h a r a c t e r i z a t i o n and c e r t i f i c a t i o n . Ann Biol Clin 1996;54:337-342; 343-8. 50. UNICEF/PAMM/MI/ICCIDD/WHO. Monitoring universal salt iodization programmes. Atlanta, G . A . : P A M M / M I / I C C I D D , 1 9 9 5 . 51. FAO/WHO E x p e r t C o m m i t e e o n F o o d A d d i t i v e s . E v a l u a t i o n o f C e r t a i n A d d i t i v e s a n d Contaminants. 8 0 6 . 1 9 9 1 . G e n e v a , S w i t z e r l a n d ,W H O / F A O . 52. Soekirman, T a r w o t j o , I., J u s ' a t , I . , S u m o d i n i n g r a t , G . , a n d J a l a l , F. E c o n o m i c g r o w t h , equity and nutritional improvement in Indonesia. 1992. Adelaide, Australia, UN ACC/SCN. 53. Pandav CS. IDD in S o u t h - E a s t Asia. In: Hetzel BS, Pandav CS, e d s . S.O.S. for a billion. N e w D e l h i :O x f o r d U n i v e r s i t y P r e s s , 1 9 9 4 : 2 1 3 - 3 1 . 54. Dunn J T . I o d i n e s u p p l e m e n t a t i o n a n d t h e p r e v e n t i o n of c r e t i n i s m . A n n NY A c a d S c i . 1993;678:158-68. 55. Benmiloud M, Chaouki ML, Gutekunst R, Teichert HM, Wood W G , Dunn J T . Oral iodized oil for correcting iodine deficiency: optimal dosing and outcome indicator selection. J C l i n E n d o c r i n o l M e t a b 1 9 9 4 ; 7 9 : 2 0 - 4 . 56. Bautista A , Barker PA, D u n n J T , S a n c h e z M, K a i s e r DL. T h e effects of o r a l iodized oil o n i n t e l l i g e n c e , t h y r o i d s t a t u s , a n d s o m a t i c g r o w t h i n s c h o o l - a g e c h i l d r e n f r o m a n area o f e n d e m i c g o i t e r . Am J C l i n N u t r 1 9 8 2 ; 3 5 : 1 2 7 - 3 4 .

28 Generalintroduction

57. Tonglet R, Bourdoux P, Minga T , Ermans A M . E f f i c a c y of low o r a l d o s e s of iodized oil i nt h e c o n t r o l o f i o d i n e d e f i c i e n c y in Z a i r e . N E n g l J M e d 1 9 9 2 ; 3 2 6 : 2 3 6 - 4 1 . 58. Dunn JT, van der Haar F. A practical guide to the correction of iodine deficiency. Wageningen,T h e N e t h e r l a n d s : I C C I D D , 1 9 9 0 . 59. DeMaeyer, E. M . , L o w e n s t e i n , F. W . , a n d T h i l l y , C . H. T h e c o n t r o l o f e n d e m i c goiter. Geneva, S w i t z e r l a n d , W H O , 1 9 7 9 . 60. Chastin I. L i p i o d o l u l t r a - f l u i d e f o r t h e p r e v e n t i o n a n d t r e a t m e n t o f e n d e m i c g o i t e r a n d associated pathologies. Roissy, Charles de Gaulle Cedex, France: Laboratoire Guerbet, 1 9 9 2 . 61. Van der Heide D, de Goeje MJ, van der Bent C. The effectiveness of oral administered iodized oil in rat and man. Annales d'endocrinologie 1989; 50: 116 (abst). 62. Ingenbleek Y, Jung L, Ferard G, Bordet F, Goncalves AM, Dechoux L Iodised rapeseed o i lf o r e r a d i c a t i o n o f s e v e r e e n d e m i c g o i t r e . Lancet 1 9 9 7 ; 3 5 0 : 1 5 4 2 - 5 . 63. Ministry of Health Rl. Guidelines for the usage of iodized oil capsules. 1992. Jakarta, I n d o n e s i a , D i r e c t o r a t e o f N u t r i t i o n , M i n i s t r y o f H e a l t h R l .

29 Chapter 2

Efficacy o fo r a l i o d i z e d p e a n u to i l isg r e a t e r t h a nt h a to fi o d i z e d p o p p y s e e d o i l among I n d o n e s i a n s c h o o l c h i l d r e n

Juliawati Untoro, Werner Schultink, Clive E West, Rainer Gross, Joseph G.A.J. Hautvast Chapter2

ABSTRACT Oral iodized poppyseed oil is the major alternative to iodized salt for correcting iodine deficiency. There is a need for a more effective and cheaper iodized o i l p r e p a r a t i o n .T h e a i m o f t h i s s t u d y w a s t o c o m p a r e t h e e f f i c a c y of i o d i z e d peanut oil with that of iodized poppyseed oil. Randomly selected school children aged 8 - 1 0y ( n = 2 5 1 ) in a n e n d e m i c i o d i n e d e f i c i e n t a r e a i n I n d o n e s i a w e r e a l l o c a t e d to f i v e g r o u p s a n d s u p p l e m e n t e d w i t h a s i n g l e o r a l d o s e o f iodized peanut oil ( 2 0 0 , 400 o r 8 0 0 m g I ) ; i o d i z e d p o p p y s e e d o i l (400 m g I ) ; o r p e a n u t o i l (placebo). U r i n a r y iodine concentration was measured at 0 , 4 , 12, 2 5 a n d 5 0 w k . Except at b a s e l i n e , urinary iodine c o n c e n t r a t i o n of a l l t r e a t m e n t groups w a s h i g h e r t h a n in t h e placebo group. Urinary iodine c o n c e n t r a t i o n of t h e g r o u p s u p p l e m e n t e d w i t h iodized peanu t oil s u p p l y i n g 200 mg I w a s s i m i l a r t o t h e c o n c e n t r a t i o n of t h e group supplemented with iodized poppyseed oil. Comparing preparations supplying 400 mg I using a mathematical model, iodine retention from the peanut oil preparation was three times higher and t h e protection period twice as long as t h a t of the poppyseed oil preparation. R e d u c t i o n of t h y r o i d v o l u m e in t h e iodized o i l g r o u p s w a s g r e a t e r than in the placebo group. There were no significant differences in serum thyroid stimulating hormone and serum free thyroxine among groups before or after treatment. Iodized peanut oil is more efficacious than iodized poppyseed oil containing t h e s a m e a m o u n t o f i o d i n e i nc o n t r o l l i n g i o d i n e d e f i c i e n c y .

32 Efficacy of oral iodized oil preparations

INTRODUCTION Effective control of iodine deficiency is still a challenge in developing countries (1). Despite the success of universal salt iodization (2,3), provision of iodized s a l t is s o m e t i m e s ineffective because of e c o n o m i c c o n d i t i o n s , a s h o r t a g e o f iodized salt in local markets, inadequately iodized salt, loss of iodine from salt because of excessive exposure to moisture, light and heat, and the use of non- iodized local salt (4-6). Single intramuscular injections of iodized oil provide adequate i o d i n ef o r t w ot o t h r e e y e a r s (7) b u t i n j e c t i o n s h a v e s e r i o u s d i s a d v a n t a g e s , including the potential to serve as a vector for communicable diseases and the expense involved (8). O r a l a d m i n i s t r a t i o n of iodized oil has been a d v o c a t e d as a n alternative, b u t e x p e r i e n c e w i t h t h i s method is l i m i t e d (9) a n d t h e o p t i m a l d o s e a n d thef r e q u e n c y o f d o s i n g r e m a i n u n c e r t a i n ( 1 0 ) . Until r e c e n t l y , t h e m a i n r a w m a t e r i a l f o r i o d i z e d o i l h a s b e e n p o p p y s e e d o i l .A study by V a n der Heide et a l . (11) indicated that iodine f r o m iodized oil prepared from e t h y l o l e a t e w a s r e t a i n e d longer in b o t h man a n d r a t s t h a n t h a t p r e p a r e d f r o m ethyl linoleate or e t h y l e s t e r s of poppyseed o i l f a t t y a c i d s . O i l s , s u c h a s p e a n u t o i l , which a r e r i c h in o l e i c a c i d , a l s o have t h e a d v a n t a g e t h a t t h e y a r e c h e a p e r as r a w material than poppyseed oil. T h e r e f o r e , we decided to compare the efficacy of a preparation o f i o d i z e d p e a n u t o i l introduced o n t o t h e I n d o n e s i a n m a r k e t w i t h t h a t o f the e s t a b l i s h e d iodized poppyseed oil p r e p a r a t i o n . W h i l e t h i s work w a s under w a y , Ingenbleek et al. (12) reported on the efficacy of iodized rapeseed oil, the composition o f w h i c h i s n o t u n l i k e t h a t o f i o d i z e d p e a n u t o i l . P r e l i m i n a r y r e s u l t s f r o m the s t u d y p r e s e n t e d i nt h i s p a p e r h a v e b e e n p u b l i s h e d p r e v i o u s l y ( 1 3 ) .

SUBJECTS A N D M E T H O D S Subjects All school children (n=355) aged 8-10 y attending four primary schools in Cilacap district, Central Java Province, Indonesia, w h e r e goiter is highly prevalent (>30%) (14), were examined by a medical assistant from the Sub-district Health Center. O n l y a p p a r e n t l y h e a l t h y s u b j e c t s w e r e c o n s i d e r e df o r e n t r y i n t ot h e s t u d y .

Study d e s i g n This study was designed as a community based, double-blind, placebo- controlled s u p p l e m e n t a t i o n t r i a l . A s a m p l e s i z e o f 5 0 p e r g r o u p w a s c a l c u l a t e d w i t h a 33 Chapter2 power index o f 2 . 8 0 , a = 0 . 0 5 a n d p = 0 . 2 0 t o o b t a i n a s i g n i f i c a n t d i f f e r e n c e of 10% i n urinary i o d i n e c o n c e n t r a t i o n b e t w e e n g r o u p s w i t h a n e x p e c t e d d r o p o u t r a t e o f2 0 % . From t h e eligible children (n=347), c h i l d r e n were randomly selected and randomly allocated to one of 5 groups (50 per group), to receive one of the following preparations: 1 m l _ o f p e a n u t o il a s p l a c e b o ; 0 . 5 ml_, 1.0 m l _a n d 2 . 0 ml_o f iodized peanut o i l (Yodiol®, 400 mg l/mL, PT K i m i a F a r m a , Indonesia), providing 200 mg, 400 m g a n d 8 0 0 m g I r e s p e c t i v e l y ; or 1m l _o f e t h y l e s t e r s o f i o d i z e d p o p p y s e e d o i l (Lipiodol® UF, 4 0 0 mg l/mL, Guerbet Laboratory, France) providing 400 mg I. T h e placebo group was used to control whether the subjects were exposed to extraneous iodine during the study. The fatty acids composition of peanut oil compared w i t ht h a t o f p o p p y s e e d o i l i ss h o w n i nT a b l e 1 .

Table 1 . F a t t y - a c i dp r o f i l e so fp o p p y s e e da n dp e a n u to i l s .

Proportion o f f a t t y acids, g / 1 0 0 g Poppyseed o i l 1 Peanut o i l 2 Saturated Palmitic a c i d ( C 1 6 : 0 ) 9.0 14.6 Stearic a c i d ( C 1 8 : 0 ) 3.0 0.2 Unsaturated Oleic a c i d ( C 1 8 : 1 , n-9) 14.0 41.1 Linoleicacid ( C 1 8 : 2 , n - 6 ) 73.0 38.9 a-Linolenic a c i d ( C 1 8 : 3 , n - 3 ) 0.0 1.5 Long c h a i nf a t t y a c i d s ( C > 2 0 ) 0.0 1.8 Other 1.0 1.9

1R e f e r e n c e( 1 5 ) . 2 PTK i m i aF a r m a ,I n d o n e s i a .

In a p r e v i o u s study by Furnee et a l . (16), t h e retention of iodine f r o m orally administered iodized o i l w a s f o u n d t o be r e d u c e d s i g n i f i c a n t l y by i n t e s t i n a l parasitic infestation. T h e r e f o r e , o n e w e e k prior t o i o d i z e d o i l a d m i n i s t r a t i o n , a l l s u b j e c t s w e r e dosed with the broad spectrum anti-helminth albendazole (400 mg per dose, SmithKline B e e c h a m , Indonesia) t o c o n t r o l Ascaris lumbricoidesa s it is k n o w n t h a t these a r e e n d e m i c ( 1 7 ) . The i o d i n e s t a t u s o f t h e c h i l d r e n w a s a s s e s s e d by 4 d i f f e r e n t indicators, i.e.: thyroid v o l u m e , u r i n a r y i o d i n e c o n c e n t r a t i o n , s e r u m T S H a n d s e r u m FT 4 a t b a s e l i n e and 2 5 a n d 5 0w k a f t e r s u p p l e m e n t a t i o n . A d d i t i o n a l m e a s u r e m e n t s o n u r i n a r y i o d i n e concentration w e r e d o n e a t 4 a n d 12w k .

34 Efficacy of oral iodized oil preparations

Methods Measurementof thyroidvolume. M e a s u r e m e n t o f the t h y r o i d v o l u m e u s i n g ultrasound w a s c a r r i e d o u t b yt h e m a i n r e s e a r c h e r (JU) w h o h a d b e e n t r a i n e d in t h e technique. The ultrasonography was performed on each subject in the sitting position using equipment with a transducer of 7.5 MHz (Phillips SDR 1480, Eindhoven, t h e N e t h e r l a n d s ) . T h e t r a n s d u c e r w a s f i r s t kept h o r i z o n t a l a t a n u p r i g h t angle t o t h e neck to observe the cross section of t h e t h y r o i d , measuring maximal width (w) a n d m a x i m a l d e p t h ( d ) . N e x t ,t h e l e n g t h (I) o f e a c h l o b e w a s d e t e r m i n e d b y longitudinal a p p l i c a t i o n o f t h e t r a n s d u c e r t ot h e s u b j e c t ' s n e c k . A c o - w o r k e r r e c o r d e d the o b s e r v a t i o n s of t h e u l t r a s o n o g r a p h y and provided a c o n t i n u o u s f l o w o f person s to b e e x a m i n e d .T h e v o l u m e w a s c a l c u l a t e d using t h e f o l l o w i n g f o r m u l a : V = 0 . 4 7 9 x d x w x I ( c m 3) (18). T h e t h y r o i d v o l u m e w a s t h e s u m o f t h e v o l u m e s of e a c h l o b e . Results o f u l t r a s o n o g r a p h y f r o m t h e study p o p u l a t i o n w e r e c o m p a r e d t o n o r m a t i ve dataf r o m p o p u l a t i o n s w i t h s u f f i c i e n t i o d i n e i n t a k e ( 1 9 ) . Serumconcentrations of thyroidstimulating hormone (TSH)and serum freethyroxine (FTJ.V e n o u s b l o o d s a m p l e s (3m l _ )w e r e d r a w n f r o m a n a n t e c u b i c a l vein from non-fasting subjects between 08.30 and 12.00 using EDTA as anti coagulant. Immediately a f t e r c o l l e c t i o n , t h e b l o o d w a s p l a c e d o n i c e , p r o t e c t e d f r o m light, and w i t h in 2-3 h, c e n t r i f u g e d at t h e laboratory of t h e district health center to obtain serum. Serum was f r o z e n in a series of containers at -70 °C before being transferred, p a c k e d i n d r y i c e ,t o t h e l a b o r a t o r y of E n d o c r i n o l o g y , A c a d e m i c Medical Center ( A m s t e r d a m ,t h e N e t h e r l a n d s ) f o r a n a l y s i s . Serum concentration of T S H was measured by immunoluminometric assay using a c o m m e r c i a l kit (Brahms Diagnostica Gmbh, Berlin, G e r m a n y ) and FT4 w a s measured by time-resolved fluoro immunoassay after immuno-extraction using a commercial kit (Delfia™, W a l l a c Oy, T u r k u , Finland). T h e coefficient of v a r i a t i o n of intra-assay and inter-assay for T S H w e r e 2 . 4 % a n d 4 . 5 % r e s p e c t i v e l y , and f o r FT4 were 3.6% and 6.4% respectively. Values for both TSH and FT4 obtained were within 10% o f t h e t a r g e t v a l u e of n o r m al a n d e l e v a t e d sample s provided every t w o months b yt h e D u t c h n a t i o n a l e x t e r n a l q u a l i t y c o n t r o l s c h e m ef o r h o r m o n e s i n s e r u m (LWBA). R e f e r e n c e range o f iodine r e p l e t e s u b j e c t s f o r s e r u m T S H is 0 . 4 - 4 . 0 mU/L andf o r F T 4 i s9 - 2 4 p m o l / L( 2 0 ) . Urinaryiodine concentration.A c a s u a l urine sample (5 ml_) w a s collected between 0 8 . 3 0 a n d 12.00 o n 2 c o n s e c u t i v e d a y s a t b a s e l i n e a n d 4 , 12, 2 5 a n d 5 0 wk after treatment. The urine samples, preserved with approximately 1 g t h y m o l , 35 Chapter2 were sent to the iodine laboratory of the Nutritional Research and Development Center i n B o g o r (Indonesia). I o d i n e c o n c e n t r a t i o n i n u r i n e w a s a n a l y z e d in d u p l i c a t e after a l k a l i n e d i g e s t i o n u s i n gt h e S a n d e l l - K o l t h o f f reaction ( 2 1 ) , a v e r a g e v a l u e s w e r e calculatedf o r e a c h c h i l d . The model for describing urinary iodine concentration after oral dosing of iodized o i l d e v e l o p e d by F u r n e e e t a l . (10) w a s u s e d .T h e m o d e l r e f l e c t s t h e e f f e c t s of i o d i n e r e t e n t i o n a n d e l i m i n a t i o n o n u r i n a r y i o d i n e c o n c e n t r a t i o n . ( Thus, l T=(a0+

(30= R a t e o f i o d i n e e l i m i n a t i o n f o r p l a c e b o s u b j e c t s ( | i m o l / L / w k ) p, = R a t e o f i o d i n e e l i m i n a t i o n f o r s u p p l e m e n t e d s u b j e c t s ( | a m o l / L / w k )

Statistical m e t h o d s The K o l m o g o r o v - S m i r n o v t e s t w a s u s e d t o c h e c k t h e n o r m a l i t y o f d a t a . D a t a are reported as mean and SD or SEM f o r normally distributed parameters and as median and 25th - 75th percentile for non-normally distributed parameters. Differences among groups were examined by analysis of variance (ANOVA) for normally distributed parameters and by the Kruskal-Wallis test for non-normally distributed p a r a m e t e r s . If s i g n i f i c a n t d i f f e r e n c e s w e r e i n d i c a t e d , c o m p a r i s o n s a m o n g groups were made with t h e least significant difference test f o r normally distributed data a n dt h e B o n f e r r o n i ' s m u l t i p l e c o m p a r i s o n t e s t a t a s i g n i f i c a n t l e v e l o f P < 0 . 0 1f o r non-normally d i s t r i b u t e d d a t a . The mathematical functions, transformed into log-linear equivalents, were fitted t o t h e f o u r v a l u e s o f u r i n a r y i o d i n e c o n c e n t r a t i o n s int h e f o u r t r e a t m e n t g r o u p s . The p a r a m e t e r s a , p a n d T w e r e e s t i m a t e d u s i n g t h e m a x i m u m l i k e l i h o o d e s t i m a t i o n technique (22) based on the average urinary iodine concentration measured in individuals o nc o n s e c u t i v e d a y s . The SPSS software package (Windows version 7.5.3, SPSS Inc., Chicago, IL) was used for all statistical analyses and a P value<0.05 was considered significant.

36 Efficacy of oral iodized oil preparations

Ethical C o n s i d e r a t i o n s The ethical guidelines of the Council for International Organizations of Medical S c i e n c e s (23) w e r e f o l l o w e d . T h e E t h i c a l C o m m i t t e e f o r Studies o n H u m a n Subjects, F a c u l t y o f M e d i c i n e , U n i v e r s i t y of I n d o n e s i a a p p r o v e d t h e s t u d y . Informed consent was obtained from parents of each subject before the start of the study. Iodized oil was given at the end of the study to those children who were still considered i o d i n e d e f i c i e n t .

RESULTS Subject c h a r a c t e r i z a t i o n There were no significant differences in a g e , t h y r o i d volume, urinary iodine concentration, s e r u m T S H a n d s e r u m FT4 a m o n g t h e g r o u p s a t b a s e l i n e (Table 2 ) . The children were, o n average aged 9.45±0.76 y a n d moderately iodine deficient, with a m e d i a n u r i n a r y i o d i n e o f 0 . 3 6 i ^ m o l / L (25th, 7 5 th p e r c e n t i l e ; 0 . 2 7 , 0 . 6 3 | a m o l / L ) . The prevalence of goiter was 24% (based on t h y r o i d volume) and the median of thyroid volume of all children was 4.51 mL (25th, 75,h percentile; 3.96, 5.33 ml_). There were no statistical significant differences in thyroid volume, urinary iodine concentration,s e r u mT S H a n d s e r u m F T 4b e t w e e n b o y s a n d g i r l s .

Urinary i o d i n e c o n c e n t r a t i o n Patterns of u r i n a r y iodine c o n c e n t r a t i o n a f t e r oral i o d i z e d o i l s u p p l e m e n t a t i o n in t h e different groups are shown in Figure 1. A l l t r e a t e d groups had significantly higher u r i n a r y i o d i n e c o n c e n t r a t i o n (P<0.001) a t a l l p e r i o d s o f f o l l o w - u p c o m p a r e d t o the placebo group which received peanut oil. T h e higher the dosage of iodine in iodized peanut oil, t h e higher the urinary iodine concentration (P<0.001). Urinary iodine concentration of the group supplemented with iodized poppyseed oil supplying 400 mg I was similar of that of the group supplemented with iodized peanut oil supplying 200 mg I and significantly lower than that of other supplemented g r o u p s a t a l l p e r i o d s o ff o l l o w u p ( P < 0 . 0 0 1 ) .

37 Chapter 2

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39 Chapter2

The r e g r e s s i o n m o d e l of u r i n a r y iodine concentration The efficacy coefficients of iodine retention, iodine elimination rate, and the protection period for different groups of treatment are shown in Table 3. The increases in i o d i n e r e t e n t i o n , e l i m i n a t i o n rate a n d p r o t e c t i o n period o f t h e t r e a t m e n t s were significantly different among the four groups (P<0.001) except the protection period for the iodized poppyseed oil supplying 400 mg I and iodized peanut oil supplying 200 mg I. Urinary iodine concentrations, as predicted by the regression model, after oral iodized oil supplementation for different groups of treatment are given in F i g u r e 2 . F r o m w e e k 4 , i o d i n e e x c r e t i o n d e c l i n e d e x p o n e n t i a l l y . If a n urinary iodine concentration of 0.79 i^mol/L is taken as the cut-off point, below which the recommended dietary allowance is not being met, then the protection period of iodized poppyseed oil supplying 400 mg I was about 42 wk, iodized peanut oil supplying 200 mg I, 400 mg I and 800 mg I were 49 wk, 77 wk and 124 wk respectively (Table 3 ) .

Table 3. Iodine retention, elimination and the model-based of protection period after oral administration of d i f f e r e n t i o d i z e d o i lt r e a t m e n t s f o r s c h o o l c h i l d r e n 1

Treatment Iodized Iodized p e a n u t o i l poppyseed oil, 4 0 0 m g I 200 m g I 400 m g I 800 m gI Iodine r e t e n t i o n , 5.88 ( 1 . 1 6 ) a 8.59(1.15)b 17.55( 1 . 1 5 ) c 40.41(1.14)" a, ( n m o l / L ) Iodine e l i m i n a t i o n 0.45 ( 0 . 0 5 ) a 0.53 ( 0 . 0 5 ) b 0.64 ( 0 . 0 5 ) c 0.75(0.05)" rate, p \ ( n m o l / L / w k ) Protection p e r i o d , 42.3 49.2 76.9 123.6 T(wk)2 (33.8,6 0 . 0 ) a (40.0,6 9 . 2 ) a (62.1,112.7)" (96.0,171.7)°

' See E q u a t i o n 1f o r m e t h o d o f c a l c u l a t i o n , v a l u e s i n p a r e n t h e s e s a r e S E . 2 Time after dosing when the urinary iodine concentration remained above 0.79 (imol/L (100 n g / L ) a f t e r correcting f o r changes in the u r i n a r y iodine c o n c e n t r a t i o n in t h e peanut oil (placebo) group, v a l u e s in p a r e n t h e s e s a r e 9 5 % C I . V a l u e s w i t h i n a r o w w i t h d i f f e r e n t superscript letters a r e s i g n i f i c a n t l y different f r o m one a n o t h e r using Bonferroni's multiple comparisons t e s t .

40 Efficacy of oral iodized oil preparations

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41 Chapter2

Goiter v o l u m e The g o i t e r v o l u m e s m e a s u r e d by u l t r a s o u n d f o r d i f f e r e n t groups of t r e a t m e n t are p r e s e n t e d in T a b l e 4 . There w e r e no s i g n i f i c a n t d i f f e r e n c e s in t h y r o i d v o l u m e s among groups at baseline (P=0.085), but after supplementation there were significant differences in goiter volumes for all treated groups compared to the placebo g r o u p w h i c h r e c e i v e d p e a n u t o i l . After a y e a r o f s u p p l e m e n t a t i o n , r e d u c t i o n in g o i t e r v o l u m e s w e r e s i g n i f i c a n t l y higher in t h e s u p p l e m e n t e d g r o u p s c o m p a r e d t o the placebo group a t a l l p e r i o d of f o l l o w up (P<0.001). T h e r e w a s no d i f f e r e n c e in the r e d u c t i o n o f g o i t e r v o l u m e a m o n g s u b j e c t s s u p p l e m e n t e d w i t h i o d i z e d p e a n u t o i l supplying 2 0 0 m g I o r 4 0 0 m g I a n d t h o s e s u p p l e m e n t e d w i t h i o d i z e d p o p p y s e e d o i l supplying 4 0 0 m gI .

Serumc o n c e n t r a t i o n s o fT S H a n dF T 4 Initial median values of TSH were not different among t he five groups and were w i t h i n t h e n o r m a l r a n g e , b u t 2 . 8 % o f i n d i v i d u a l s had v a l u e s a b o v e 5 m U / L . A t 50w k a f t e r t r e a t m e n t , v a l u e s o fT S H r e m a i n e d w i t h i nt h e n o r m a l r a n g e ( m e d i a n ( 2 5 th - 75th percentiles); placebo, 1.60 (1.18-2.30) mU/L; iodized oil groups, 1.80 (1.30-

2.70) mU/L) a n d n o n e h a d l e v e l s a b o v e 5 m U / L . M e a n s e r u m FT 4 c o n c e n t r a t i o n s a t baseline were in t h e normal range and were not different among the five groups.

There was a small non-significant increase of serum FT4 c o n c e n t r a t i o ns at 25 wk among a l l g r o u p s i n c l u d i n g t h e p l a c e b o ( m e a n ± S D ;p l a c e b o , 1 7 . 3 2 ± 3.08 p m o l / L ; iodized o i l g r o u p s , 17.98 ± 3 . 1 3 pmol/L), a n d v a l u e s returned t o baseline at 50 w k (mean ± S D ;p l a c e b o , 1 6 . 7 4± 3 . 0 5 p m o l / L ; i o d i z e d o i l g r o u p s , 1 6 . 9 7± 2 . 5 1 p m o l / L ) .

DISCUSSION This study shows that oral iodized oil is an effective alternative to salt iodization for the control of iodine deficiency. This study also f o u n d that the f a t t y acids composition of t h e iodized oil determines the efficacy of t h e t r e a t m e n t . Four outcome indicators were used to assess the efficacy of different oral iodized oil supplementation: urinary iodine concentration, thyroid volume, serum TSH and serum F T 4c o n c e n t r a t i o n s . Urinary iodine concentrations showed large v a r i a b i l i t y and w e r e v e r y high in some subjects. Urinary iodine concentration was increased significantly among all

42 Efficacy of oral iodized oil preparations

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o C |i CD •S 2 C o o is si $ & n U5 O CD . 2 TO E CM IT) CO CD •«s o > CC > o

43 Chapter2

groups of treatments and placebo between 0 and 4 wk. The slight differences in urinary i o d i n e c o n c e n t r a t i o n o f t h e p l a c e b o g r o u p ( P < 0 . 0 5 ) , c o u l d i n d i c a t e t h a t s o m e children might have been exposed to an extraneous source of iodine, possible iodized salt (2,24). The urinary iodine concentration after supplementation of all groups of t r e a t m e n t s at different periods of follow up (4, 12, 2 5 and 50 wk) were significantly h i g h e r t h a nt h o s e o f t h e p l a c e b o g r o u p . The e f f i c a c y of t h e iodized poppyseed oil p r e p a r a t i o n supplying 400 mg I a s indicated b y u r i n a r y i o d i n e c o n c e n t r a t i o n ,w a s s i m i l a r t o i o d i z e d p e a n u t o i l supplying 200 m g I a n d s i g n i f i c a n t l y l o w e r t h a n i o d i z e d p e a n u t o i ls u p p l y i n g 4 0 0 or 8 0 0 m g I a t all p e r i o d s o f f o l l o w u p . B a s e d o n a m a t h e m a t i c a l m o d e l ( 1 0 ) , c o m p a r i n g t h e i o d i z e d oil preparations supplying 400 mg I a f t e r adjustment for the increase of urinary iodine concentration in the placebo group, three times more iodine was retained from the iodized peanut oil preparation than from the iodized poppyseed oil preparation. I n a d d i t i o n , i o d i z e d p e a n u t o i l g a v e a p e r i o d o f p r o t e c t i o n a g a i n s t i o d i n e deficiency t w i c e a s l o n g a s t h a t p r o v i d e d b y i o d i z e d p o p p y s e e d o i l ( 7 7 w k v s . 4 2 w k respectively). T h e s e f i n d i n g s c o n f i r m e d t h e r e s u l t s f r o m p r e v i o u s s t u d i e s in r a t s a n d man (11), i n w h i c h it w a s s h o w n t h a t iodine w a s r e t a i n e d longer f r o m a p r e p a r a t i o n prepared from ethyl oleate compared with a preparation prepared from ethyl linoleate o rf r o m e t h y l e s t e r s d e r i v e d f r o m p o p p y s e e do i l . A s t u d y b y I n g e n b l e e k et a l . (12) o n t h e e f f e c t i v e n e s s of i o d i z e d r a p e s e e d o i l appeared w h i l e t h i s s t u d y w a s b e i n g c a r r i e d o u t . T h e s e a u t h o r s found t h a t iodized rapeseed s u p p l y i n g 752 m g I g a v e a l o n g e r period o f p r o t e c t i o n in m o d e r a t e iodine deficient adults (30 w k ) c o m p a r e d t o iodized poppyseed supplying 729 mg (17 w k ) when a n i o d i n e c o n c e n t r a t i o n in u r i n e o f 0 . 7 9 n m o l / L w a s t a k e n a s t h e c u t - o f f point. Most iodine in t h e r a p e s e e d o i l p r e p a r a t i o n w a s bound t o o l e i c a c i d ( 5 2 . 5 %) a n d i n poppyseed o i l p r e p a r a t i o n t o l i n o l e i c a c i d ( 7 2 . 7 % ) .C o m p a r i n g i o d i z e d p e a n u t o i lw i t h iodized poppyseed oil, t h e proportion of iodine derived from iodized oleic acid is higher (41 v s . 14%) and f r o m linoleic acid is lower (39 v s . 73%) respectively. Our data show that iodized peanut oil supplying 400 mg I is estimated to have a protection p e r i o d o f a b o u t 7 7 w k , a n d i o d i z e d p e a n u t o i l s u p p l y i n g 8 0 0 m g I g i v e s a protection p e r i o d o f 124w k i n m o d e r a t e i o d i n e d e f i c i e n t s c h o o l c h i l d r e n .A p a r t from the t y p e o f o i l u s e d a n d t h e l o c a t i o n , o u r s t u d y d i f f e r e d in a s e n s e t h a t t h e s u b j e c t s from Chad (12) were older (18-40 y) and were more iodine deficient than the children f r o m o u r s t u d y .

44 Efficacy of oral iodized oil preparations

Compared to t he previous studies in school children (Table 5), our results showedt h a t t h e s a m e p r e p a r a t i o n o f o r a l i o d i z e d p o p p y s e e d o i l s u p p l y i n g 4 0 0 m g I , could p r o t e c t s c h o o l c h i l d r e n f r o m i o d i n e d e f i c i e n c y f o r 4 2w k ,w h i c h w a s a b o u t t w i c e as l o n g a s t h a t of B e n m i l o u d e t a l . (20) a n d t h r e e t i m e s longer t h a n t h a t w a s f o u n d by F u r n e e e t a l . ( 1 0 ) w h o u s e d a c u t - o f f p o i n t f o r u r i n a r y i o d i n e c o n c e n t r a t i o n o f 0 . 4 0 lamol/L Differences in r e s u l t s among t h e s e s t u d i es might be d u e t o t h e s e v e r i t y of iodine deficiency. The median urinary iodine concentration at baseline was 0.21 nmol/L a n d 0 . 1 6 n m o l / L i n t h e s t u d y of Benmiloud et a l . (20) and Furnee e t a l ( 1 0 ) respectively. Other possible factors are exposure to goitrogenic substances, nutritional s t a t u s ,t h e i n d i c a t o r s e m p l o y e d a n d c u t - o f f p o i n t su s e d . We h a v e a l s o e v i d e n c e t h a t a h i g h d o s e o f 8 0 0 m g I i s a b l e t o c o r r e c t i o d i n e deficiency, without any side-effects as f o u n d in t h e study by Elnagar et a l . (25) in Sudan. T h e y f o u n d t h a t d o s e s o f 4 0 0 m g I a n d 8 0 0 m g I w e r e s l i g h t l y less e f f e c t i v e than the 200 mg I a n d induced some adverse reactions, such as iodine induced inhibition o f h o r m o n e s y n t h e s i s ( W o l f f - C h a i k o ff e f f e c t ) . Thyroid volumes of the iodized oil supplemented groups were significantly lower t h a n i nt h e p l a c e b o g r o u p . M e d i a n t h y r o i d v o l u m e d e c r e a s e d s i g n i f i c a n t l y i n a l l groups, a n d t h e r e d u c t i o n of t h y r o i d v o l u m e i n a l l t r e a t m e n t g r o u p s w a s s i g n i f i c a n t l y higher t h a nt h a t i nt h e p l a c e b o g r o u p .T h e r e d u c t i o n o f t h y r o i d v o l u m e i nt h e p l a c e b o group might be d u e t o i n t r o d u c t i o n of iodized s a l t in t h e a r e a d u r i n g t h e s t u d y (24). The r e d u c t i o n o f t h y r o i d v o l u m e w a s p o s i t i v e l y c o r r e l a t e d w i t h t h e c h a n g e o f u r i n a r y iodine concentration among all groups (r=0.22). T h e thyroid volumes of previously iodine deficient children decreased to normal values in groups receiving either iodized poppyseed oil or iodized peanut oil, which suggest that the treatment of iodine d e f i c i e n t s u b j e c t s u s i n g o r a l i o d i z e d o i l e f f e c t i v e l y r e d u c e d g o i t e r s i z e . The efficacy of treatment indicated by the normalization of urinary iodine concentrations and thyroid volumes was not supported by changes in serum concentrations of T S H a n d FT 4. O u r r e s u l t s c o n t r a s t w i t h t h o s e r e p o r t e d b y E l t o m e t al. (9), E l n a g a r e t a l . ( 2 5 ) a n d T o n g l e t e t a l . ( 2 6 ) .T h e y f o u n d t h a t t h e e f f i c a c y of o r a l iodized o i l s u p p l e m e n t a t i o n c o u l d b ed e m o n s t r a t e d b y n o r m a l i z a t i o n o f s e r u mT 4a n d TSH concentrations, reduction of goiter size measured by palpation or by an increase in urinary iodine concentration. Our data showed that median TSH concentrations were in the normal range before iodine treatment and only 2.8%

45 Chapter 2

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46 Efficacy of oral iodized oil preparations were higher than the upper normal limit. The responses of serum TSH were not correlated t o t h e dose or t y p e of iodized o i l . T h e mean level of serum FT4 before iodine treatment was in the normal range, and slightly increased after iodine treatments, it d i d not differ significantly among the placebo and treatment groups. Our results concur w i t h t h o s e of G u t e k u n s t et a l . (27) and Delange et a l . (28) w h o observed no relationship between serum TSH and thyroid volume. Bourdoux (29) reported that the circulating levels of thyroid hormones and TSH in mild iodine deficient population, are not different from those observed in iodine-replete population. While in moderate iodine deficient population, with the prevalence of goiter r a n g i n g f r o m 2 0t o 5 0 % ,i tw a s o b s e r v e d t h a t t h e l e v e l s o f c i r c u l a t i n g T 3a n dT 4 were s t i l l i n t h e n o r m a l r a n g e ( 2 9 ) .T h e f i n d i n g t h a t u r i n a r y i o d i n e c o n c e n t r a t i o n a n d thyroid volume of iodine deficient children became normal after supplementation, although s e r u m T S Ha n d s e r u m F T 4c o n c e n t r a t i o n s d i d n o t s h o wt h e s a m e r e s p o n s e to t r e a t m e n t , s u g g e s t s t h a t s e r u m T S H a n d FT 4 m i g h t b e l e s s r e l i a b l e indicators f o r assessing a n d m o n i t o r i n g t r e a t m e n t o f m o d e r a t e i o d i n e d e f i c i e n c y in s c h o o l c h i l d r e n than u r i n a r y i o d i n e c o n c e n t r a t i o n o r t h y r o i d v o l u m e ( 3 0 ) . We conclude that a single oral dose of iodized peanut oil compared to a single oral dose of iodized poppyseed oil results in three times higher iodine retention leading to a period of protection twice as long in iodine deficient school children. T h u s iodized o i l p r e p a r e d f r o m o l e ic a c i d rich o i l s , s u c h a s p e a n u t o i l a n d rapeseed o i l s h o u l d b e g i v e n p r e f e r e n c e a b o v e p r e p a r a t i o n b a s e d o n p o p p y s e e d o i l in p r o g r a m s t o c o n t r o l i o d i n e d e f i c i e n c y .

47 Chapter2

REFERENCES

1. Todd C H , D u n n J T . Intermittent oral a d m i n i s t r a t i o n of potassium iodide solution f o r the c o r r e c t i o n o f i o d i n e d e f i c i e n c y . Am J C l i n N u t r 1 9 9 8 ; 6 7 : 1 2 7 9 - 8 3 . 2. UNICEF. T h e s t a t e o f t h e w o r l d ' s c h i l d r e n 1998. N e w Y o r k : O x f o r d U n i v e r s i t y Press, 1998. 3. West CE, Hautvast JGAJ. Nutrition: from 'whither' to 'wither' micronutrient malnutrition? Lancet 1 9 9 7 ; 3 5 0 S u p p l 3 : S I I I 1 5 . 4. Pandav CS. IDD in S o u t h - E a s t Asia. In: Hetzel BS, Pandav CS, e d s . S.O.S. f o r a billion. N e w D e l h i : O x f o r d U n i v e r s i t y P r e s s , 1 9 9 4 : 2 1 3 - 3 1 . 5. Kavishe FP. C a n A f r i c a meet the goal of eliminating iodine deficiency disorders by the y e a r 2 0 0 0 ? Food N u t r B u l l 1 9 9 6 ; 1 7 : 2 6 2 - 7 . 6. Stewart C , S o l o m o n s N W , M e n d o z a I , M a y S , M a b e r l y G . S a l t i o d i n e v a r i a t i o n w i t h i n an e x t e n d e d G u a t e m a l a n c o m m u n i t y : T h e f a i l u r e o f i n t u i t i v e a s s u m p t i o n s . Food N u t r Bull1996;17:258-61 . 7. Bautista A , Barker PA, Dunn J T , S a n c h e z M, K a i s e r DL. T h e e f f e c t s of o r a l iodized oil o n i n t e l l i g e n c e , t h y r o i d s t a t u s , a n d s o m a t i c g r o w t h in s c h o o l - a g e c h i l d r e n f r o m a n area o f e n d e m i c g o i t e r . Am J C l i n N u t r 1 9 8 2 ; 3 5 : 1 2 7 - 3 4 . 8. Dunn JT. The use of oral iodized oil and other alternatives for the elimination of iodine d e f i c i e n c y d i s o r d e r s . In: H e t z e l B S , P a n d a v C S , e d s . S . O . S . f o r a b i l l i o n . N e w Delhi, I n d i a : O x f o r d U n i v e r s i t y P r e s s , 1 9 9 4 : 1 0 8 - 1 7 . 9. Eltom M, Karlsson FA, Kamal A M , Bostrom H, Dahlberg PA. The effectiveness of oral i o d i z e d o i l i n t h e t r e a t m e n t a n d p r o p h y l a x i s o f e n d e m i c g o i t e r . J C l i n Endocrinol Metab 1 9 8 5 ; 6 1 : 1 1 1 2 - 7 . 10. Furnee C A , P f a n n G A , W e s t C E ,v a n d e r Haar F, v a n d e r Heide D . , H a u t v a s t J G A J . New m o d e l f o r d e s c r i b i n g u r i n a r y i o d i n e e x c r e t i o n : i t s u s ef o r c o m p a r i n g d i f f e r e n t o r a l preparations o f i o d i z e d o i l . Am J C l i n N u t r 1995; 6 1 : 1257-62. 11. Van der Heide D, de Goeje MJ, van der Bent C. The effectiveness of oral administered iodized oil in rat and man. Annales d'endocrinologie 1989;50:116 (abst). 12. Ingenbleek Y, Jung L, Ferard G, Bordet F, Goncalves AM, Dechoux L. Iodised rapeseed o i lf o r e r a d i c a t i o n o f s e v e r e e n d e m i c g o i t r e . Lancet 1 9 9 7 ; 3 5 0 : 1 5 4 2 - 5 . 13. Untoro J , S c h u l t i n k W , G r o s s R, W e s t C E , H a u t v a s t J G A J . E f f i c a c y of d i f f e r e n t t y p e s of i o d i s e d o i l [ l e t t e r ] . Lancet 1 9 9 8 ; 3 5 1 : 7 5 2 - 3 . 14. Ministry of Health Rl and Tim GAKI Undip. Endemic goiter map of Central Java, Indonesia. 1996. S e m a r a n g , I n d o n e s i a , U n i v e r s i t a s D i p o n e g o r o . 15. Chastin I . L i p i o d o l u l t r a - f l u i d e f o r t h e p r e v e n t i o n a n d t r e a t m e n t o f e n d e m i c g o i t e r a n d associated pathologies. Roissy, Charles de Gaulle Cedex, France: Laboratoire Guerbet, 1 9 9 2 . 16. Furnee CA, v a n der Haar F, W e s t CE, H a u t v a s t J G A J . A c r i t i c a l a p p r a i s a l of goiter assessment and t h e r a t i o of u r i n a r y iodine t o c r e a t i n i n e f o r evaluating iodine s t a t u s . Am J C l i n N u t r 1 9 9 4 ; 5 9 : 1 4 1 5 - 7 . 17. Pegolow K, G r o s s R, Pietrzik K, Lukito W , Richards A L , Fryauff DJ. Parasitological and nutritional situation of school children in the Sukaraja district, West Java, Indonesia. Southeast A s i a n J T r o p M e d P u b l i c H e a l t h 1 9 9 7 ; 2 8 : 1 7 3 - 9 0 . 18. Delange F, B e n k e r G , C a r o n P, e t a l . T h y r o i d v o l u m e a n d u r i n a r y i o d i n e i n E u r o p e a n schoolchildren: s t a n d a r d i z a t i o n of v a l u e s f o r assessment of i o d i n e d e f i c i e n c y . Eur J Endocrinol 1 9 9 7 ; 1 3 6 : 1 8 0 - 7 . 19. WHO, I C C I D D . R e c o m m e n d e d n o r m a t i v e v a l u e s f o r t h y r o i d v o l u m e in c h i l d r e n a g e d 6-15y e a r s . BullW o r l d H e a l t h O r g a n 1 9 9 7 ; 7 5 : 9 5 - 7 . 48 Efficacyof oral iodized oil preparations

20. Benmiloud M, Chaouki ML, G u t e k u n s t R, Teichert HM, W o o d W G , Dunn JT. Oral iodized oil for correcting iodine deficiency: optimal dosing and outcome indicator selection. J C l i n E n d o c r i n o l M e t a b 1 9 9 4 ; 7 9 : 2 0 - 4 . 21. Dunn JT, Crutchfield HE, Gutekunst R, Dunn AD. Two simple methods for measuring i o d i n e i n u r i n e . Thyroid 1 9 9 3 ; 3 : 1 1 9 - 2 3 . 22. Kleinbaum DG, Kupper LL, Muller KE. Applied regression analysis and other multivariate m e t h o d s . B o s t o n : P W S - K e n t P u b l i s h i n g C o m p a n y , 1 9 8 8 . 23. CIOMS. International Guidelines for Ethical Review of Epidemiological Studies. Geneva, Switzerland: Council f o r International Organizations for Medical Sciences, 1991. 24. Untoro J , W e s t C E , S c h u l t i n k W, Gross R, Hautvast J G A J . I m p a c t of s a l t iodization on i o d i n e s t a t u s of Indonesian s c h o o l c h i l d r e n living i n a m o d e r a t e l y iodine deficient area. Submitted f o r p u b l i c a t i o n . 25. Elnagar B, Eltom M, Karlsson FA, Ermans AM, Gebre MM, Bourdoux PP. The effects o f d i f f e r e n t d o s e s o f o r a l i o d i z e d o i l o n g o i t e r s i z e , u r i n a r y i o d i n e , a n dt h y r o i d - related h o r m o n e s . J C l i n E n d o c r i n o l M e t a b 1 9 9 5 ; 8 0 : 8 9 1 - 7 . 26. Tonglet R, Bourdoux P, Minga T , Ermans A M . E f f i c a c y of low o r a l d o s e s of iodized oil i nt h e c o n t r o l o f i o d i n e d e f i c i e n c y i n Z a i r e . NE n g lJ M e d 1 9 9 2 ; 3 2 6 : 2 3 6 - 4 1 . 27. Gutekunst R, Smolarek H, Hasenpusch U, et al. Goitre epidemiology: thyroid volume, iodine excretion, thyroglobulin and thyrotropin in Germany and Sweden. Acta E n d o c r i n o l C o p e n h 1 9 8 6 ; 1 1 2 : 4 9 4 - 5 0 1 . 28. Delange F, Hershman J M , Ermans M. Relationship between the serum thyrotropin level, t h e p r e v a l e n c e of g o i t e r a n d t h e p a t t e r n o f i o d i n e m e t a b o l i s m in I d j w i i s l a n d . J Clin E n d o c r i n o l M e t a b 1 9 7 1 ; 3 3 : 2 6 1 - 8 . 29. Bourdoux PP. Biochemical evaluation of iodine status. In: Delange F, Dunn JT, Glinoer D, e d s . I o d i n e D e f i c i e n c y in E u r o p e . N e wY o r k : P l e n u m P r e s s , 1 9 9 3 : 1 1 9 - 2 4 . 30. Untoro J , W e s t C E , S c h u l t i n k W , G r o s s R, H a u t v a s t J G A J . C o m p a r i s o n o f indicators to assess iodine status and its improvement through supplementation with iodized oil. Submitted f o r p u b l i c a t i o n .

49 Chapter 3

Comparison o f i n d i c a t o r s toa s s e s s i o d i n e s t a t u s a n d i t s i m p r o v e m e n t through s u p p l e m e n t a t i o n w i t h i o d i z e do i l

Juliawati Untoro, Clive E West, Werner Schultink, Rainer Gross, Joseph G.A.J. Hautvast Chapter 3

ABSTRACT Sensitivity and specificity of indicators for assessing iodine status in populations and measuring the impact of programs aimed to reduce iodine deficiency are critical factors for selecting such indicators. The present study examined t h e r e l a t i o n s h i p a m o n g p r i m a ry indicators f o r assessing iodine deficiency and m o n i t o r i n g effectiveness of o r a l a d m i n i s t r a t i o n of iodized o i l . G o i t e r prevalence by palpation, thyroid volume by ultrasound, urinary iodine concentration, serum concentrations of t h y r o i d s t i m u l a t i n g hormone (TSH) and f r e e t h y r o x i n e (FT4) w e r e measured i n 1 8 6s c h o o l c h i l d r e n i n a n e n d e m i c i o d i n e d e f i c i e n t a r e a i n I n d o n e s i a , a t baseline, 2 5 a n d 5 0 w k a f t e r oral a d m i n i s t r a t i o n of i o d i z e d o i l . Serum t h y r o g l o b u l i n (Tg) c o n c e n t r a t i o n w a s a s s e s s e d in a s u b s a m p l e o f 4 0 s c h o o l c h i l d r e n a t b a s e l i n e . Goiter prevalence at baseline was 22% and 23% by palpation and ultrasound respectively, and the median urinary iodine concentration was 0.36 ^mol/L, suggesting that t h e area w a s moderately iodine deficient. However, the median of serum T S H a n d T g c o n c e n t r a t i o ns and mean serum FT4 c o n c e n t r a t i o n at baseline were in t h e n o r m a l r a n g e . T h y r o i d v o l u m e w a s p o s i t i v e l y related t o g o i t e r assessed by palpation, however there was about 40% misclassification. After one year of treatment, thyroid volume and goiter prevalence were significantly reduced and urinary iodine concentration increased. Serum FT4 concentration increased within the normal range, but serum T S H concentration remained t h e s a m e . Reduction of thyroid v o l u m e w a s a s s o c i a t e d w i t h g o i t e r grade a t baseline and c h a n g e in u r i n a r y iodine c o n c e n t r a t i o n . U r i n a r y i o d i n e c o n c e n t r a t i o n a n d t h y r o i d v o l u m e a r e u s e f u l b u t serum concentrations of TSH and FT4 are not useful as indicators for assessing iodine status a n d measuring the impact of oral iodized oil s u p p l e m e n t a t i o n among moderately i o d i n e d e f i c i e n t s c h o o lc h i l d r e n .

52 Indicators of iodine status

INTRODUCTION In 1990 it w a s estimated that worldwide about 1600 million people w e r e at risk o f d e v e l o p i n g i o d i n e d e f i c i e n c y d i s o r d e r s (IDD) ( 1 ) .T h e p r e v a l e n c e a n d s e v e r i t y of iodine deficiency within a population, and the progress towards its elimination after intervention, can be assessed through various outcome indicators. The selection of an indicator is dependent on the acceptance of the indicator by the target population and f i e l d staff performing the assessment, on t h e ease of use in field conditions, and on the available resources in terms of money, laboratory equipment and staff (2). Another consideration for indicator selection is the performance in t e r m s of s e n s i t i v i t y a n d s p e c i f i c i t y (3-6). A c o m m o n l y used i n d i c a t o r is the prevalence of goiter as assessed through palpation. However, grading of goiter size by palpation has large intra and inter-observer variability. Therefore, in addition, o t h e r i n d i c a t o r s o f i o d i n e o rt h y r o i d s t a t u s a r e o f t e n u s e d ( 7 ) . WHO/UNICEF/ICCIDD ( 2 ) r e c o m m e n d t h e m e a s u r e m e n t o ft h y r o i d s i z e u s i n g palpation and ultrasonography, the measurement of iodine concentration in urine and thyroid hormone concentrations (8). The use of single indicators, or combinations f o r s t u d i e s o r s u r v e y s , a r e n o t f u l l y s t a n d a r d i z e d but d e p e n d o n s t u d y specific circumstances. So far the number of studies comparing the relative sensitivity and specificity between indicators in assessing iodine status of a population is limited and have given conflicting results (3-5,8). A similar lack of information e x i s t s f o r t h e a s s e s s m e n t of t h e d e g r e e of c h a n g e in i o d i n e s t a t u s a f t e r intervention such as salt iodization. For example, the prevalence of goiter in a population may remain unchanged after successful salt iodization whereas iodine concentration i nt h e u r i n e h a s i n c r e a s e d ( 9 ) . The a i m of t h e p r e s e n t s t u d y w a s t o compare iodine c o n c e n t r a t i o n in c a s u a l urine s a m p l e , g o i t e r p r e v a l e n c e by p a l p a t i o n , t h y r o i d s i z e b y u l t r a s o u n d , a n d s e r u m concentrations of free thyroxine (FTJ, thyroid stimulating hormone (TSH) and thyroglobulin (Tg) for the assessment of iodine status in a population of school children. Furthermore, changes in these indicators were compared after oral supplementation w i t h i o d i z e do i l .

53 Chapter 3

SUBJECTS A N D M E T H O D S Subjects Subjects were randomly selected from school children aged 8-10 years (n=186) attending four primary schools in Cilacap district, Central Java Province, Indonesia.T h i s s t u d y w a s d e s i g n e d a s a p a r t o f a c o m m u n i t y b a s e d , o r a l i o d i z e d o i l supplementation t r i a l . A s a m p l e s i z e o f 1 8 6 w a s c a l c u l a t e d w i t h a p o w e r o f 0 . 8 f o r a significance level at 0.05 to obtain a significant difference of 11% between indicators. T h e study area w a s classified as a high-risk area f o r iodine deficiency, with an estimated total goiter rate of more than 30% (10). All subjects were examined by a medical assistant from the Sub-district Health Center, and only apparently h e a l t h y s u b j e c t s w e r e c o n s i d e r e d s u i t a b l ef o r e n t r y i n t ot h e s t u d y .

Study d e s i g n At b a s e l i n e t h e i o d i n e s t a t u s of s u b j e c t s w a s a s s e s s e d using f i v e i n d i c a t o r s : goiter grade m e a s u r e d by p a l p a t i o n , t h y r o i d v o l u m e measured by ultrasonography, urinary iodine c o n c e n t r a t i o n , a n d s e r u m c o n c e n t r a t i o n s of T S H and FT4 . A f t e r the baseline assessment all s u b j e c t s were supplemented with an oral dose of iodized oil, w h i c h w a s l a r g e e n o u g h t o c o v e r iodine r e q u i r e m e n t s f o r a t l e a s t 4 9 w k . D e t a i l s about t h e d o s e a n d t y p e of iodized o i l a r e presented elsewhere (11). Iodine s t a t u s by a l l f i v e indicators was a g a i n a s s e s s e d at 25 wk and 50 wk a f t e r treatment with iodized o i l .A d d i t i o n a l l y , m e a s u r e m e n t of u r i n a r y i o d i n e c o n c e n t r a t i o n w a s d o n e a t 4 and 12 w k . T h e concentration of serum T g was measured in a subsample of 40 children a t b a s e l i n e .

Methods Measurement of thyroid size. Thyroid size was assessed using palpation and ultrasound techniques. Palpation of the thyroid was carried out by a district health w o r k e r w h o w a s e x p e r i e n c e d in t h e a s s e s s m e n t according t o W H O / U N I C E F / ICCIDD c r i t e r i a ( 2 ) . Measurement of the t h y r o i d v o l u m e using u l t r a s o u n d w a s c a r r i e d o u t by t h e main r e s e a r c h e r (JU) w h o h a d b e e n t r a i n e d in t h e t e c h n i q u e . Ultrasonography was performed o n e a c h s u b j e c t in t h e s i t t i n g p o s i t i o n u s i n g e q u i p m e n t with a t r a n s d u c e r of 7.5 MHz (Phillips SDR 1480, Eindhoven, t h e Netherlands). T h e t r a n s d u c e r was first kept h o r i z o n t a l at a n u p r i g h t angle t o t h e neck t o o b s e r v e t h e c r o s s s e c t i o n of the t h y r o i d , m e a s u r i n g m a x i m a l w i d t h (w) a n d m a x i m a l d e p t h ( d ) . N e x t , t h e l e n g t h ( I ) 54 Indicators of iodine status

of each lobe was determined by longitudinal application of the transducer to the subject's neck. A c o - w o r k e r recorded t h e observations of t h e ultrasonography and provided a c o n t i n u o u s f l o w o f p e r s o n s t o be e x a m i n e d . T h e v o l u m e w a s c a l c u l a t e d using t h e f o l l o w i n g f o r m u l a : V (cm3) =0.479 x d x w x I ( 6 ) . T h e t h y r o i d v o l u m e w a s the s u m of t h e v o l u m e s of both lobes. Results of ultrasonography from t h e study population w e r e c o m p a r e d t o n o r m a t i v e d a t a f r o m p o p u l a t i o n s w i t h s u f f i c i e n t iodine intake ( 1 2 ) . Serum concentrations of thyroid stimulating hormone (TSH), free thyroxine (FTJand thyroglobulin (Tg). Venous b l o o d s a m p l e s (3 m L )w e r e d r a w n from a n a n t e c u b i c a l v e i n f r o m n o n - f a s t i n g s u b j e c t s between 0 8 . 3 0 a n d 12.00 u s i n g EDTA as a n t i c o a g u l a n t . Immediately after collection, t h e blood w a s placed on i c e , protected from light, and within 2-3 h, centrifuged at the laboratory of the district health c e n t e r t o o b t a i n s e r u m . S e r u m w a s f r o z e n in a s e r i e s of c o n t a i n e r s a t - 7 0 ° C before being transferred, packed in dry ice, to the laboratory of Endocrinology, Academic M e d i c a l C e n t e r ( A m s t e r d a m,t h e N e t h e r l a n d s ) f o r a n a l y s i s . Serum concentration of T S H was measured by immuno luminometric assay

using a c o m m e r c i a l k i t ( I L M A ; B r a h m s D i a g n o s t i c a G m b h , B e r l i n ,G e r m a n y ) a n d F T 4 byt i m e - r e s o l v e d f l u o r o i m m u n o a s s a y a f t e r i m m u n o - e x t r a c t i o n u s i n g a c o m m e r c i a l k i t (Delfia™, W a l l a c O y , T u r k u , F i n l a n d ) . T h e c o e f f i c i e n t of v a r i a t i o n o f i n t r a - a s s a y a n d

inter-assay f or T S H w e r e 2.4% a n d 4 . 5 % respectively, and f o r FT4 w e r e 3 . 6 % and

6.4% respectively. Values for both T S H and FT4 o b t a i n e d , w e r e w i t h i n 10% o f t h e target value of normal and elevated samples provided every two months by the Dutch national external quality control scheme for hormones in serum (LWBA). Reference range of iodine replete s u b j e c t s for serum T S H is 0 . 4 - 4 . 0 mU/L a n d f o r

FT4is9-24pmol/L(13). The s e r u m c o n c e n t r a t i o n of T g w a s measured by ILMA using a commercial kit (Brahms Diagnostica G m b h , B e r l i n , G e r m a n y ) . T h e m e t h o d w a s s t a n d a r d i z e d in house u s i n g s e r u m d i f f e r i n g f o u r - f o l d in t a r g e t c o n c e n t r a t i o n s . Intra-assay a n d i n t e r - assay coefficient of variation were 7-10% and 6-7% respectively depending on concentration. From a s a m p l e of 2 5 0 p e r s o n s s t r a t i f i e d by s e x into f i v e a g e g r o u p s from 2 0t o 7 0 y , t h e c o n c e n t r a t i o n o f T g v a r i e d f r o m 1t o 4 5 p m o l / L a n d v a l u e s w e r e not related to age and sex. Up until the present time, external quality control materials a r e s t i l l u n d e r d e v e l o p m e n t ( 1 4 ) . Urinaryiodine concentration.A c a s u a l urine s a m p l e (5 mL) w a s collected between 0 8 . 0 0 h a n d 1 2 . 0 0 h o n 2 c o n s e c u t i v e d a y s a t b a s e l i n e a n d 4 , 1 2 , 2 5 a n d 55 Chapter 3

50 w k a f t e r t r e a t m e n t . T h e u r i n e s a m p l e s , p r e s e r v e d w i t h a p p r o x i m a t e l y 1g t h y m o l , were sent to the iodine laboratory of the Nutritional Research and Development Center in Bogor (Indonesia). Iodine concentration in urine w a s a n a l y z e d based on alkaline d i g e s t i o n using t h e S a n d e l l - K o l t h o ff reaction (15). Urinary iodine level w a s measured i nd u p l i c a t e a n dt h e a v e r a g e c a l c u l a t e d f o r e a c h c h i l d .

Statistical m e t h o d s The Kolmogorov-Smirnov t e s t w a s used t o c h e c k w h e t h e r t h e d i s t r i b u t i o n of the variables was normal. Data are reported as mean and SD for normally distributed parameters and as median and 25th - 75th percentile for non-normally distributed parameters. Correlation between normally distributed parameters was measured by Pearson test and for non-normally distributed parameters by Spearman rank test. Differences between groups were examined by analysis of variance (ANOVA) for normally distributed parameters and by the Mann Whitney and K r u s k a l - W a l l i s t e s t f o r n o n - n o r m a l l y d i s t r i b u t e d p a r a m e t e r s . The s o f t w a r e p a c k a g e o f S P S S ( w i n d o w s v e r s i o n 7 . 5 . 2 , S P S S Inc., C h i c a g o , IL) was used for all statistical analyses and a P value<0.05 was considered significant.

Ethical C o n s i d e r a t i o n s The guidelines of the Council for International Organizations of Medical Sciences (16) w e r e f o l l o w e d . T h e e t h i c a l c o m m i t t e e f o r s t u d i e s on h u m a n s u b j e c t s , Faculty of Medicine, U n i v e r s i t y of Indonesia approved t h e study. Informed consent was o b t a i n e d f r o m p a r e n t s o f e a c h s u b j e c t before t h e s t a r t of t h e s t u d y . Iodized o i l was g i v e n a t t h e e n d o f t h e s t u d y t o t h o s e c h i l d r e n w h o w e r e s t i l l c o n s i d e r e d i o d i n e deficient.

RESULTS The a v e r a g e a g e o f t h e s u b j e c t s w a s 9 . 4 ± 0 . 8 y , a n d t h e s a m p l e i n c l u d e d 8 4 boys and 102 g i r l s . T h e average body weight and height were 22.5 + 3 . 2 kg and 121.1 ± 5.9 cm respectively. At baseline the prevalence of goiter as assessed by palpation w a s 2 1 . 5 %w h e r e a s i tw a s 2 2 . 6 %a s a s s e s s e d b y u l t r a s o u n d .T h e m e d i a n urinary iodine c o n c e n t r a t i o n of t h e p o p u l a t i o n w a s 0 . 3 6 nmol/L, s u g g e s t i n g t h a t t h e 56 Indicatorsof iodine status

subjects were moderately iodine deficient. However, the median serum

concentration of TSH and mean serum concentration of FT4 at baseline were in normal ranges (Table 1). The median serum level of Tg in a subsample of 40 children w a s 10.5 (6.0-17.5) p m o l / L All b u t o n e v a l u e w e r e in t h e n o r m a l r a n g e( 1 - 45 p m o l / L ) .

Table 1. Iodine s t a t u s of t h e s c h o o l c h i l d r e n expressed by d i f f e r e n t indicators at d i f f e r e n t time p e r i o d sd u r i n gt h es t u d y( n = 1 8 6 ) .

Period Thyroid v o l u m e 1 Goiter b y Urinary i o d i n e Serum t h y r o i d Serum f r e e (mL) palpation concentration1 stimulating thyroxine2 (%) (nmol/L) hormone1 (pmol/L) (mU/L) Baseline 4.54 22 0.36 1.8 16.9+ 2.4 (3.99-5.30) (0.29-0.65) (1.2-2.5) 25w k 3.57 20 1.98 1.7 17.9+ 3.1 (2.99-4.25) (1.20-3.51) (1.1-2.2) 50w k 3.20 9 1.12 1.8 17.0+ 2.5 (2.86-3.48) (0.84-1.90) (1.3-2.7) P <0.0013 <0.014 <0.0013 NS <0.015

1M e d i a n ( 2 5 th- 7 5 thp e r c e n t i l e ) 2M e a n± S D 3K r u s k a l - W a l l i st e s t 4S p e a r m a nt e s t 5 A N O V A

The sensitivity and specificity of goiter measured by palpation against ultrasound w e r e 5 7 %a n d 8 9 % a t b a s e l i n e , a n d 6 0 % a n d 8 1 % at 2 5 w k , w h i l e a t 5 0 wk o f f o l l o w u p , n o n e o f t h e s c h o o l c h i l d r e n h a d g o i t e r a s m e a s u r e d by u l t r a s o u n d . There was a significant agreement (P<0.001) between goiter grades by palpation and t h y r o i d v o l u m e measured by ultrasound at baseline and 25 w k (Table 2 ) . T h e thyroid volume was significantly greater in subjects with goiter than in normal subjects, a n d it w a s a l s o g r e a t e r in s u b j e c t s w i t h grade 2 t h a n w i t h g r a d e 1 g o i t e r . There w a s n o s i g n i f i c a n t a g r e e m e n t between t h y r o i d g r a d e s m e a s u r e d by p a l p a t i o n andt h y r o i d v o l u m e s a t 5 0w k o ff o l l o w - u p (P= 0 . 4 5 ) . There w a s a s i g n i f i c a n t r e d u c t i o n i nt h y r o i d v o l u m e s a n d in t h e p r e v a l e n c e o f goiter measured by palpation at 50 wk after supplementation with oral iodized o i l . The r e d u c t i o n i nt h e g o i t e r g r a d e m e a s u r e d b y p a l p a t i o n w a s s i g n i f i c a n t l y a s s o c i a t e d

57 Chapter 3

o o -C o co CD » T - CO - T. o o >> Q- co K il t ^ CO CO *= io w _c r^ oi 05 c o o co E CM in o CO 1 ^ CO O ^ ?- O 0) » CO 05 CO CO CO t - O) CO to <= = 2 CD £ o z c o to E o o o o o o T3 CO CO CO O T^ c\i h- 05

O CO CD t CO CO CM CM CO O CO CO CO 00 CO t3 T3 '.= 'j o O CO CM 1 - i - o o co = i 05 in 0 5 CO •<3- CM CM CO CO CM CO 0 0 05 CO C z O d d d z T3 I 8 i l z C CD CO i - CO 3 o o 1° o r» CO o C\j T^ CO

O D i _ CD >. . C ><"2 <5"- i- ^ o o ^ s5 m T3 -I CO CD • D CD O CO o T- CO H CO C •2; CO co CO ^ CO o CD O 2 V —-^ - o CM CO V co "c co U CO 3 CO CO CO c CO C\J CD co ST in co 5 CO -^ r^ co CD E 05 CM •* r^ ^C_D s >t CD « n 2 co in ui co co m o CD » in N o in 05 o m OJ « U ) 0 5 "2® ^ CO o 05 in o CO 00 CO CD O 2 £ CO ^- o CM CO C5 "" "~" V C3) °>0> ' ' V • * 00 O CO O ._ c CO CO ^ f CO CM CM O ) C CD '= CD • o •* in CO ^ i _ ± ; 3 c O T3 ^ iri CO o Q . C • D CO CD O 05 0 5 c\T CO ^—a) , CD CD CO CD 5? S CO li T - O 1"- i - r~ r r O CO CD o CD ^— CD T3 CD O Q..5 c CO g a. a. !c *- t CO c CO ._ 10 CD r: co to i n * - CD § 2 jg. E S E B m r^ o o o o o - i o >< ~ CD co o ( T , • p CD jo E CL Z CD Z C3 O CO ^ m n CD fc CD " a z c CM CO c ^to F J= CO CO r +i c\i c CD ?! < CO c i - C a> £ s 5 D T3 CO CO C O ) CD CD 5 ? in o C CO U- CO < CO sz CM i n S ^ w S V- u

58 Indicators ofiodine status with the reduction in thyroid volume, and the changes in thyroid volume were significantly g r e a t e r f o r s u b j e c t s w h o i n i t i a l l y h a d g o i t e r (P < 0 . 0 0 1 ) (Table 2 ) . M e d i a n urinary iodine concentration was significantly increased at 25 wk compared to baseline and reduced between 25 and 50 wk after supplementation. However all children maintained urinary iodine concentrations above 0.4 |amol/L (Table 2). A weak, but statistically significant, inverse correlation was found between the logarithm of urinary iodine concentration and thyroid volume at baseline (r=-0.15; P<0.05, Figure 1). Urinary iodine concentration was not related to any other indicators a t b a s e l i n e o r a n y i n d i c a t o r s a t a n y p e r i o d s o f m e a s u r e m e n t s (Table3 ) . There w e r e n o s i g n i f i c a n t a s s o c i a t i o n s between g o i t e r g r a d e s (palpation) and urinary iodine c o n c e n t r a t i o n , s e r u m c o n c e n t r a t i o n s of T S H a n d F T 4at baseline a n d at a l l p e r i o d s o ff o l l o w u p ( T a b l e 2 ) .G o i t e r g r a d e ( p a l p a t i o n ) a t b a s e l i n e w a s a l s o n o t related t o s e r u m T g c o n c e n t r a t i o n s in a s u b s a m p l e o f 4 0 c h i l d r e n at b a s e l i n e (data not s h o w n ) . S u b j e c t s w i t h a p a l p a b l e g o i t e r d i d n o t h a v e l o w e r u r i n a r y i o d i n e , h i g h e r serum T S H , o r lower serum FT4 c o n c e n t r a t i o n s than subjects without goiter at a n y time o f m e a s u r e m e n t .

Serum TSH and serum FT4 did not respond significantly to treatment with iodized oil. T h e mean of s e r u m FT4 s l i g h t l y increased at 25 wk in both goiter and normal g r o u p s , a n d w e n t d o w nt o i n i t i a l l e v e l s a f t e r 5 0 w k o f t r e a t m e n t . T h e c h a n g e s of FT4 were not significant and there was no difference between the normal and goiter groups (Table 2). A significant inverse correlation was found between the serum concentrations of TSH and of FT4 (r=-0.18; P<0.05, Figure 2) and a significant c o r r e l a t i o n w a s a l s o f o u n d b e t w e e n t h e s e r u m c o n c e n t r a t i o n s o fT S H a n d ofT g i na s u b s a m p l e o ft h e p o p u l a t i o n (r=0.52;P < 0 . 0 1 ) . There were significant differences in the mean change of urinary iodine concentration between goitrous and normal subjects. Children who had goiter at baseline had greater iodine retention in their bodies at 4, 12 and 25 wk after treatment, compared t o t h e n o n - g o i t r o u s children. A t t h e 5 0 t h w k a f t er intervention, both groups had a median urinary iodine within normal range and none of the children h a d g o i t e r a s m e a s u r e d b y u l t r a s o u n d ( T a b l e4 ) .

59 Chapter3

Thyroid v o l u m e ( m l _ ) Figure 1 .L i n e a r l o g a r i t h m r e l a t i o n s h i p b e t w e e n t h y r o i dv o l u m e a n d u r i n a r y iodine c o n c e n t r a t i o n ( n = 1 8 6 ; r = - 0 . 1 5 ,P < 0 . 0 5 ) . T h e c u r v e d l i n e s i n d i c a t e t h e 95% C I .

26- D • c a o 24 J CD c 0 0) 22 ° D D a c a o 0 D DDD 20 D D o __ o °a D OD

x o D a 18 B-iL B n _ a oo D Q DO sz —a- 16 r——S-JL. G " 8aQ BPD" D B H a • a°,s> a aiS D E 0 a 0 "•-—-—^ 14 0 a° CD o D° c w D 12. a

10 • 1 2 3 4 5

Serum TSH c o n c e n t r a t i o n (mU/L)

Figure2 . R e l a t i o n s h i p b e t w e e nt h y r o i d s t i m u l a t i n g h o r m o n e ( T S H ) a n d s e r u m free t h y r o x i n e ( n = 1 8 6 ; r = - 0 . 1 8 ,P<0.05). T h e c u r v e d l i n e s i n d i c a t e t h e 9 5 % C I . 60 Indicators ofiodine status

o o o CO c co <*— 1^ 05 C M in CM m co i n w ^ cc • * in T m c\i oJ c\j CM +1 +1 +1 +1 CO 0) E +1 +1 CO +1 +1 (D c CD I*- CM h- l-» 5J in •vt o C 05 00 If) OJ *- 1^ o *- 1^ 0 z T3 X S CO !£i N cb 1-^ _C o D ) C >. o .c E CD CO c 0) IT) O O CO in 0 in 0 CD CD CO T- c CO 2 £

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61 Chapter 3

Table 4. Relationship between changes of urinary iodine concentration at different time periodsa n dg o i t e r m e a s u r e db yu l t r a s o u n db e f o r ea n da f t e r i n t e r v e n t i o n

Goiter ( u trasound) N Changes o f u r i n a r y i o d i n e c o n c e n t r a t i o n 1 Before End 4w k 12 w k 25w k 50w k Normal Normal 144 4.98 3.01 1.37 0.83 (2.40-9.61) (1.55-6.27) (0.73-2.60) (0.39-1.33) Goiter Normal 42 8.48 5.11 2.01 0.78 (3.53-13.94) (1.95-8.86) (0.79-3.69) (0.47-1.46) P 2 <0.05 <0.01 <0.05 NS

1 Median (25,h-75th percentile), urinary iodine concentration after treatment at baseline, |imol/L 2M a n nW h i t n e yt e s t

DISCUSSION The r e s u l t s of t h i s s t u d y illustrate some d i f f i c u l t i e s and inadequacies usually encountered in a s s e s s i n g iodine s t a t u s of a p o p u l a t i o n a n d m o n i t o r i n g t h e c h a n g e s in status after intervention. T h e school children in t h i s study had been j u d g e d as moderately i o d i n e d e f i c i e n t a t b a s e l i n e . T h i sj u d g m e n t w a s b a s e d o n t h e p r e v a l e n c e of goiter measured by p a l p a t i o n and u l t r a s o u n d , a t 2 1 . 5 % and 2 2 . 6 % respectively, and on a median urinary iodine concentration of 0.36 umol/L (2). However, the serum TSH, serum FT4 and serum Tg concentrations were in the normal range, suggesting t h a t t h e p o p u l a t i o n h a da d e q u a t e l y c o m p e n s a t e d f o r a l o w i o d i n e i n t a k e .

Measurement o ft h y r o i d s i z e Surveys f o r c u r r e n t l y a s s e s s i n g t h e p r e v a l e n c e o f g o i t e r m o s t l y r e l y o n t h y r o i d palpation (7,17), and t h e presence of goiter is usually expressed according to the WHO classification (2). In populations suffering from moderate or severe iodine deficiency, e s p e c i a l l y a m o n g a d u l t s , t h y r o i d p a l p a t i o n p r o v i d e s a r e l i a b l e m e t h o d f o r goiter assessment. However, the assessment becomes more problematic in areas with mild iodine deficiency especially when children are surveyed, because most iodine deficient subjects would, even in extreme cases, only have small goiters (4,18). Gutekunst and Martin-Teichert (19) showed that palpation often wrongly classifies thyroid size, when compared with ultrasound measurements. A study 62 Indicators of iodine status among school children in northern and central Italy, f o u n d a discrepancy of more than 20% b e t w e e n thyroid palpation and ultrasound (4). T h e present study shows that about 43% of t h e children j u d g e d to have palpable goiter did not have goiter according to ultrasound measurements, and may therefore be wrongly classified. Gutekunst et a l . (5,18) reported t h a t a m o n g c a s e s w i t h palpable grade 1 g o i t e r , a n error r a t ea s h i g h a s3 0 %m i g h t o c c u r . O u r s t u d y f o u n d t h a t s e n s i t i v i t y a n d s p e c i f i c i t y of palpation against goiter measured by ultrasonography were 57% and 89% respectively at baseline, and the positive and negative predictive value was 6 0 % and 8 8 % r e s p e c t i v e l y . T h e s e d a t a s h o w t h a t palpation cannot provide an a c c u r a t e assessment of t h e e x t e n t o f i o d i n e d e f i c i e n c y among c h i l d r e n w i t h m i l d t o m o d e r a t e iodine deficiency, since t h e s e n s i t i v i t y relative t o ultrasonography is not v e ry high. Thus, a s s e s s m e n t of t h y r o i d v o l u m e b y u l t r a s o u n d is p r e f e r a b l e t o t h y r o i d palpation especially for monitoring the effectiveness of iodine deficiency control program (4,18,20,21). H o w e v e r , p a l p a t i o n s t i l l h a s a u s e f u l r o l e i n i d e n t i f y i n g t h o s e a r e a s a n d populations w i t h i o d i n e d e f i c i e n c y ( 2 ) .

Urinary i o d i n e c o n c e n t r a t i o n Urinary iodine concentration is widely recognized as a valid means for determining iodine i n t a k e in a p o p u l a t i o n (3,17). S e v e r a l a p p r o a c h e s t o c l a s s i f y t h e severity of i o d i n e d e f i c i e n c y in a p o p u l a t i o n have b e e n p r o p o s e d (2,22), t h e criteri a used by WHO/ICCIDD/UNICEF (2), which are based on median urinary iodine concentration in c a s u a l samples, being used most commonly . T h e present study found that the urinary iodine concentration was not significantly associated with thyroid palpation grading. T h i s might be d u e t o t h e f a c t t h a t all t h e s c h o o l children had a deficient or marginally deficient status at baseline. Furthermore, iodine excretion is a m a r k e r f o r d i e t a r y iodine intake a n d r e f l e c t s current iodine s t a t u s (2), while g o i t e r r e p r e s e n t s t h e i n t e g r a t i o n o f e v e n t s e x t e n d i n g o v e r t i m e , i t i s a h i s t o r i c a l relic that does not necessary indicate the present state of iodine nutrition (23). Therefore, i n d i v i d u a l s w i t h g o i t e r m i g h t h a v ea d e q u a t e u r i n a r y i o d i n e s t a t u s . Although there was no association between urinary iodine and goiter assessed by t h y r o i d palpation, a s i g n i f i c a n t inverse correlation was f o u n d between the logarithm of t h e u r i n a r y iodine c o n c e n t r a t i o n and t h y r o i d v o l u m e , i n d i c a t i n g t h a t with h i g h e r u r i n a r y i o d i n e c o n c e n t r a t i o n s , t h y r o i d v o l u m e s w e r e s m a l l e r .

63 Chapter 3

Thyroid h o r m o n e s

Generally there was no relationship between serum TSH and FT4 and the other iodine status indicators. This finding corresponds with those reported by Delange et al. (24), Gutekunst et al. (5) and Pardede et a l . (3) who also f a i l e d t o observe a c o r r e l a t i o n b e t w e e n s e r u mT S H a n dt h y r o i d v o l u m e i n c h i l d r e n a n d a d u l t s . A r i s e i ns e r u mT S H i so b s e r v e d w h e n i o d i n e d e f i c i e n c y l e a d st o c h r o n i c i n a d e q u a t e production of T 4 a n d T 3 i n s e v e r e endemic a r e a s (25). S t u d i e s have s h o w n t h a t t h e thyroids of iodine depleted rats are much more sensitive to TSH than those with normal urinary iodine concentrations (26). G u t e k u n s t et a l . (5) suggested that the reduced T S H l e v e l i s a p h y s i o l o g i c a l r e s p o n se t o p r o t e c t t h e t h y r o i d f r o m a d d i t i o n a l growth a n d i t i s s t i l l d i s c u s s e d w h e t h e r T S H i s i n d e e d a g r o w t h f a c t o r f o r t h e t h y r o i d cell. I n a d d i t i o n ,t h e t h y r o i d h a s a n e n o r m o u s c a p a c i t y t o s t o r e i o d i n e a n d c a n b u f f e r the hormone s e c r e t i o n rate. T h u s serum T S H may not reflect recent dietary iodine as indicated by urinary iodine concentration. Indeed, in most endemic iodine deficient a r e a s , m e a s u r e m e n t of s e r u m T S H c o n c e n t r a t i o n s of s u b j e c t s w i t h goiter, have b e e nw e l lw i t h i n n o r m a l l i m i t s ( 2 3 ) .

Our data show that serum concentrations of T S H , FT4 a n d T g were in t h e normal r a n g e ,a l t h o u g h t h e p r e v a l e n c e o f g o i t e r w a s m o r et h a n 2 0 %a n d t h e m e d i a n urinary iodine c o n c e n t r a t i o n less t h a n 0 . 4 0 ^mol/L. A s i m i l a r observation of normal levels o f c i r c u l a t i n g T 3,T 4a n d T S H w a s m a d e in c o u n t r i e s w h e r e t h e p r e v a l e n c e of goiter was 20 t o 50%, a n d the urinary iodine concentration indicated mild iodine deficiency ( 2 2 ) .

Even t h o u g h serum concentrations of T S H , FT4 a n d T g were in t h e normal range, t h e r e w a s a s i g n i f i c a n t inverse correlation between s e r u m c o n c e n t r a t i o n s of

FT4and o f T S H a t b a s e l i n e (r=-0.18) and b e t w e e n s e r u m c o n c e n t r a t i o n of T S H a n d of T g in a s u b s a m p l e (r=0.52). T h i s o b s e r v a t i o n is p r o b a b l y related t o t h e reported hight u r n o v e r o ft h e s m a l l i o d i n e p o o l i nt h et h y r o i d ,w h i c h s u p p o s e d l y o c c u r s i nn o n - adult s u b j e c t s ( 2 2 ) .

Monitoring i m p a c t o f i n t e r v e n t i o n s At 25 w k of f o l l o w u p , t h e p r e v a l e n c e of goiter measured by ultrasound w a s reduced from 23% t o 3%, while urinary iodine concentration increased from 0.36 (imol/L to 1.98 nmol/L in which about 6% of the population had urinary iodine concentration l e s s t h a n 0 . 7 9 ( i m o l / L . H o w e v e r , t h e p r e v a l e n c e o f g o i t e r m e a s u r e d b y palpation only slightly reduced, f r o m 22% t o 20% a t 25 wk of follow up, and the 64 Indicators ofiodine status

serum T S H a n d F T 4 c o n c e n t r a t i o n s b o t h r e m a i n e d i nt h e n o r m a l r a n g e . These d a t a showed t h a t both urinary iodine concentration and goiter measured by ultrasound indicated t h e same level of improvement on iodine s t a t u s, but goiter measured by

palpation, serum TSH and serum FT4 c o n c e n t r a t i o n indicated different levels of iodine s t a t u s . After 5 0w k o f t r e a t m e n t w i t h o r a l i o d i z e d o i l ,t h e r e w a s a s i g n i f i c a n t reduction int h y r o i d v o l u m e s , p r e v a l e n c e o f g o i t e r a n d a n i n c r e a s e i nt h e m e d i a n u r i n a r y i o d i n e

concentration. A s i g n i f i c a n t increase in s e r u m FT4 w a s a l s o o b s e r v e d , e v e n t h o u g h both the initial and final level were within normal range. However, there was no significant c h a n ge o n t h e s e r u m T S H c o n c e n t r a t i o n . T h i s r e s u l t s s u g g e s t t h a t in t h e population investigated, t h y r o i d volume measured by ultrasound, t h y r o i d palpation and urinary iodine c o n c e n t r a t i o n all g a v e a s i m i l a r indication of t h e impact after 50

wk of iodine supplementation, which was not so with serum TSH and FT4. This finding confirms the results of a previous study among iodine deficient school children i nA l g e r i a ( 1 3 ) . The reduction of t h y r o i d volumes at t h e 50 wk were significantly greater for children w i t h h i g h e r g r a d e o f g o i t e r a t b a s e l i n e a n d i o d i n e w a s r e t a i n e d l o n g e r i nt h e body until 25 wk f o r goitrous children compared t o t h e i r non-goitrous counterpart. These results suggested that the efficacy of oral iodized oil supplementation was higher in subjects with more severe iodine deficiency, and there was agreement between t h e c h a n g e s a s i n d i c a t e d b yt h e d i f f e r e n t i n d i c a t o r s . We c o n c l u d e t h a t urinary iodine c o n c e n t r a t i o n and t h y r o i d v o l u m e measured by ultrasound are the most useful epidemiological indicators for assessing iodine status and m e a s u r i n g t h e impact of iodized oil s u p p l e m e n t a t i o n among moderately iodine d e f i c i e n t s c h o o l c h i l d r e n . T h e s e p a r a m e t e r s f o u n d t h e s a m e d e g r e e o f i o d i n e deficiency at b a s e l i n e a n d a f t e r s u p p l e m e n t a t i o n . T h e o t h e r indicators d i d n o t s h o w concordant levels of iodine deficiency either at baseline or after treatment, suggesting that palpation, serum TSH, serum Tg and serum FT4 concentrations might be less reliable indicators for assessing and monitoring treatment in moderately iodine deficient school children than urinary iodine concentration or thyroid v o l u m e . A l t h o u g h t h e s e d a t a h i g h l i g h t t h e l i m i t a t i o n s o f t h y r o i d p a l p a t i o n ,t h i s technique still has a useful place in assessing iodine status because no sophisticated equipment is required. However it is necessary for observers to be trained i nt h et e c h n i q u e .

65 Chapter3

REFERENCES

1. ICCIDD/UNICEF/WHO. Global prevalence of iodine deficiency disorders. 1993. Geneva, Switzerland, Micronutrient Deficiency Information System, WHO. MDIS Working p a p e r # 1 . 2. WHO/UNICEF/ICCIDD. I n d i c a t o r s f o r a s s e s s i n g i o d i n e d e f i c i e n c y d i s o r d e r s a n d t h e i r control p r o g r a m s . G e n e v a : W H O , 1 9 9 4 . 3. Pardede LVH, H a r d j o w a s i t o W, G r o s s R, e t a l . Urinary iodine excretion is t h e most appropriate o u t c o m e i n d i c a t o r f o r iodine d e f i c i e n c y a t f i e l d c o n d i t i o n s a t d i s t r i c t l e v e l . J N u t r 1 9 9 8 ; 1 2 8 : 1 1 2 2 - 6 . 4. Vitti P, Martino E, Aghini LF, et al. T h y r o i d volume measurement by ultrasound in children as a t o o l for the assessment of mild iodine deficiency. J Clin Endocrinol Metab 1 9 9 4 ; 7 9 : 6 0 0 - 3 . 5. Gutekunst R, Smolarek H, Hasenpusch U, et al. Goitre epidemiology: thyroid volume, iodine excretion, thyroglobulin and thyrotropin in Germany and Sweden. Acta E n d o c r i n o l C o p e n h 1 9 8 6 ; 1 1 2 : 4 9 4 - 5 0 1 . 6. Delange F , B e n k e r G , C a r o n P, e t a l .T h y r o i d v o l u m e a n d u r i n a r y i o d i n e i n E u r o p e a n schoolchildren: s t a n d a r d i z a t i o n of v a l u e s f o r assessment of i o d i n e d e f i c i e n c y . Eur J Endocrinol 1 9 9 7 ; 1 3 6 : 1 8 0 - 7 . 7. Thilly CH, Delange F, Stanbury JB. Epidemiologic surveys in endemic goiter and cretinism. In: S t a n b u r y J B , H e t z e l BS, e d s . E n d e m i c Goiter a n d Endemic C r e t i n i s m . NewY o r k : J o h n W i l e y & S o n s , I n c . , 1 9 8 0 : 1 5 7 - 7 9 . 8. Berghout A, Wiersinga WM, Smits NJ, Touber JL. The value of thyroid volume measured by ultrasonography in the diagnosis of goitre. Clin Endocrinol Oxf 1988;28:409-14. 9. Aghini L F ,A n t o n a n g e l i L, P i n c h e r a A , e t a l . E f f e c t o f i o d i z e d s a l t o n t h y r o i d v o l u m e o f children l i v i n g i n a n a r e a previously characterized by m o d e r a t e iodine d e f i c i e n c y . J Clin E n d o c r i n o l M e t a b 1 9 9 7 ; 8 2 : 1 1 3 6 - 9 . 10. Ministry of Health Rl and Tim GAKI Undip. Endemic goiter map of Central Java, Indonesia. 1996. S e m a r a n g , I n d o n e s i a , U n i v e r s i t a s D i p o n e g o r o . 11. Untoro J , S c h u l t i n k W, W e s t CE, G r o s s R, Hautvast J G A J . Efficacy of oral iodized peanut oil is greater than that of iodized poppyseed oil among Indonesian school children. Submitted f o r p u b l i c a t i o n . 12. WHO, I C C I D D . R e c o m m e n d e d normative v a l u e s f o r t h y r o i d v o l u m e in c h i l d r e n a g e d 6-15 y e a r s . Bull W o r l d H e a l t h O r g a n 1 9 9 7 ; 7 5 : 9 5 - 7 . 13. Benmiloud M, Chaouki ML, Gutekunst R, Teichert HM, W o o d WG, Dunn JT. Oral iodized oil for correcting iodine deficiency: optimal dosing and outcome indicator selection. J C l i n E n d o c r i n o l M e t a b 1 9 9 4 ; 7 9 : 2 0 - 4 . 14. Feldt RU, P r o f i l i s C, C o l i n e t E, et a l . Human t h y r o g l o b u l i n reference material (CRM 457); 1st p a r t : A s s e s s m e n t of h o m o g e n e i t y , s t a b i l i t y a n d i m m u n o r e a c t i v i t y ; 2 n d p a r t : Physicochemical c h a r a c t e r i z a t i o n and c e r t i f i c a t i o n . Ann Biol Clin 1996;54:337-342; 343-8. 15. Dunn JT, Crutchfield HE, Gutekunst R, Dunn AD. Two simple methods for measuring i o d i n e i n u r i n e . Thyroid 1 9 9 3 ; 3 : 1 1 9 - 2 3 . 16. CIOMS. International Guidelines for Ethical Review of Epidemiological Studies. Geneva, Switzerland: Council for International Organizations for Medical Sciences, 1991. 17. Dunn JT, van der Haar F. A practical guide to the correction of iodine deficiency. Wageningen,T h e N e t h e r l a n d s : I C C I D D , 1 9 9 0 .

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18. Gutekunst R, Chaouki ML, Dunn JT, Benmiloud M. Field assessment of goiter: comparison of palpation, surfac e outline and ultrasonography. Int Symp on Iodine and t h e T h y r o i d 1 9 9 0 ; ( a b s t ) . 19. Gutekunst R, Martin-Teichert H. Requirements for goiter surveys and the determination of thyroid size. In: Delange F, Dunn JT, Glinoer D, eds. Iodine Deficiency in E u r o p e . N e w Y o r k : P l e n u m P r e s s , 1 9 9 3 : 1 0 9 - 1 5 . 20. Berghout A , W i e r s i n g a W M , S m i t s N J ,T o u b e r J L Determinants o f t h y r o i d v o l u m e a s measured by ultrasonograph y in h e a l t h y adults in a non-iodine deficient area. Clin Endocrinol O x f 1 9 8 7 ; 2 6 : 2 7 3 - 8 0 . 21. Hegedus L, Perrild H, Poulsen LR, et al. The determination of thyroid volume by ultrasound and its relationship to body w e i g h t , age, and sex in n o r m a l s u b j e c t s . J Clin E n d o c r i n o l M e t a b 1 9 8 3 ; 5 6 : 2 6 0 - 3 . 22. Bourdoux PP. Biochemical evaluation of iodine status. In: Delange F, Dunn JT, Glinoer D, e d s . I o d i n e D e f i c i e n c y i n E u r o p e . N e wYork : P l e n u m P r e s s , 1 9 9 3 : 1 1 9 - 2 4 . 23. Stanbury JB, Pinchera A. Measurements of iodine deficiency disorders. In: Hetzel BS, P a n d a v C S , e d s . S . O . S . f o r a b i l l i o n . N e w D e l h i , I n d i a : O x f o r d U n i v e r s i ty Press, 1994:73-88. 24. Delange F, Hershman J M , Ermans M. Relationship between the serum thyrotropin level, t h e p r e v a l e n c e of g o i t e r a n d t h e p a t t e r n o f i o d i n e m e t a b o l i s m in I d j w i i s l a n d . J Clin E n d o c r i n o l M e t a b 1971;33:261-8. 25. Chopra IJ, Hershman J M , H o r n a b r o o k RW. S e r u m t h y r o i d hormone and t h y r o t r o p i n levels in subjects from endemic goiter regions of New Guinea. J Clin Endocrinol Metab 1 9 7 5 ; 4 0 : 3 2 6 - 3 3 . 26. Bray GA. Increased sensitivity of thyroid in iodine-depleted rats to the goitrogenic effects o f t h y r o t r o p i n . J C l i n I n v e s t 1 9 6 8 ;4 7 : 1 6 4 0 - 4 .

67 Chapter 4

Effect of s t u n t i n g , i o d i n e d e f i c i e n c y a n d oral i o d i z e d o i l s u p p l e m e n t a t i o n o n cognitive p e r f o r m a n c e i ns c h o o l c h i l d r e n from a n e n d e m i c iodine d e f i c i e n t a r e a o f Indonesia

Juliawati Untoro, Clive E West, Werner Schultink, Rainer Gross, Joseph G.A.J. Hautvast Chapter 4

ABSTRACT Previous studies have shown that nutritional supplementation of undernourished c h i l d r e n h a s a b e n e f i c i a l e f f e c t o nt h e i r i n t e l l e c t u a l c a p a c i t y . T h e a i m of t h i s s t u d y w a s t o e x a m i n e w h i c h f a c t o r s w e r e r e l a t e d t o c o g n i t i v e p e r f o r m a n c e in children l i v i n g i n a n i o d i n e d e f i c i e n t a r e a i n C e n t r a l J a v a , I n d o n e s i a . I n a d d i t i o n ,t h e effect of oral dosing with iodized oil was examined in a randomized placebo- controlled t r i a l i n w h i c h c o g n i t i v e p e r f o r m a n c e w a s m e a s u r e d a t b a s e l i n e a n d 5 0 w k after treatment using C a t t e l l ' s culturally f a i r intelligence t e s t . Height, w e i g h t , t h y r o i d volume, u r i n a r y i o d i ne c o n c e n t r a t i o n , s e r u m t h y r o i d s t i m u l a t i n g hormone a n d s e r u m thyroxine were also measured at baseline and 50 wk after dosing. T h i s work was part of a larger study examining the efficacy of iodized oil preparations in school children a g e d 8-10 y e a r s . T h u s t h e placebo group (n=43) was compared with 121 children r e c e i v i n g 2 0 0 m g , 4 0 0 m go r 8 0 0 m go f i o d i n ef r o m i o d i z e d p e a n u to i l . The median cognitive performance at baseline was low (82; 25th-75th percentiles, 77-95) compared with the norm of 100, 32% of the children were underweight, 58% w e r e s t u n t e d , 3 % w e r e w a s t e d , a n d 4 0 % w e r e anemic. Multiple regression analysis showed that father's education and hemoglobin concentration weret h e m a i n d e t e r m i n a n t s o f c o g n i t i v e p e r f o r m a n c e a t b a s e l i n e , a n d u r i n a r y i o d i n e concentration a n d h e i g h t f o r a g e Z - s c o r e w e r e t h e most important determinants f o r improvement in cognitive performance after supplementation with iodized oil. Compared w i t h t h e p l a c e b o g r o u p , t h e r e w a s a s i g n i f i c a n t increase i n u r i n a r y iodine concentration a n d r e d u c t i o n i nt h y r o i d v o l u m e b u t n o c h a n g e i nt h e o t h e r p a r a m e t e r s measured. Wec a nc o n c l u d et h a t c o g n i t i v e p e r f o r m a n c e a f t e r i o d i z e d o i l s u p p l e m e n t a t i o n did i m p r o v e i nt h o s e c h i l d r e n w h o h a da t b a s e l i n e l o w u r i n a r y i o d i n e c o n c e n t r a t i o n o r who were stunted. We also can conclude that anemia at baseline and father's education d o p l a y a r o l e i n c o g n i t i v e p e r f o r m a n c e .

70 Iodine deficiency, stunting and cognitive performance

INTRODUCTION There is a considerable body of evidence suggesting that iodine deficiency limiting mental development. Such evidence comes from ecological studies comparing c h i l d r e n in i o d i n e a d e q u a t e a n d i o d i n e d e f i c i e n t a r e a s ( 1 - 4 ) , c a s e - c o n t r o l studies (5), studies in which mothers were treated with iodized oil (6) and comparisons of iodized oil dosed children with undosed children in another area (7,8). However, from such studies, it is not possible to determine whether iodine supplementation of i o d i n e d e f i c i e n t c h i l d r e n c a n s t i m u l a t e t h e i r m e n t a l p e r f o r m a n c e . When Bautista et al. (9) examined t h e effect of iodine supplementation on mental performance in a d o u b l e - b l i n d , placebo-controlled study, they found no difference between t r e a t e d and untreated children based on t h e Stanford-Binet and Bender- Gestalt t e s t s . In a s u b s e q u e n t d o u b l e - b l i n d , p l a c e b o - c o n t r o l l e d study group using a series of t e s t s covering t h e f u l l range of s e v e n f a c t o r s identified as primary mental abilities by Thurstone, Shresta et al. (10) showed that iodine supplementation increased IQb ya b o u t 10p o i n t s c o m p a r e d w i t ht h e c o n t r o l g r o u p . Early s t u d i e s s u g g e s t e d t h a t t h e a d m i n i s t r a t i o n o f o r a l i o d i z e d o i l r e s u l t e d i na significant r e d u c t i on int h e p r e v a l e n c e a n d s i z e o f g o i t e r in t h e p o p u l a t i o n (11-13).A controlled trial study with oral iodized oil in a small highland village in Bolivia, showed in t h e i o d i n e s u p p l e m e n t a t i o n study of B a u t i s t a e t a l . ( 9 ) mentioned a b o v e , that t h e d e c r e a s e in g o i t e r s i z e w a s s i g n i f i c a n t l y a s s o c i a t ed w i t h i m p r o v e m e n t in I Q score particularly in girls, even though correction of iodine deficiency did not increase mental p e r f o r m a n c e . More d a t a a r e r e q u i r e d t o s h o w w h e t h e r t h e r e w o u l d be a p o s s i b l e e f f e c t o f o r a l i o d i z e d o i l a d m i n i s t r a t i o n o nt h e d e v e l o p m e n t o f c o g n i t i v e performance i n i o d i n e d e f i c i e n t s c h o o lc h i l d r e n . Underweight, stunting and iron d e f i c i e n c y are other risk f a c t o r s for impaired cognitive performance (14-18). Populations at risk for iodine deficiency disorders (IDD) are a l s o likely t o have concurrent deficiencies of t h e s e risk f a c t o r s . Physical growth retardation in infancy and early childhood are associated with poorer performance on cognitive tests (15,16,19,20). In addition, previous studies have shown that correcting nutritional anemia improves cognitive performance (21-23). The e f f e c t of s u p p l e m e n t a t i o n w i t h iodine a n d i r o n have b e e n s h o w n t o b e a d d i t i v e (10). This study aimed to investigate the association between stunting, anemia, iodine d e f i c i e n c y a n d c o g n i t i v e p e r f o r m a n c e a m o n g i o d i n e d e f i c i e n t s c h o o l c h i l d r e n , andt o m e a s u r e t h e i m p a c t o f i o d i n e s u p p l e m e n t a t i o n o nc o g n i t i v e p e r f o r m a n c e . 71 Chapter 4

SUBJECTS A N D M E T H O D S Subjects Subjects were randomly selected from school children aged 8-10 years (n=164) attending four primary schools in Cilacap district, Central Java Province, Indonesia, w h e r e g o i t e r is h i g h l y p r e v a l e n t (total g o i t e r rate >30%) (24). A l l s e l e c t e d subjects were e x a m i n e d by a medical a s s i s t a n t from t h e sub-district health center, and o n l y a p p a r e n t l y h e a l t h y s u b j e c t s w e r e c o n s i d e r e df o r e n t r y i n t ot h e s t u d y .

Study d e s i g n This study was in two phases: first, a cross-sectional phase and then a double-masked, placebo-controlled intervention phase. In the second phase, one group of children was given a single oral liquid dose of iodized peanut oil and a control g r o u p w a s given a n o r a l d o s e of pure peanut oil in order to check whether the s u b j e c t s w e r e e x p o s e d t o e x t r a n e o u s iodine d u r i n g t h e s t u d y . A s a m p l e s i z e o f at l e a s t 3 6s u b j e c t s p e r g r o u p w a s c a l c u l a t e d w i t h a p o w e r i n d e x o f 2 . 8 , a = 0 . 0 5 a n d P=0.20 w h i c h w a s r e g a r d e d a s s u f f i c i e n t t o o b t a i n a s i g n i f i c a n t d i f f e r e n c e of 10% i n cognitive performance between groups. This study was part of a larger study examining t h e e f f i c a c y o f i o d i z e d o i l p r e p a r a t i o n s ins c h o o l c h i l d r e n a g e d 8 - 1 0y e a r s . Thus t h e placebo group (n=43) was compared with 121 c h i l d r e n receiving 200 mg (n=41), 400 mg (n=40) or 800 mg (n=40) of iodine from iodized peanut oil. The urinary iodine concentration and thyroid volume of all treatment groups were significantly improved after the supplementation, but there were no differences among t h e s u p p l e m e n t e d groups in c o g n i t i v e performance. T h e r e f o r e w e c o m b i n e d thet h r e e i o d i z e d o i l s u p p l e m e n t e d g r o u p s i n t o o n eg r o u p . A p r e v i o u s s t u d y i n M a l a w i s h o w e d t h a t t h e d u r a t i o n of e f f e c t i v e n e s s of o r a l l y administered iodized oil w a s significantly reduced by intestinal parasitic infestation (25). T h e r e f o r e , one week prior to administration of iodized oil, a l l subjects in t h i s study, w e r e d o s e d w i t h t h e broad s p e c t r u m anti-helminth albendazole (400 mg p e r dose, SmithKline Beecham, Indonesia) to control Ascaris lumbricoides a s it was knownt h a tt h e s e p a r a s i t e s a r e e n d e m i c i nt h e s t u d y a r e a ( 2 6 ) .

Methods Measurementof thyroidsize. T h y r o i d size was measured at baseline and 50 w k a f t e r t r e a t m e nt using ultrasound by t h e main r e s e a r c h er (JU) w h o had b e e n trained in the technique. Ultrasonography was performed on each subject in the 72 Iodine deficiency, stunting and cognitive performance

sitting position. F i r s t , t h e t r a n s d u c e r was kept horizontal at a n upright angle t o t h e neck t o o b s e r v e t h e c r o s s s e c t i o n of t h e t h y r o i d , m e a s u r i n g maximal w i d t h (w) a n d maximal thickness (d). Next, the length (I) of each lobe was determined by longitudinal a p p l i c a t i o n o f t h e t r a n s d u c e r t ot h e s u b j e c t ' s n e c k . A c o - w o r k e r r e c o r d e d the o b s e r v a t i o n s of t h e u l t r a s o n o g r a p h y and p r o v i d e d a c o n t i n u o u s f l o w of p e r s o ns to b e e x a m i n e d .T h e v o l u m e (V) w a s c a l c u l a t e d u s i n g t h e f o l l o w i n g f o r m u l a : V ( c m 3) =0.479 x d x w x I ( 2 7 ) . T h e t h y r o i d volume was the sum of t he volumes of both lobes. Result of ultrasonography from the study population was compared to normative d a t af r o m p o p u l a t i o n s w i t h s u f f i c i e n t i o d i n e i n t a k e ( 2 8 ) . Biochemical measurements. V e n o u s blood samples (3 mL) were drawn from a n a n t e c u b i c a l v e i n f r o m n o n - f a s t i n g s u b j e c t s between 0 8 . 3 0 a n d 12.00 using EDTA as a n t i c o a g u l a n t . Immediately after collection, t h e blood w a s placed on i c e , protected from light and within 2-3 h centrifuged at the laboratory of the district health c e n t e r t o o b t a i n s e r u m .A s a m p l e o f b l o o d w a s t a k e n f o r d e t e r m i n a t i o n o f t h e concentration of hemoglobin (only at baseline) using a HemoCue portable hemoglobinometer ( 2 9 ) . S e r u m w a sf r o z e n i na s e r i e s o f c o n t a i n e r s a t - 7 0 ° C before being t r a n s f e r r e d , p a c k e d in d r y ice, t o t h e laboratory of Endocrinology, Academic Medical Center (Amsterdam, t h e Netherlands) for analysis. Serum levels of t h y r o i d stimulating hormone (TSH) were measured by immunoluminometric assay techniques using a commercial kit (Brahms Diagnostica Gmbh, Berlin, Germany)

and s e r u m f r e e t h y r o x i n e (FT 4) w a s m e a s u r e d by t i m e - r e s o l v e d f l u o r o immunoassay after i m m u n o - e x t r a c t i o n u s i n g a c o m m e r c i a l k i t ( D e l f i a ™ ,W a l l a c O y ,T u r k u , F i n l a n d ) . The coefficient of variation of intra-assay and inter-assay for TSH were 2.4% and

4.5% respectively, and f o r FT4 w e r e 3.6% and 6 . 4 % respectively. Values obtained for both T S H a n d FT 4, w e r e w i t h i n 10% o f t h e t a r g e t value of normal a n d elevated samples provided every two months by t h e Dutch national external quality control scheme for hormones in serum (LWBA). The reference range of iodine replete subjects f o r s e r u mT S H i s0 . 4 - 4 . 0 m U / La n df o r F T 4,9 - 2 4 p m o l / L ( 1 3 ) . A urine sample was collected between 08.00 h and 12.00 h on two consecutive d a y s a t b a s e l i n e a n d a t 5 0 w k a f t e r t r e a t m e n t . T h e s a m p l e s , p r e s e r v e d with a p p r o x i m a t e l y 1 g t h y m o l , w e r e sent t o t h e iodine laboratory of t h e Nutritional Research and Development Center in Bogor (Indonesia) for analysis. Iodine concentration in u r i n e w a s a n a l y z e d based o n a l k a l i n e d i g e s t i on using t h e S a n d e l l - Kolthoff r e a c t i o n (30) a n d w a s m e a s u r e d i n d u p l i c a t e a n d t h e a v e r a g e c a l c u l a t e d f o r each c h i l d . 73 Chapter 4

Assessment of cognitive performance. This was determined using Cattell's "Culture-Fair Intelligence Test" (CFIT) consisting of four subtests: series, classifications, matrices and c o n d i t i o n s (topology) (31) at b a s e l i n e and 5 0 w k a f t e r treatment by a t e a m o f d i s t r i c t psychologists. T h i s t e s t is a v a i l a b l e i n t h r e e l e v e l s : scale 1, f o r a g e s 4 t o 8 y a n d m e n t a l l y r e t a r d e d a d u l t s ; s c a l e 2 ,f o r a g e s 8 t o 13a n d average a d u l t s ;a n d s c a l e 3 ,f o r g r a d e s 10t o 16a n d s u p e r i o r a d u l t s .T h e C F I T s c a l e 2, w h i c h h a s b e e n a d a p t e d t o t h e I n d o n e s i a n l a n g u a g e , w a s u s e d i nt h i s s t u d y . T h e average o f c o g n i t i v e s c o r e s c o n s i d e r i n g a s n o r m a l i s 1 0 0 ( r a n g e ,9 0 - 1 0 9 ) ( 3 1 , 3 2 ) . Anthropometric measurements. The measurements were made in duplicate (33) b y a t r a i n e d a s s i s t a n t b e f o r e a n d 5 0 w k a f t e r intervention. H e i g h t w a s measured t o t h e n e a r e s t mm u s i n g a m i c r o t o i s e , w e i g h t t o nearest 0.1 kg u s i n g a n electronic s c a l e ,a n d m i d - u p p e r a r m c i r c u m f e r e n c e (MUAC) t o t h e n e a r e s t m m u s i n g a measuring tape. Results are expressed as t h e mean and, if t w o measurements differed by 2 m m f o r height , 0 . 1 kg f o r weight and by 1 m m f o r MUAC, t h e y w e r e repeated. Anthropometri c indices were calculated using Epi Info v e r . 6.0 software and t h e d a t a w e re presented as Z-scores of weight-for-age (WAZ), height-for-age (HAZ), and weight-for-height (WHZ). These indices were compared to reference data of t h e National Center of Health Statistics (33) to j u d g e whether t h e subjects were u n d e r w e i g h t , s t u n t e d o rw a s t e d r e s p e c t i v e l y u s i n g a c u t - o f f p o i n t o f - 2S D .

Statistical m e t h o d s The K o l m o g o r o v - S m i r n o v t e s t w a s u s e d t o c h e c k t h e n o r m a l i t y of d a t a . D a t a are reported as mean and SD or SEM f o r normally distributed parameters and a s median and 25,h - 75lh percentiles for non-normally distributed parameters. Differences between two groups were examined by student's t-test for normally distributed parameters or by the Mann Whitney test for non-normally distributed parameters. When more than two groups were compared, analysis of variance (ANOVA) for normally distributed data or the Kruskal-Wallis test for non-normally distributed data, were used to test whether there were significant differences. If significant d i f f e r e n c e s were indicated, c o m p a r i s o n s among groups w e r e made w i t h the l e a s t s i g n i f i c a n t d i f f e r e n c e t e s t f o r n o r m a l l y d i s t r i b u t e d d a t a a n d t h e Bonferroni's multiple c o m p a r i s o n t e s t a t a s i g n i f i c a n t level o f P < 0 . 0 1 f o r non-normally distributed data. Correlation between continuous variables was determined by multiple regression analysis or Pearson test. The software package of Epi Info version 6

74 Iodine deficiency, stunting and cognitive performance

(CDC, Atlanta, G A ) a n d S P S S W i n d o w s v e r s i o n 7 . 5 . 2 (SPSS I n c . , C h i c a g o , I L ) w a s usedf o r a l l s t a t i s t i c a l a n a l y s e s , a n d a P v a l u e < 0 . 0 5 w a s c o n s i d e r e d s i g n i f i c a n t .

Ethical C o n s i d e r a t i o n The guidelines of the Council for International Organizations of Medical Sciences (34) were followed for ethical considerations. The ethical committee for studies on human subjects, Faculty of Medicine, University of Indonesia approved the s t u d y . Informed c o n s e n t was o b t a i n e d f r o m p a r e n t s of each s u b j e c t before t h e start o ft h e s t u d y .A tt h e e n d o ft h e s t u d y , i o d i z e d o i lw a s g i v e nt ot h o s e c h i l d r e n w h o were still iodine deficient, and iron c a p s u l e s were distributed to children who were anemic.

RESULTS Subjects c h a r a c t e r i s t i c s The mean h e i g h t , w e i g h t and mid-upper arm c i r c u m f e r e n c e (MUAC) of the school c h i l d r e n w h o p a r t i c i p a t e d in t h i s s t u d y w e r e 121.1 c m , 2 2 . 3 k g a n d 17.3 c m respectively. Overall 3 2 % of t h e children were underweight, 58% s t u n t e d and 3% wasted. A s t h e m e d i a n u r i n a r y i o d i n e c o n c e n t r a t i o n o f t h e c h i l d r e n w a s 0 . 3 6 ( x m o l / L the population was moderately iodine deficient, however the prevalence of goiter measured by ultrasonography was 35%, suggesting that the population was severely i o d i n e d e f i c i e n t (35). Based o n h e m o g l o b i n < 1 1 0 g / L , 4 0 % o f t h e c h i l d r e n were anemic. T h e r e were no significant differences in a g e , a n t h r o p o m e t r i c status, hemoglobin c o n c e n t r a t i o n (Table 1 ) a n d i o d i n e s t a t u s (Table 2 ) a t b a s e l i n e b e t w e e n placebo a n d s u p p l e m e n t e d g r o u p s .

Iodines t a t u s ,a n t h r o p o m e t r i c s t a t u s a n dc o g n i t i v e p e r f o r m a n c e The median v a l u e of c o g n i t i v e performance scores of t h e population studied was 84 (25,h-75lh percentiles; 77-95) and there was no difference between the placebo a n d s u p p l e m e n t e d g r o u p a t b a s e l i n e . A f t e r 5 0 w k s u p p l e m e n t a t i o n w i t h o r a l iodized peanut oil, t h e r e were significant increases in urinary iodine concentration and r e d u c t i o n in t h y r o i d v o l u m e int h e s u p p l e m e n t e d group c o m p a r e d t o t h e c o n t r o l group. However, t h e s e r u m T S H a n d s e r u m FT4 c o n c e n t r a t i o n s did not respond t o the t r e a t m e n t and remained in t h e normal range. C o g n i t i v e performance t e n d e d t o increase but there was no significant difference between the increase in the 75 Chapter4

supplemented group and the placebo group (Table 2). There was a significant positive correlation between thyroid volume and stunting at all different periods of measurement: b a s e l i n e ( r = 0 . 2 9 ,P < 0 . 0 1 ) ; 2 5w k ( r = 0 . 3 0 ,P < 0 . 0 1 ) a n d 5 0 w k ( r = 0 . 3 0 , P<0.01).

Table 1 . B a s e l i n ec h a r a c t e r i s t i c s o ft h es c h o o l c h i l d r e n 1 Peanut o i l Iodized p e a n u t o i l (Placebo) (n=43) (n=121) Age ( y ) 9.2910.70 9.2710.70 Males/females 15/28 61/60 Hemoglobin c o n c e n t r a t i o n (g/L) 113.0±18.1 114.4117.2 Anemia (Hb < 1 1 0 g / L ;% ) 36.4 48.4 Height ( c m ) 120.415.5 120.615.9 Weight ( k g ) 22.413.3 22.3+3.1 Mid-upper a r m c i r c u m f e r e n c e (cm) 17.211.5 17.5+1.4 Stunting, H A Z < - 2 (%) 62.8 55.4 Underweight, W A Z < - 2 (%) 30.2 29.8 Wasting, W H Z < - 2 (%) 0.0 3.4

1M e a n1 S D

Factors r e l a t e dt o c o g n i t i v e p e r f o r m a n c e Urinary iodine concentration (P<0.05), hemoglobin status (P<0.05), father's education ( P < 0 . 0 1 ) a n d s c h o o l p e r f o r m a n c e (P<0.05) w e r e a s s o c i a t e d w i t h c o g n i t i v e performance scores of the school children at baseline (Table 3). There was no significant difference in cognitive performance between boys and girls. However, multiple regression analysis between log t r a n s f o r m e d cognitive performance score at baseline and parameters which were related to cognitive performance in a univariate analysis showed that only hemoglobin concentration and father's education r e m a i n e d s i g n i f i c a n t (P<0.05) (Table4 ) . Analysis of v a r i a n c e s h o w e d t h a t change s in c o g n i t i v e performance after 50 wk of supplementation were significantly associated with urinary iodine concentration (P<0.01) , H A Z ( P < 0 . 0 1 ) a n d s c h o o l p e r f o r m a n c e (P<0.05) a t b a s e l i n e , and t h e changes in c o g n i t i v e performance were significantly different between t h e supplemented g r o u p a n d p l a c e b o g r o u p ( T a b l e 3 ) .T h e s a m e i n d e p e n d e n t v a r i a b l e s , examined using a multiple regression analysis with changes in cognitive performance over 50 wk as dependent variable, showed that urinary iodine concentration a n d H A Z a t b a s e l i n e w e r et h e o n l y s i g n i f i c a n t d e t e r m i n a n t s ( P < 0 . 0 5 ) .

76 Iodinedeficiency, stuntingand cognitive performance

Table 2 . I o d i n e s t a t u s , a n t h r o p o m e t r i c status a n d c o g n i t i v e p e r f o r m a n c e at b a s e l i n e a n d 5 0 wk a f t e r s u p p l e m e n t a t i o n a m o n g I n d o n e s i a n s c h o o l c h i l d r e n a g e d 8 - 1 0y 1

Period Peanut o i l iodized p e a n u t o i l (Placebo) (n=43) (n=121) Urinary i o d i n e Baseline 0.38 (0.26-0.63) 0.36(0.28-0.61) concentration ( u m o l / L ) 50w k 0.70(0.61-0.83) 1.46 (0.95-1.94)t Difference 0.30(0.10-0.45) 0.96 ( 0 . 5 0 - 1 . 5 0 ) t

Thyroidv o l u m e ( m L ) Baseline 4.89±1.50 5.1411.32 50w k 4.73±1.43 3.58±0.57 * Difference -0.17±0.18 -1.5711.20*

Serum t h y r o i d s t i m u l a t i n g Baseline 1.80(1.27-2.50) 1.70(1.10-2.40) hormone c o n c e n t r a t i o n 50w k 1.70(1.38-2.58) 1.80(1.30-2.70) (mU/L) Difference 0.00 ((-0.50)-0.50) 0.10((-0.34)-0.80)

Serum f r e e t h y r o x i n e Baseline 16.8±2.7 16.912.1 concentration ( p m o l / L ) 50w k 16.8±3.3 17.212.4 Difference 0.0±3.1 0.412.4

Weight f o r a g e Z - s c o r e Baseline -1.62±0.60 -1.60±0.72 50w k -1.50±0.65 -1.52+0.71 Difference 0.02±0.22 0.0010.23

Height f o r a g e Z - s c o r e Baseline -2.14±0.73 -2.12±0.88 50w k -1.87±0.76 -1.88±0.84 Difference 0.16±(-0.03) 0.14±(-0.03)

Cognitive p e r f o r m a n c e Baseline 82 ( 7 4 - 9 8 ) 84 ( 8 0 - 9 3 ) scores 50w k 88(81-103) 89(81-95) Difference 4((-13)-6) 2((-11)-8)

Values a r e e x p r e s s e d a s m e a n ± S D o r m e d i a n (25 th, 7 5 th p e r c e n t i l e s ) . Differences between groups of normally distributed data using student t-test: *, P<0.01; differences between groups of non-normally distributed data using Mann-Whitney test: t, P<0.01

77 Chapter 4

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80 Iodine deficiency, stunting and cognitive performance

DISCUSSION The results indicate t h a t iodine status and s t u n t i n g are linked t o changes in child cognitive performance after the children were supplemented with iodized o i l . Iodized oil supplementation did not increase cognitive performance in the supplemented group as a w h o l e . However subjects supplemented with iodized o i l , who were iodine d e f i c i e n t at baseline, increased t h e i r cognitive performance more thant h o s e w h ow e r e m o r e i o d i n e r e p l e t e .A p r e v i o u s s t u d y i n I n d o n e s i a s h o w e d t h a t thyroid volume and urinary iodine concentration of iodine deficient school children were significantly related to cognitive performance (36). In a placebo-controlled study in Bolivia, Bautista et al. (9), showed that decrease in goiter size was significantly associated w i t h improvement in IQ s c o r e s p a r t i c u l a r l y in g i r l s , b u t t h e r e was no difference in mental performance between supplemented and placebo groups. A study in Malawi showed that iodine supplementation increased IQ by about 10p o i n t s c o m p a r e d w i t ht h e c o n t r o l g r o u p ( 1 0 ) . The measurement of cognitive performance using Cattell' s CFIT a d a p t e d t o the Indonesian language, w a s u s e d i nt h i s g r o u p o f i o d i n e d e f i c i e n t s c h o o l c h i l d r e n . The p o p u l a t i o n s t u d i e d h a d l o w s c o r e s o f c o g n i t i v e p e r f o r m a n c e a n d s u f f e r e d f r o m a number o f n u t r i t i o n a l p r o b l e m s , i n c l u d i n g i o d i n e d e f i c i e n c y , a n e m i a a n d s t u n t i n g .W e found t h a t cognitive performance was positively correlated with baseline v a l u e s of urinary iodine concentration, hemoglobin concentration and father's education. However, multiple regression analysis indicated t h a t hemoglobin concentration and father's education, both at baseline, were the most important determinants of cognitive p e r f o r m a n c e . W e d i d n o t f i n d a p o s i t i v e c o r r e l a t i o n between t h e e d u c a t i o n of m o t h e r s a n d c o g n i t i v e p e r f o r m a n c e of s c h o o l c h i l d r e n , p r o b a b l y a s t h e m a j o r i t y o f the mothers (96%) had 6 y e a r s of education or less. T h e higher the education of father, t h e h i g h e r t h e c o g n i t i v e scores a n d t h e higher t h e educational achievement of the school children as indicated by school grades. Intelligence is a complex variable and depends on many factors (37) including stimulation from the environment, s u c h a s e d u c a t i o n l e v e l o f p a r e n t s . There is much evidence that iron deficiency anemia impairs cognitive development (23,38-40). W ef o u n d t h a t 4 0 %o ft h e s c h o o l c h i l d r e n w e r e a n e m i c a n d the cognitive scores of t h e a n e m i c children (Hb<110 g / L ) were 3 p o i n t s lower than their non-anemic counterparts. We suggest that anemia adversely affected the cognitive performance of these school children. Our findings are in line with the results of previous study in Malawi that showed iron supplementation resulted in 81 Chapter 4 improvement o f I Qb y 3 . 7 p o i n t s ( 1 0 ) . Oral iodized o i l s u p p l e m e n t a t i o n resulted in a n i m p r o v e m e n t of iodine s t a t u s as i n d i c a t e d by a n i n c r e a s e in u r i n a r y iodine c o n c e n t r a t i o n and d e c r e a s e in t h y r o i d volume. H o w e v e r , t h e i o d i n e s u p p l e m e n t a t i o n d i d n o t r e s u l t i n a l a r g e r improvement in cognitive performance scores compared to the placebo group, as the average cognitive performance score did not improve one year after treatment with oral iodized oil. Such a finding was also reported from a previous study in Spain (8) where s u p p l e m e n t a t i o n w i t h o r a l i o d i z e d o i l d i d n o t i m p r o v e m e n t a l a n d p s y c h o m o t o r performance o f c h i l d r e nf r o m a n i o d i n e d e f i c i e n t a r e a . Although t h e r e w a s n o d i f f e r e n c e b e t w e e n t h e c h a n g e s in c o g n i t i v e s c o r e s o f the iodine supplemented and placebo groups 50 wk after dosing, this is not necessarily inconsistent with previously reported effects of supplementation with iodized o i l o n c o g n i t i v e performance. Firstly, s i n c e t h e r e w a s a n inverse correlation between urinary iodine concentration at baseline and increase in cognitive score, this would suggest that iodine deficient children did benefit from iodine supplementation. In the study of Shresta et al. (10), the median urinary iodine concentration was 0 . 1 5 nmol/L c o m p a r e d w i t h 0 . 3 6 | i m o l / L in o u r s t u d y p o p u l a t i o n . Children w i t h a b a s e l i n e urinary iodine c o n c e n t r a t i o n <0.40 ^ m o l / L i n t h e i o d i z e d o i l supplemented group h a d g r e a t e r changes in c o g n i t i v e performance t h a n t h e i r more iodine r e p l e t e c o u n t e r p a r t s . S e c o n d l y , t h e s t r e n g t h o f t h e r e l a t i o n s h i p o b s e r v e d w i t h baseline iodine status as measured by urinary iodine concentration is a t t e n u a t e d . Although urinary iodine concentration is a good indicator of iodine status at the group level, it is a poor indicator at t h e individual level because of t h e large i n t r a - individual variation in urinary iodine concentration (41,42). Thirdly, the effect observed had been attenuated by e x p o s u r e of t h e population, both t h e iodized oil supplemented group and the placebo group, to iodine derived from iodized salt which h a s b e c o m e i n c r e a s i n g l y a v a i l a b l e i nt h e a r e ad u r i n g t h e s t u d y p e r i o d ( 4 3 ) . The s i g n i f i c a n t reduction in t h y r o i d volume in t h e supplemented group, w a s associated w i t h a t r e n d t o w a r d s i n c r e a s e d c o g n i t i v e p e r f o r m a n c e s c o r e s , b u t t h i s d i d not reach statistical significance (P=0.42), possibly because of the reasons mentioned above in relation to urinary iodine concentration. Changes in serum concentrations of TSH and FT4 were not correlated with changes in cognitive performance. However, this would be expected as there was no change in the serum concentration of t h e s e hormones with iodine supplementation as discussed earlier (42). Pardede et al. (36) also found no relationship between cognitive 82 Iodine deficiency, stunting and cognitive performance

performance and serum TSH concentration in a cross-sectional study of school children i n E a s tJ a v a . Stunting was a l s o f o u n d t o be r e l a t e d t o increased c o g n i t i ve performance in this study. There has been much debate about whether stunting is a harmless adaptation t o p o o r d i e t a r y intakes or h a s a f u n c t i o n a l consequence (44). A s t u d y in Jamaica found that the deficit in mental development of stunted children was attributable t o u n d e r - n u t r i t i o n (15,45) a n d a p r e v i o u s s t u d y i n I n d o n e s i a a l s o s h o w e d a positive correlation between cognitive performance and HAZ among iodine deficient school children (36). In a study of children with endemic goiter in Northeastern Sicily, Vermiglio et al. (46) showed that children with cognitive deficiency had stunted growth and delayed skeletal maturity. Stunting may not directly cause poor intellectual development in children, but the same underlying factors t h a t cause stunting such as s o c i o - e c o n o m i c status of t h e f a m i l y , may also impair c h i l d r e n ' s i n t e l l e c t u a l g r o w t h ( 4 7 ) . M o s t o f t h e c h i l d r e n i nt h i s s t u d y w e r e f r o m poor families, and their dietary intakes were below the recommended dietary intakes. In a d d i t i o n , n o r m a l l i n e a r g r o w t h is d e t e r m i n e d by v a r i a b l e c o n t r i b u t i o n s f r o m genetic, nutritional and endocrine factors and continues until bone maturation in early a d u l t h o o d . O n e o f t h e major hormones t h a t influence g r o w t h d u r i n g c h i l d h o o d is t r i i o d o t h y r o n i n e (48): b e f o r e puberty, it may be t h e major determinant for normal maturation of bone (49). Untreated hypothyroidism in children results in profound growth retardation and delayed skeletal maturation. Linear growth is almost completely h a l t e d , b u t c a n b e r e s u m e d q u i c k l y by r e p l a c e m e n t of t h y r o i d hormones to p r o d u c e a r a p i d c a t c h - u p period o f g r o w t h (50). I n t h i s s t u d y w e f o u n d a p o s i t i v e correlation b e t w e e n t h y r o i d v o l u m e a n d s t u n t i n g a t a l l p e r i o d s o f m e a s u r e m e n t . We c a n c o n c l u d e t h a t c o g n i t i v e p e r f o r m a n c e a f t e r iodized o i l s u p p l e m e n t a t i o n did i m p r o v e i nt h o s e c h i l d r e n w h o h a da t b a s e l i n e l o w u r i n a r y i o d i n e c o n c e n t r a t i o n o r who were stunted. We also can conclude that anemia at baseline and father's education d o p l a y a r o l e i nc o g n i t i v e p e r f o r m a n c e . T h i s i l l u s t r a t e s t h e r o l e o f n u t r i t i o n and s o c i a lf a c t o r s i nc o g n i t i v e d e v e l o p m e n t a n d p e r f o r m a n c e inc h i l d r e n .

83 Chapter4

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1. Bleichrodt N, Garcia I, Rubio C, Moreale de Escobar G, Escobar del Rey F. Developmental disorders associated with severe iodine deficiency. In: Hetzel BS, Dunn JT, Stanbury JB, eds. The prevention and control of iodine deficiency disorders. A m s t e r d a m , T h e Netherlands: Elsevier Science Publisher B.V., 1987:65- 84. 2. Boyages SC, Collins JK, Maberly GF, Jupp JJ, Morris J, Eastman CJ. Iodine deficiency impairs intellectual and neuromotor development in apparently-normal persons. A study of rural inhabitants of north-central China. Med J A u s t 1989;1 5 0 : 676-82. 3. Ma T , W a n g Y Y , Wang D, Chen Z P , Chi SP. Neuropsychological studies in iodine deficiency areas in C h i n a . In: Delong G R , Robbins J , C o n d l i f f e PG, e d s . Iodine a n d the b r a i n . N e wY o r k : P l e n u m P r e s s , 1 9 8 9 : 2 5 9 - 6 8 . 4. Tiwari B D , G o d b o l e M M , C h a t t o p a d h y a y N, M a n d a l A , M i t h a l A . L e a r n i n g d i s a b i l i t i e s and p o o r motivation t o a c h i e v e d u e t o p r o l o n g ed iodine d e f i c i e n c y . Am J C l i n Nutr 1996;63:782-6. 5. Muzzo S, Leiva L, Carrasco D. Influence of a moderate iodine deficiency upon intellectual c o e f f i c i e n t of s c h o o l - a g e c h i l d r e n . I n : M e d e i r o s N G , M a c i e l R M B , H a l p e r n A, e d s . I o d i n e d e f i c i e n c y d i s o r d e r s a n d c o n g e n i t a l h y p o t h y r o i d s m . S a o P a u l o :A C H E , 1986:40-5. 6. Cao XY, Jiang XM, Dou ZH, et al. Timing of vulnerability of the brain to iodine deficiency in e n d e m i c c r e t i n i s m . NE n g lJ M e d 1 9 9 4 ; 3 3 1 : 1 7 3 9 - 4 4 . 7. Dodge PR, Palkes H, Fierro BR, Ramirez I. Effect on intelligence of iodine in oil administered to young A n d e a n children - a p r e l i m i n a r y report. In: Stanbury JB, e d . Endemic g o i t e r . W a s h i n g t o n , D . C . : P a nA m e r i c a n H e a l t h O r g a n i z a t i o n , 1 9 6 9 : 3 7 8 - 8 0 . 8. Bleichrodt N, Escobar del Rey F, Moreale de Escobar G, Garcia I, Rubio C. Iodine deficiency, implications for mental and psychomotor in children. In: Delong GR, Robbins J , C o n d l i f f e PG, e d s . Iodine and the brain. New Y o r k : Plenum Publishing Corporation, 1 9 8 9 : 2 6 9 - 8 6 . 9. Bautista A , Barker PA, Dunn J T , S a n c h e z M, Kaiser D L The e f f e c t s of o r a l iodized oil o n i n t e l l i g e n c e , t h y r o i d s t a t u s , a n d s o m a t i c growth in s c h o o l - a g e c h i l d r e n f r o m a n area o f e n d e m i c g o i t e r . Am J C l i n N u t r 1 9 8 2 ; 3 5 : 1 2 7 - 3 4 . 10. Shresta RM, West CE, Bleichrodt N, van de Vijver FJR, Hautvast JGAJ. Supplementation with iodine and iron improves mental development in Malawian children. Submitted f o r p u b l i c a t i o n . 11. Untoro J , S c h u l t i n k W, West CE, G r o s s R, Hautvast JGAJ. Efficacy of oral iodized peanut oil is greater than that of iodized poppyseed oil among Indonesian school children. Submitted f o r p u b l i c a t i o n . 12. Eltom M, Karlsson FA, Kamal A M , Bostrom H, Dahlberg PA. The effectiveness of oral i o d i z e d o i l i n t h e t r e a t m e n t a nd p r o p h y l a x i s of e n d e m i c g o i t e r . J C l i n Endocrinol Metab 1 9 8 5 ; 6 1 : 1 1 1 2 - 7 . 13. Benmiloud M, Chaouki ML, Gutekunst R, Teichert HM, W o o d WG, Dunn JT. Oral iodized oil for correcting iodine deficiency: optimal dosing and outcome indicator selection. J C l i n E n d o c r i n o l M e t a b 1 9 9 4 ; 7 9 : 2 0 - 4 . 14. Scrimshaw N S . E f f e c t s o f i r o n d e f i c i e n c y a n d p r o t e i n - c a l o r i e m a l n u t r i t i o n o n c o g n i t i v e behavior and neurological function. In: Stanbury JB, ed. The Damaged Brain of Iodine D e f i c i e n c y . NewY o r k : C o g n i z a n t C o m m u n i c a t i o n C o r p o r a t i o n , 1 9 9 3 : 5 9 - 6 5 . 15. Grantham MS, Powell C, Fletcher P. Stunting, severe malnutrition and mental development i n y o u n g c h i l d r e n . E u r J C l i n N u t r 1 9 8 9 ; 4 3 : 4 0 3 - 9 . 84 Iodine deficiency, stunting andcognitive performance

16. Grantham MS, Powell C, Walker S. Nutritional supplements, stunting, and child development [ l e t t e r ] . L a n c e t 1 9 8 9 ; 2 : 8 0 9 - 1 0 . 17. Husaini MA, Jahari AB, Pollitt E. The effects of high energy and micronutrient supplementation on iron status in nutritionally at risk infants. Biomed Environ Sci 1996;9:325-40. 18. Pollitt E, G o r m a n KS, E n g l e P L , M a r t o r e l l R, R i v e r a J . E a r l y s u p p l e m e n t a r y feeding and c o g n i t i o n : e f f e c t s o v e r t w o d e c a d e s . Monogr S o c R e s C h i l d D e v 1 9 9 3 ; 5 8 : 1 - 9 9 . 19. Powell C, Grantham MS. The associations between nutritional status, school achievement and school attendance in twelve-year-old children at a Jamaican school. West I n d i a n M e d J 1 9 8 0 ; 2 9 : 2 4 7 - 5 3 . 20. Simeon D, Grantham MS. C o g n i t i v e function, undernutrition, and missed breakfast [letter]. Lancet 1 9 8 7 ; 2 : 7 3 7 - 8 . 21. Pollitt E, Hathirat P, Kotchabhakdi NJ, Missell L, Valyasevi A. Iron deficiency and educational a c h i e v e m e n t i nT h a i l a n d . Am J C l i n N u t r 1 9 8 9 ; 5 0 : 6 8 7 - 9 6 . 22. Pollitt E, S o e m a n t r i A G , Y u n i s F, S c r i m s h a w NS. C o g n i t i v e e f f e c t s of iron-deficiency anaemia [ l e t t e r ] . Lancet 1 9 8 5 ; 1 : 1 5 8 . 23. Idjradinata, P. and Pollitt, E. Reversal of developmental delays in iron-deficient anaemic i n f a n t s t r e a t e d w i t h i r o n . L a n c e t 1993; 341:1-4. 24. Ministry of Health Rl and Tim GAKI Undip. Endemic goiter map of Central Java, Indonesia. 1996.S e m a r a n g , I n d o n e s i a , U n i v e r s i t a s D i p o n e g o r o . 25. Furnee CA, W e s t CE, v a n der Haar F, Hautvast JGAJ. Effect of intestinal parasite treatment on the efficacy of oral iodized oil for correcting iodine deficiency in schoolchildren. Am J C l i n N u t r 1 9 9 7 ; 6 6 : 1 4 2 2 - 7. 26. Pegolow K, Gross R, Pietrzik K, Lukito W, Richards AL, Fryauff DJ. Parasitological and nutritional situation of school children in the Sukaraja district, West Java, Indonesia. Southeast A s i a n J T r o p M e d P u b l i c H e a l t h 1 9 9 7 ; 2 8 : 1 7 3 - 9 0 . 27. Delange F, B e n k e r G , C a r o n P, e t a l . T h y r o i d v o l u m e a n d u r i n a r y i o d i n e i n E u r o p e a n schoolchildren: s t a n d a r d i z a t i o n of v a l u e s f o r a s s e s s m e n t of i o d i n e d e f i c i e n c y . Eur J Endocrinol 1 9 9 7 ; 1 3 6 : 1 8 0 - 7 . 28. WHO, I C C I D D . R e c o m m e n d e d normative v a l u e s f o r t h y r o i d v o l u m e i n c h i l d r e n a g e d 6-15 y e a r s . BullW o r l d H e a l t h O r g a n 1 9 9 7 ; 7 5 : 9 5 - 7 . 29. Hudson-Thomas M, B i n g h a m KC, S i m m o n s W K . A n e v a l u a t i o n of t h e Hemocue f o r measuring haemoglobin in field studies in Jamaica. Bull World Health Organ 1994;72:423-6. 30. Dunn JT, Crutchfield HE, Gutekunst R, Dunn AD. Two simple methods for measuring i o d i n e i n u r i n e . Thyroid 1 9 9 3 ; 3 : 1 1 9 - 2 3 . 31. IPAT. Measuring intelligence with the culture fair test. 3 ed. Champaign, IL: The Institute f o r P e r s o n a l i t y a n dA b i l i t y T e s t i n g , 1 9 7 3 . 32. Cronbach L J . E s s e n t i a l o f p s y c h o l o g i c a l t e s t i n g . N e w Y o r k : H a r p e r C o l l i n s Publisher, 1990. 33. WHO. M e a s u r i n g c h a n g e i n n u t r i t i o n a l s t a t u s : g u i d e l i n e s f o r a s s e s s i n g t h e n u t r i t i o n a l impacts of supplementary feeding programs for vulnerable groups. Geneva, Switzerland: W o r l d H e a l t h O r g a n i z a t i o n , 1 9 8 3 . 34. CIOMS. International Guidelines for Ethical Review of Epidemiological Studies. Geneva, Switzerland: Council f o r International Organizations for Medical Sciences, 1991. 35. WHO/UNICEF/ICCIDD. I n d i c a t o r s f o r a s s e s s i n g i o d i n e d e f i c i e n c y d i s o r d e r s a n d t h e i r control p r o g r a m s . G e n e v a : W H O , 1 9 9 4 .

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36. Pardede L V H , H a r d j o w a s i t o W, G r o s s R, e t a l . Urinary iodine excretion is t h e most appropriate o u t c o m e i n d i c a t o r f o r iodine d e f i c i e n c y a t f i e l d c o n d i t i o n s a t d i s t r i c t l e v e l . J N u t r 1 9 9 8 ; 1 2 8 : 1 1 2 2 - 6 . 37. Connolly KJ, Pharoah PO. Subclinical effects of iodine deficiency: problems of assessment. I n : S t a n b u r y J B , e d .T h e d a m a g e d b r a i n o f i o d i n e d e f i c i e n c y . N e w Y o r k : Cognizant C o m m u n i c a t i o n C o r p o r a t i o n , 1 9 9 3 : 2 7 - 3 5 . 38. Pollitt E . I r o n d e f i c i e n c y a n d c o g n i t i v e f u n c t i o n . Annu R e v N u t r 1 9 9 3 ; 1 3 : 5 2 1 - 3 7 . 39. Soewondo S, H u s a i n i M , P o l l i t t E. E f f e c t s of i r o n d e f i c i e n c y on a t t e n t i o n a n d l e a r n i n g processes in p r e s c h o o l c h i l d r e n : B a n d u n g , I n d o n e s i a . Am J C l i n N u t r 1989;50:667- 73. 40. Pollitt E, S a c o P C , L e i b e l RL, V i t e r i FE. I r o n d e f i c i e n c y and b e h a v i o r a l development in i n f a n t s a n d p r e s c h o o l c h i l d r e n . Am J C l i n N u t r 1 9 8 6 ; 4 3 : 5 5 5 - 6 5 . 41. Furnee CA, v a n der Haar F, W e s t CE, H a u t v a s t J G A J . A c r i t i c a l a p p r a i s a l of goiter assessment a n d t h e r a t i o o f u r i n a r y i o d i n e t o c r e a t i n i n e f o r e v a l u a t i n g i o d i n e s t a t u s . Am J C l i n N u t r 1 9 9 4 ; 5 9 : 1 4 1 5 - 7 . 42. Untoro J , W e s t C E , S c h u l t i n k W , G r o s s R, H a u t v a s t J G A J . C o m p a r i s o n o f i n d i c a t o r s to assess iodine status and its improvement through supplementation with iodized oil. Submittedf o r p u b l i c a t i o n . 43. Untoro J , W e s t C E , S c h u l t i n k W, G r o s s R, Hautvast J G A J . I m p a c t of s a l t iodization on i o d i n e s t a t u s of Indonesian school c h i l d r e n living i n a m o d e r a t e l y iodine deficient area. Submitted f o r p u b l i c a t i o n . 44. Waterlow JC. What do we mean by adaptation? In: Blaxter K, Waterlow JC, e d s. Nutritional a d a p t a t i o n i n m a n . L o n d o n :J o h n L i b b e y , 1 9 8 5 : 1 - 1 2 . 45. Grantham MS, Powell CA, Walker SP, Himes JH. Nutritional supplementation, psychosocial s t i m u l a t i o n , a n d m e n t a l d e v e l o p m e n t of s t u n t e d c h i l d r e n : t h e J a m a i c a n Study. Lancet 1 9 9 1 ; 3 3 8 : 1 - 5 . 46. Vermiglio F, Sidoti M, Finocchiaro MD, et al. Defective neuromotor and cognitive ability in i o d i n e - d e f i c i e n t schoolchildren of an e n d e m i c goiter region i n S i c i l y . J C l i n Endocrinol M e t a b 1 9 9 0 ; 7 0 : 3 7 9 - 8 4 . 47. UNICEF. T h e s t a t e o f t h e w o r l d ' s c h i l d r e n 1998. New Y o r k : O x f o r d U n i v e r s i t y P r e s s , 1998. 48. Williams G R , R o b s o n H , S h a l e t S M . T h y r o i d h o r m o n e a c t i o n s o n c a r t i l a g e a n d b o n e : interactions w i t h o t h e r h o r m o n e s a t t h e e p i p h y s e a l p l a t e a n d e f f e c t s o n l i n e a r g r o w t h . J E n d o c r i n o l 1 9 9 8 ; 1 5 7 : 3 9 1 - 4 0 3. 49. Underwood L E ,V a n W y k J J . N o r m a l a n d a b e r r a n t g r o w t h . I n : W i l s o n J D , F o s t e r D W , eds. Williams Textbook of Endocrinology. Philadelphia, PA: W.B. Saunders Company, 1 9 9 2 : 1 0 7 9 - 1 3 8 . 50. Boersma B , W i t J M . C a t c h - u p g r o w t h . Endocr Rev 1 9 9 7 ;1 8 : 6 4 6 - 6 1 .

86 Chapter 5

Impacto fs a l ti o d i z a t i o n o ni o d i n e s t a t u so f Indonesian s c h o o lc h i l d r e n l i v i n gi n a m o d e r a t e l y i o d i n e d e f i c i e n t a r e a

Juliawati Untoro, Clive E West, Werner Schultink, Rainer Gross, Joseph G.A.J. Hautvast Chapters

ABSTRACT Objective: To evaluate the impact of the Indonesian salt iodization program on iodine status of school children living in an endemic iodine deficient area, as indicated by urinary iodine concentration, goiter size measured by palpation and ultrasound, s e r u m t h y r o i d s t i m u l a t i n g hormone (TSH) c o n c e n t r a t i o n and s e r u m f r e e thyroxine (FT 4) c o n c e n t r a t i o n . Design: A l o n g i t u d i n a l p r o s p e c t i v e c o h o r t s t u d y a m o n g I n d o n e s i a n s c h o o lc h i l d r e n . Setting: S u b j e c t s l i v i n g i na n e n d e m i c i o d i n e d e f i c i e n t a r e aw e r e e n r o l l e d v o l u n t a r i l y . Subjects: Fifty one apparently healthy school children aged 8-10 y in an iodine deficient a r e a i nC e n t r a l J a v a , I n d o n e s i a , w e r er e c r u i t e d . Methods: T h y r o i d size measured by p a l p a t i o n and ultrasonography, urinary iodine concentration, s e r u m T S H a n d s e r u m FT4 c o n c e n t r a t i o n s were measured on t h r e e occasions a t 0 , 2 5a n d 5 0w k . Att h e s a m et i m e p e r i o d s , s u b j e c t s w e r e r e q u e s t e d t o bring s a l t s a m p l e s t h a t w e r e u s e d a tt h e i r h o m e s . Results: After one year of introduction on salt iodization, the proportion of household u s e d a d e q u a t e l y i o d i z e d s a l t i n c r e a s e d s i g n i f i c a n t l y , f r o m 2 %t o 5 4 % ,b u t there was inconsistency in using iodized salt within households during the study period. Median urinary iodine concentration of population studied improved from 0.38 n m o l / Lt o 0 . 7 0 ( i m o l / L , b u tt h i s l e v e l i ss t i l l b e l o w 0 . 7 9 n m o l / Lw h i c h i s r e g a r d e d as a d e q u a t e i o d i n e s t a t u s . I o d i n e s t a t u s a s i n d i c a t e d b y u r i n a r y i o d i n e c o n c e n t r a t i o n and t h y r o i d v o l u m e , o f c h i l d r e n w h o c o n s u m e d iodized s a l t w a s s i g n i f i c a n t l y higher than those consumed non-iodized salt. However, the prevalence of goiter, concentrations o f s e r u m F T 4and s e r u m T S H o f c h i l d r e n c o n s u m i n g i o d i z e d s a l t w e r e not s i g n i f i c a n t l y d i f f e r e n t t h a nt h o s e w h o c o n s u m e d n o n - i o d i z e d s a l t . Conclusions: The impact of legislation requiring iodized salt for the Indonesian population is n o t s u c c e s s f u l a l t h o u g h s i g n i f i c a n t progress has been m a d e in r e c e n t years. Consequently, iodine deficiency is still a serious public health problem in Indonesiaa n d i n c r e a s e d e f f o r t is n e e d e dt o e r a d i c a t e i o d i n e d e f i c i e n c y .

88 Salt iodization and iodine status

INTRODUCTION The cause of iodine deficiency is mainly geological rather than social and economic. Iodine d e f i c i e n c y c a n n o t b e e l i m i n a t e d by c h a n g i n g d i e t a r y h a b i t s n o r b y eating specific kinds of f o o d s grown in t h e same a r e a . T h e r e f o r e , correction of t h e deficiency h a s t o b e a c h i e v e d b y s u p p l y i n g i o d i n e f r o m a n e x t e r n a l s o u r c e .T h i s c a n be done in a number of ways including periodic supplementation of deficient populations w i t h i o d i z e d o i l c a p s u l e s o r o t h e r p r e p a r a t i o n s , o r b yf o r t i f y i n g f o o d s w i t h iodine. The food most commonly chosen is salt. The iodization of salt is the approach m o s t c o m m o n l y proposed i n o r d e r t o p r o v i d e a l o n g t e r m a n d s u s t a i n a b l e solution a s i t i s e x p e c t e d t h a t t h i s w i l l e n a b l e i o d i n et o r e a c h t h e e n t i r e p o p u l a t i o n( 1 - 3). A major international e f f o r t t o implement t h e p r o c e s s has b e g u n . F o r t i f i c a t i o n o f salt has been s u c c e s s f u l in e l i m i n a t i n g iodine d e f i c i e n c i e s in m a n y countries (4). I t was e s t i m a t e d t h a t n e a r l y 6 0 p e r c e n t o f e d i b l e s a l t in t h e w o r l d is n o w i o d i z e d , a n d among t h o s e c o u n t r i e s int h e w o r l d w i t h a r e c o g n i z e d i o d i n e d e f i c i e n c y p r o b l e m ,t h e majority has passed appropriate legislation to ensure universal salt iodization (4). However, data on the effectiveness of iodized salt for controlling iodine deficient population i ss t i l l s c a n t y .

Indonesia has had a law m a n d a t i n g t h e f o r t i f i c a t i o n of s a l t w i t h iodate (KI0 3) since 1994: t h e minimum level of f o r t i f i c a t i o n has been s e t at 3 0 mg l / k g . A r e c e nt study showed that about one half of the salt in the market in Indonesia was adequately i o d i z e d ( 5 ) .S a l t i s i o d i z e d i n m o r et h a n 3 0 0 p r o c e s s i n g p l a n t s d i s t r i b u t e d over 24 provinces in the country, many of these are small and do not operate continuously (6),w h i c h m i g h t e n d a n g e r a s u s t a i n a b l e p r o g r a m o f s a l t i o d i z a t i o n . Considering a w i d e variation in s a l t iodine content at t h e national level, t h i s study examines the impact of the introduction of salt iodization program on the iodine status of school children living in an iodine deficient area, as indicated by urinary iodine concentration, thyroid size measured by palpation and ultrasound, serum thyroid stimulating hormone (TSH) and serum free thyroxine (FTJ concentrations.

SUBJECTS A N D M E T H O D S Subjects Subjects (n=51) were randomly selected from school children aged 8-10 years attending four primary schools in Cilacap district, Central Java Province, 89 Chapters

Indonesia, w h e r e g o i t e r is h i g h l y prevalent (total g o i t e r rate >30%) (7). A l l s e l e c t e d subjects w e r e e x a m i n e d by a m e d i c a l a s s i s t a n t f r o m t h e S u b - d i s t r i c t Health C e n t e r , and o n l y a p p a r e n t l y h e a l t h y s u b j e c t s w e r e c o n s i d e r e d f o r e n t r y i n t ot h e s t u d y .

Study d e s i g n This s t u d y w a s d e s i g n e d a s a l o n g i t u d i n a l s t u d y as p a r t of a l a r g e r s t u d y o n the e f f i c a c y of i o d i z e d o i l ( 8 ) .A s a m p l e s i z e o f a t l e a s t 4 9 , w a s c a l c u l a t e d b a s e d o n the possibility to estimate the prevalence of adequately iodized salt with a confidence level of 9 0 % a n d a C I w i d t h of 10% u s i n g a d e s i g n effect of 2 a n d an assumption t h a t t h e prevalence w o u l d be a b o u t 10%. A t o t a l of 51 school children participated v o l u n t a r i l y in t h i s s t u d y . Each o f t h e m w a s a s k e d t o s u b m i t s a m p l e s o f salt t h a t w e r e used in t h e i r home a t t h r e e o c c a s i o n s , i.e.: 0, 2 5 a n d 5 0 w k . Urinary iodine c o n c e n t r a t i o n ,t h y r o i d s i z e m e a s u r e d b y p a l p a t i o n a n d u l t r a s o u n d ,s e r u mT S H and FT4 concentrations were determined at the same period of salt samples collection. A n t h r o p o m e t r i c p a r a m e t e rs w e r e m e a s u r e d a sd e s c r i b e d p r e v i o u s l y ( 9 ) .

Methods Measurementof thyroidsize. T h y r o i d s i z e w a s m e a s u r e d by p a l p a t i o n a n d ultrasound (10). P a l p a t i o n o f t h e t h y r o i d w a s p e r f o r m e d b y o n e t r a i n e d experienced medical o f f i c e r a t t h e S u b - d i s t r i c t H e a l t h C e n t e r a t 0 , 2 5 a n d 5 0 w k . M e a s u r e m e n t o f thyroid volume using ultrasound was carried out at t h e same t i m e as palpation by the main r e s e a r c h e r (JU) who had been t r a i n e d in t h e t e c h n i q u e . Ultrasonography was p e r f o r m e d o n e a c h s u b j e c t i nt h e s i t t i n g p o s i t i o n . F i r s t , t h e t r a n s d u c e r w a s k e p t horizontal a t a n u p r i g h t a n g l e t o t h e n e c k t o o b s e r v e t h e c r o s s s e c t i o n o f t h et h y r o i d , measuring maximal width (w) and maximal depth (d). Next, t h e length (I) of each lobe w as determined by longitudinal application of the transducer to the subject's neck. A c o - w o r k e r recorded t h e o b s e r v a t i o n s of t h e u l t r a s o n o g r a p h y and p r o v i d e d a continuous flow of persons t o be e x a m i n e d . T h e v o l u m e was calculated using t h e following f o r m u l a :V ( c m 3) = 0 . 4 7 9 x d x w x I ( 1 1 ) .T h et h y r o i d v o l u m e w a s t h e s u mo f the volumes of both lobes. Result of ultrasonography from the study population were c o m p a r e d t o n o r m a t i v e d a t af r o m p o p u l a t i o n s w i t h s u f f i c i e n t i o d i n e i n t a k e ( 1 2 ) .

Serumconcentrations of TSHand FT 4. Venous b l o o d s a m p l e s (3 m l _ ) w e r e drawn f r o m a n a n t e c u b i c a l v e i n f r o m n o n - f a s t i n g s u b j e c t s between 0 8 . 3 0 a n d 12.00 using EDTA as anticoagulant. The blood was placed on ice, protected from light, and w i t h i n 2-3 h c e n t r i f u g e d at t h e laboratory of t h e district health center t o obtain 90 Salt iodization and iodine status serum. Serum was frozen in a series of containers at -70 °C before being transferred, p a c k e d i nd r y i c e ,t o t h e l a b o r a t o r y o f E n d o c r i n o l o g y , A c a d e m i c M e d i c a l Center ( A m s t e r d a m,t h e N e t h e r l a n d s ) f o r a n a l y s i s . The method used for measuring blood levels of the TSH was immunoluminometric a s s a y techniques using a c o m m e r c i a l k i t ( B r a h m s Diagnostica

Gmbh, Berlin, Germany) and FT4 was measured by time-resolved fluoro immunoassay after immuno-extraction u s i n g a c o m m e r c i a l kit (Delfia™, W a l l a c Oy, Turku, Finland). T h e coefficient of v a r i a t i o n of intra-assay and inter-assay for TSH were 2.4% and 4.5% respectively, and f o r FT4 w e r e 3.6% and 6.4% respectively.

Values f o r b o t hT S H a n d F T 4o b t a i n e d ,w e r ew i t h i n 1 0 % o ft h et a r g e t v a l u e o f n o r m a l and elevated samples provided every two months by t h e Dutch national external quality control scheme for hormones in s e r u m (LWBA). Reference range of iodine replete s u b j e c t s f o r s e r u m T S H i s0 . 4 - 4 . 0 m U / La n df o r F T 4 i s9 - 2 4 p m o l / L ( 1 3 ) . Urinaryiodine concentration.A c a s u a l u r i n e s a m p l e (5 mL) w a s collected between 0 8 . 0 0 h a n d 12.00 h o n 2 c o n s e c u t i v e days at 0, 25 a n d 5 0 wk of study. The u r i n e s a m p l e s , p r e s e r v e d w i t h a p p r o x i m a t e l y 1g t h y m o l , w e r e s e n t t o t h e i o d i n e laboratory of the Nutritional Research and Development Center in Bogor (Indonesia). I o d i n e c o n c e n t r a t i o n in u r i n e w a s a n a l y z e d , b a s e d o n a l k a l i n e d i g e s t i o n using the Sandell-Kolthoff reaction (14), for duplicate and the average calculated from e a c h c h i l d . Semi-quantitative saltiodine spot test. Children w e r e r e q u e s t e d t o b r i n g t o school s a m p l e s o f s a l t u s e d a t t h e i r h o m e s a t 0 , 2 5 a n d 5 0 w k . T o l i m i t a n y p o s s i b l e exchange o f s a m p l e s , e a c h c h i l d w a s g i v e n a s e a l e d p l a s t i c c o n t a i n e r w i t h h i s n a m e on it. A commercial spot test kit (Biofarma, Indonesia) was used f o r detecting the levels of potassium iodate (KI03) in salt samples. The test gave approximate concentration of t h e i o d i n e c o n t e n t in s a l t . U s i n g a c o l o r c h a r t , t h e i o d i n e l e v e l s in a salt s a m p l e w e r e e s t i m a t e d ( 3 ) .

Statistical m e t h o d s The normality of d a t a w a s t e s t e d by t h e Kolmogorov-Smirnov t e s t . Data a r e reported as mean and SD f o r normally distributed parameters and a s median and 25th - 75th percentile for non-normally distributed parameters. Differences among groups were examined by analysis of variance (ANOVA) for normally distributed parameters or by the Kruskal-Wallis for non-normally distributed parameters. If significant differences were indicated, c o m p a r i s o n s among g r o u p s w e r e made w i th 91 Chapter 5 the l e a s t s i g n i f i c a n t d i f f e r e n c e t e s t f o r n o r m a l l y d i s t r i b u t e d d a t a a n d t h e Bonferroni's multiple c o m p a r i s o n t e s t a t a s i g n i f i c a n t level o f P < 0 . 0 1 f o r n o n - n o r m a l l y distributed data. Correlation between continuous normally distributed variables was analyzed using Pearson test and for non-normally distributed variables by Spearman rank test. T h e s o f t w a r e package of SPSS (Windows v e r s i o n 7.5.2, SPSS Inc., C h i c a g o , IL) was used for all statistical analyses and a P value<0.05 was considered significant.

Ethical C o n s i d e r a t i o n s The guidelines of the Council for International Organizations of Medical Sciences (15) were f o l l o w e d for ethical considerations. T h e Ethical Committee for Studies on H u m a n S u b j e c t s , Faculty of Medicine, U n i v e r s i t y of Indonesia a p p r o v e d the s t u d y . Informed c o n s e n t was o b t a i n e d f r o m parents of each s u b j e c t before t h e start o ft h e s t u d y .

RESULTS Subjects c h a r a c t e r i s t i c s The s u b j e c t s of t h i s s t u d y w e r e 2 0 b o y s a n d 3 1 g i r l s w i t h a n a v e r a g e a g e o f 9.4±0.7 y, and t h e mean weight and height were 22.5±3.3 kg and 120.8±5.8 cm respectively. Overall 31.4% of the children were underweight (weight for age Z- score<-2 S D ) , 5 8 . 8 % s t u n t e d (height f o r a g e Z - s c o r e < - 2 SD) a n d n o n e w a s w a s t e d (weight f o r h e i g h t Z-score<-2 S D ) .

Iodized s a l t i nt h e h o u s e h o l d s The proportion of adequately iodized salt increased significantly during one year of study (P<0.001). A t the beginning of the study, about two years after salt legislation was promulgated, 2 % of t h e samples were adequately iodized at more than 30 mg l/kg a n d 34% w e r e not iodized at a l l . O n e year after the start of the study, 54% o f t h e collected salt samples were adequately iodized and 11% o f the samples were not iodized (Table 1). However, inconsistency in using iodized salt was found within the households (Table 2). None of the subjects submitted adequately iodized salt at all three sampling periods during the study; only 14% twice submitted adequately iodized salt; and 35% of subjects never submitted adequately i o d i z e d s a l t . 92 Saltiodization and iodine status

Table 1 . N u m b e r o f h o u s e h o l ds a l t s a m p l e sa t0 ,2 5a n d5 0w kc o n t a i n i n g d i f f e r e n t l e v e l so f iodineb r o u g h tt os c h o o lb y5 1c h i l d r e ni nC i l a c a p ,C e n t r a lJ a v a ,I n d o n e s i a 1

Time o f s a l t c o l l e c t i o n (wk) 0 25 50 Salt n o t i o d i z e d 18(35%) 9(18%) 5 (10% ) (0 m gl / k g ) Salt n o t a d e q u a t e l y iodized 32 ( 6 3 % ) 23 ( 4 6 % ) 18(36%) (<30 m g l / k g ) Salt n o t i o d i z e d 1 ( 2 % ) 18(36%) 27 ( 5 4 % ) (>30 m g l / k g ) Total 51 50 50

Spearmanr a n kt e s t ,P < 0 . 0 0 1 ,

Iodine i n d i c a t o r s a n dt y p e o f s a l t u s e d i nt h e h o u s e h o l d s The p r e v a l e n c e of g o i t e r measured by p a l p a t i o n remained at 17% a t 5 0 w k . However, t h e p r e v a l e n c e o f g o i t e r m e a s u r e d b y u l t r a s o u n d w a s s i g n i f i c a n t l y r e d u c e d to 14% a t 25 wk and 50 w k . Urinary iodine concentration of children studied was

significantly increased at 25 wk, but serum TSH and serum FT4 concentrations remained i nt h e n o r m a l r a n g e ( T a b l e3 ) . Children w h o b r o u g h t s a l t w h i c h w a s a d e q u a t e l y iodized, h a d a b e t t e r iodine status t h a n c h i l d r e n w h o b r o u g h t i n a d e q u a t e l y i o d i z e d s a l t ( P < 0 . 0 0 1 ) .T h e h i g h e r t h e concentration of i o d i n e in t h e s a l t t h e h i g h e r t h e u r i n a r y iodine c o n c e n t r a t i o n (Table 4). A n a l y s i s o f v a r i a n c e s h o w e d t h a t c h i l d r e n w h o c o n s u m e d a d e q u a t e l y iodized s a l t had s m a l l er thyroid volumes (P<0.05) than those who consumed non-iodized salt.

However, s e r u m FT4 a n d T S H c o n c e n t r a t i o n s of s c h o o l c h i l d r e n consuming iodized salt w e r e not s i g n i f i c a n t l y different to t h o s e who consumed non-iodized salt (Table 3).

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94 Saltiodization andiodine status

Table 3. Parameters of iodine status at 0 , 2 5 a n d 5 0 w k in s c h o o l children in C i l a c a p , Central J a v a , I n d o n e s i a 1.

Time o fs a l t c o l l e c t i o n (wk) 0 25 50 (n=51) (n=50) (n=50) Thyroid v o l u m e ( m L ) 4.68±1.51 4.48± 1 . 4 3 4.54±1.45

Prevalence o fg o i t e r( % ) Palpation 17.7 16.7 16.7 Ultrasound 26.0 a 14.3b 14.3b

Urinary i o d i n e 0.38 (0.24-0.64) 0.67(0.50-1.02)" 0.70 (0.61-0.83) d concentration ( u m o l / L )

Serum t h y r o i d s t i m u l a t i n g 1.70( 1 . 2 0 - 2 . 3 0 ) 1.60( 0 . 9 6 - 2 . 2 0 ) 1.60( 1 . 1 8 - 2 . 3 0 ) hormone c o n c e n t r a t i o n (mU/L)

Serum f r e e t h y r o x i n e 16.74±2.66 17.3213.08 16.74±3.05 concentration ( p m o l / L )

1V a l u e s a r ep r e s e n t e d a sm e a n ± S Do rm e d i a n ( 2 5 th- 7 5 ,h p e r c e n t i l e ) . Correlation between non n o r m a l l y distributed variables were examined using Spearman rank t e s t : v a l u e s w i t h d i f f e r e n t superscripts letters (a,b )a r es i g n i f i c a n t l y d i f f e r e n t f r o mo n e another (P<0.05). Differences among > 2g r o u p s w e r e examined using Kruskal-Wallis test when n o tn o r m a l l y d i s t r i b u t e d a n d i fs i g n i f i c a n t (P<0.05) w e r e t e s t e d u s i n g B o n f e r r o n i ' s p o s t - hoc multiple comparisons test: v a l u e s of e a c h parameter with different superscripts letters (c,d )a r e s i g n i f i c a n t l y d i f f e r e n t f r o m o n e a n o t h e r (P<0.01).

DISCUSSION This study indicates that salt iodization was significantly associated with improvement of urinary iodine status in Indonesian school children living in an endemic iodine deficient area. In rural areas of many developing countries, where iodine d e f i c i e n c y is m o s t s e v e r e , p o p u l a t i o n s are largely d e p e n d e n t o n s u b s i s t e n c e foods. Their diet is typically based on one or two cereals, tubers or pulses. If households have l i v e s t o c k , s o m e d a i r y p r o d u c t s a r e a l s o c o n s u m e d . T h e r e f o r e , t h e only way f o r such people t o obtain iodine is f r o m outside sources suc h as iodized salt o r i o d i z e d o i l s u p p l e m e n t s .

95 Chapters

Table 4 . Relationships between parameters of iodine status in s c h o o l children in C i l a c a p , Central Java, Indonesia and iodine content of salt samples which were pooled from three periods o f c o l l e c t i o n ( 0 ,2 5 , 5 0w k ) 1.

Iodine c o n t e n t i n s a l t ( m g / k g ) 0 <30 >30 (n=32) (n=73) (n=46) Thyroid v o l u m e (mL) 4.89±1.32a 4.65+1.55 a 4.21+1.35 b

Urinary i o d i n e 0.40 (0.27-0.69) 0.60 ( 0 . 3 7 - 0 . 7 7 ) c 0.71 ( 0 . 6 0 - 0 . 8 5 ) d concentration ( u m o l / L )

Serumthyroid 1.70(1.30-2.30) 1.60(1.00-2.00) 1.70(1.10-2.50) stimulating h o r m o n e concentration (mU/L)

Serum f r e e t h y r o x i n e 17.84+6.07 17.0812.96 16.97+2.76 concentration (pmol/L)

1V a l u e s a r e p r e s e n t e d a s m e a n t S Do r m e d i a n ( 2 5 ,h- 7 5 th p e r c e n t i l e ) . Differences among >2 g r o u p s w e r e e x a m i n e d using A N O V A t e s t w h e n n o r m a l l y distributed and if s i g n i f i c a n t, were tested using least significant differences multiple comparisons test: values of each parameter with d i f f e r e n t superscripts letters (a, b) are s i g n i f i c a n t l y different from one another (P<0.05). Differences among >2 groups were examined using Kruskal- Wallis test when not normally distributed and if significant were tested using Bonferroni's post-hoc multiple comparisons test: values of each parameter with different superscripts letters (c, d ) a r e s i g n i f i c a n t l y d i f f e r e n t f r o m o n e a n o t h e r (P<0.01).

The first national IDD p r o g r a m in Indonesia, which began in 1974, provided iodized oil injections to people in e n d e m i c areas and began to iodize salt. UNICEF selected universal salt iodization as the means of reaching the goal of eliminating IDD. Progress towards this goal is determined by estimating the proportion of households with adequately iodized salt in countries affected by IDD (2). By the early 1990s, a b o u t h a l f o f I n d o n e s i a ' s s a l t w a s i o d i z e d . I n d o n e s i a i n t r o d u c e d a l a w in 1994, mandating the fortification of salt with iodate to the minimum level of fortification of 30 mg l/kg. The national program involves teachers and school children w h o l e a r n a b o u t IDD a n d t h e use of i o d i z e d s a l t t o a v o i d t h e p r o b l e m (4). In 1995, a n a t i o n a l s u r v e y of iodized salt consumption in 2 2 0 , 0 0 0 households showed that half of them were using adequately iodized salt (>30 mg l/kg ), 28% inadequately iodized s a l t (<30 mg l/kg) and t h e rest n o n - i o d i z ed salt (5), w h i c h is in line w i t h o u r results. O v e r a p e r i o d of o n e y e a r , t h e proportion of a d e q u a t e l y iodized 96 Salt iodization and iodine status

salt (>30 mg l/kg) in t h e area s t u d i e d was significantly increased f r o m 2% t o 5 4 % , the i n a d e q u a t e l y iodized s a l t (<30 m g l / k g ) was p r o p o r t i o n a l l y reduced f r o m 6 3 % t o 36% a n d n o n - i o d i z e d s a l t w a s r e d u c e df r o m 3 5 %t o 1 0 % . Our data suggests that there was progress in increasing the proportion of iodized salt used in the area studied, although about 45% salt used in the households was not a d e q u a t e l y iodized or not i o d i z e d at a l l . H o w e v e r , households were n o t c o n s i s t e n t in t h e i r use o f i o d i z e d s a l t d u r i n g t h e one y e a r study p e r i o d . I n addition, none of subjects studied used adequately iodized salt at all t i m e periods and 35% of the subjects never brought adequately iodized salt from their homes. Our f i n d i n g s i n d i c a t e t h a t there w a s s t i l l a l o w a w a r e n e s s o f t h e p o p u l a t i o n a t r i s k o f the n e e d t o u s e a d e q u a t e l y iodized s a l t . C h e a p e r non-iodized s a l t w a s f o u n d t o be available in t h e market in t h e area s t u d i e d a n d t h i s subverted t h e effectiveness of the i o d i z e d s a l t p r o g r a m .T h i s s t u d y u n d e r l i n e s t h e i m p o r t a n c e o f m o n i t o r i n g t h e s a l t iodization program as well as of educating the population on the importance of iodized s a l t . In the Tiberina valley, in Italy, Aghini et al. (16) found that iodized salt prophylaxis w a s a b l e t o p r e v e n t t h e d e v e l o p m e n t of g o i t e r in c h i l d r e n born a f t e r t h e implementation of iodized salt consumption, and to control t h y r o i d enlargement in older c h i l d r e n . H o w e v e r , i t w a s l e s s e f f e c t i v e in r e d u c i n g t h e s i z e o f g o i t e r i n c h i l d r e n exposed t o i o d i n e d e f i c i e n c y i nt h e f i r s t y e a r s o f l i f e a n d l a t e r g i v e n a c c e s st o i o d i z e d salt. In our study, one year after the introduction of salt iodization, urinary iodine concentration h a d i n c r e a s e d f r o m a m e d i a n l e v e l a t 0 w k o f 0 . 3 8 f x m o l / Lt o 0 . 7 0 | i m o l /L, and p r e v a l e n c e of g o i t e r measured by u l t r a s o u n d d e c r e a s ed f r o m 2 6 % t o 14%. Prevalence of goiter measured by palpation remained at 17%, but this could be attributed to misclassification in goiter measured by palpation compared to when measured by ultrasound (17). In addition palpation might not be sufficiently sensitive t o d e t e c t s m a l l r e d u c t i o n i nt h y r o i d v o l u m e . We f o u n d t h a t c h i l d r e n w h o c o n s u m e d i o d i z e d s a l t h a d h i g h e r c o n c e n t r a t i o n s of u r i n a r y iodine a n d s m a l l e r t h y r o i d v o l u m e s t h a n t h o s e w h o d i d n o t . However, w e did not find significant differences in serum FT4 and serum TSH among children consuming salt that was iodized at different levels. These results are in line with those reported earlier with iodized oil (8,17). We have also shown that serum concentrations of FT 4 a n d T S H in c h i l d r e n d o n o t r e s p o n d t o d o s i n g w i t h i o d i z e d o i l (17). It i s a l s o u n l i k e l y t h a t t h e c o n c e n t r a t i o n s of o t h e r h o r m o n e s in s e r u m w o u l d b e useful f o r m o n i t o r i n g c h a n g e s i n i o d i n e s t a t u s b r o u g h t a b o u t e i t h e r b yt h e u s e o f o r a l 97 Chapter5 iodized o i l o r i o d i z e d s a l t . For e x a m p l e , t h y r o g l o b u l i n c o n c e n t r a t i o n d i d n o t c o r r e l a t e int h i s p o p u l a t i o n w i t h u r i n a r y iodine c o n c e n t r a t i o n (17) a n d i n a d d i t i o n ,t h e r e a r e n o international standard for its measurement (18). Serum FT4 a n d TSH levels were initially and remained in the normal range after supplementation with iodized oil although u r i n a r y i o d i n e c o n c e n t r a t i o n a n dt h y r o i d v o l u m e d i d r e s p o n d t o d o s i n g ( 1 7 ) . Our finding indicated that salt iodization is not simply a matter of passing legislation. Provision of iodized salt is sometimes ineffective because of economic conditions, a s h o r t a g e o f i o d i z e d s a l t i n l o c a l m a r k e t s , i n a d e q u a t e l y i o d i z e d s a l t , l o s s of iodine f r o m s a l t because of e x c e s s i v e exposure t o moisture, light a n d heat, a n d the use of non-iodized local salt (19-21). In addition, cooking practices of the population m i g h t i n f l u e n c e t h e a v a i l a b i l i t y of i o d i n e s u p p l i e d by i o d i z e d s a l t . A s t u d y ont h e e f f e c t of I n d o n e s i a n c o o k i n g p r a c t i c e s o n s t a b i l i t y o f i o d i z e d s a l t s h o w e d t h a t some s p i c e s s u c h a s c h i l i a n d a c i d s m i g h t c a u s e l o s s e s o f i o d i n e ( 2 2 ) . The hot Indonesian climate increases salt requirements and rice-eating populations a l s o c o n s u m e m o r e s a l tt h a n o t h e r s b e c a u s e r i c e i t s e l f c o n t a i n v e r y l i t t l e in s a l t ( 2 3 ) . Legislation in I n d o n e s i a , r e q u i r e s s a l t t o c o n t a i n a t l e a s t 3 0 m g l / k g . T o counteract this iodine deficiency, a salt intake of 4-5 g per person per day is necessary to provide the iodine requirement of 120 jig for children aged 8-10 y. However little information is available on the intake of salt in Indonesia. It is assumed t h a t p e r c a p u t c o n s u m p t i o n is a b o u t 10 g / d of w h i c h 5 0 % i s d i s c r e t i o n a r y . A s t u d y o f s a l t i n t a k e u s i n g a l i t h i u m - l a b e l e d s a l t , s h o w e d t h a t t h e a v e r a g e d a i l y s a l t consumption in r u r a l G u a t e m a l a n boys w a s 1 . 8 ±0 . 6 g a n d B e n i n e s e b o y s 5 . 7 ± 2 . 8 g, of w h i c h 72 ± 12% a n d 5 0 ± 13% r e s p e c t i v e l y came f r o m d i s c r e t i o n a r y sources (24). M o r e i n f o r m a t i o n i sr e q u i r e d o na v e r a g e s a l t c o n s u m p t i o n i n I n d o n e s i a . It i s c o n c l u d e d f r o m t h e p r e s e n t study t h a t t h e impact of l e g i s l a t i o n requiring iodized salt for the Indonesian population has not been successful although significant p r o g r e s s h a s b e e n m a d e i n r e c e n t y e a r s . C o n s e q u e n t l y , iodine d e f i c i e n c y iss t i l l a s e r i o u s p u b l i c h e a l t h p r o b l e m i n I n d o n e s i a a n d i n c r e a s e d e f f o r t is n e e d e d t o eradicate i o d i n e d e f i c i e n c y .

98 Saltiodization andiodine status

REFERENCES

1. Trowbridge FL, Harris SS, Cook J, et al. Coordinated strategies for controlling micronutrient m a l n u t r i t i o n : a t e c h n i c a l w o r k s h o p . J N u t r 1 9 9 3 ; 1 2 3 : 7 7 5 - 8 7 . 2. UNICEF. Micronutriets: Mid-decade goals. CF/PROG/IC/93-070 24/11/1993. New York, U N I C E F , 1 9 9 3 . 3. UNICEF/PAMM/MI/ICCIDD/WHO. Monitoring universal salt iodization programmes. Atlanta, G . A . : PAMM/MI/ICCIDD, 1 9 9 5 . 4. UNICEF. T h e s t a t e o f t h e w o r l d ' s c h i l d r e n 1998. N e w Y o r k : O x f o r d U n i v e r s i ty P r e s s , 1998. 5. BPS and UNICEF. Iodized salt consumption at the household level 1996. 1996. Jakarta, I n d o n e s i a , C e n t r a l B u r e a u o f S t a t i s t i c s (BPS) a n d U N I C E F . 6. ICCIDD. I n d o n e s i a ' s b a t t l e a g a i n s t I D D . I D D N e w s l e t t e r 12(4), 56-58. 1 9 9 6 . 7. Ministry of Health Rl and Tim GAKI Undip. Endemic goiter map of Central Java, Indonesia. 1996.S e m a r a n g , I n d o n e s i a , U n i v e r s i t a s D i p o n e g o r o . 8. Untoro J , S c h u l t i n k W, W e s t CE, G r o s s R, Hautvast JGAJ. Efficacy of o r a l iodized peanut oil is greater than that of iodized poppyseed oil among Indonesian school children. Submitted f o r p u b l i c a t i o n . 9. Untoro J , W e s t C E , S c h u l t i n k W, G r o s s R, Hautvast J G A J . E f f e c t of s t u n t i n g , i o d i n e deficiency and oral iodized oil supplementation on cognitive performance in school children from an endemic iodine deficient area of Indonesia. Submitted for publication. 10. WHO/UNICEF/ICCIDD. I n d i c a t o r s f o r a s s e s s i n g i o d i n e d e f i c i e n c y d i s o r d e r s a n d t h e i r control p r o g r a m s . G e n e v a : W H O , 1 9 9 4 . 11. Delange F, B e n k e r G , C a r o n P, e t a l .T h y r o i d v o l u m e a n d u r i n a r y i o d i n e i n E u r o p e a n schoolchildren: s t a n d a r d i z a t i o n of v a l u e s f o r a s s e s s m e n t of iodine d e f i c i e n c y . Eur J Endocrinol 1 9 9 7 ; 1 3 6 : 1 8 0 - 7 . 12. WHO, I C C I D D . R e c o m m e n d e d n o r m a t i v e v a l u e s f o r t h y r o i d v o l u m e in c h i l d r e n a g e d 6-15y e a r s . Bull W o r l d H e a l t h O r g a n 1 9 9 7 ; 7 5 : 9 5 - 7 . 13. Benmiloud M, Chaouki ML, Gutekunst R, Teichert HM, W o o d WG, Dunn JT. Oral iodized oil for correcting iodine deficiency: optimal dosing and outcome indicator selection. J C l i n E n d o c r i n o l M e t a b 1 9 9 4 ; 7 9 : 2 0 - 4 . 14. Dunn JT, Crutchfield HE, Gutekunst R, Dunn AD. Two simple methods for measuring i o d i n e i n u r i n e . Thyroid 1 9 9 3 ; 3 : 1 1 9 - 2 3 . 15. CIOMS. International Guidelines for Ethical Review of Epidemiological Studies. Geneva, Switzerland: Council for International Organizations for Medical Sciences, 1991. 16. Aghini L F ,A n t o n a n g e l i L, P i n c h e r a A , e t a l . E f f e c t o f i o d i z e d s a l t o n t h y r o i d v o l u m e o f children living in a n a r e a previously characterized by moderate iodine d e f i c i e n c y . J Clin E n d o c r i n o l M e t a b 1 9 9 7 ; 8 2 : 1 1 3 6 - 9 . 17. Untoro J , W e s t C E , S c h u l t i n k W , G r o s s R, H a u t v a s t J G A J . C o m p a r i s o n o f indicators to a s s e s s i o d i n e s t a t u s a n d i t s i m p r o v e m e n t t h r o u g h s u p p l e m e n t a t i o n w i t h i o d i z e do i l . Submitted f o r p u b l i c a t i o n . 18. Feldt RU, P r o f i l i s C, C o l i n e t E, e t a l . Human t h y r o g l o b u l in reference material (CRM 457); 1st p a r t : A s s e s s m e n t of h o m o g e n e i t y , s t a b i l i t y a n d i m m u n o r e a c t i v i t y ; 2 n d p a r t : Physicochemical c h a r a c t e r i z a t i o n and certification. Ann Biol Clin 1996;54:337-342; 343-8. 19. Pandav CS. IDD i n South-East Asia. In: Hetzel BS, Pandav CS, e d s . S.O.S. for a billion. N e w D e l h i :O x f o r d U n i v e r s i t y P r e s s , 1 9 9 4 : 2 1 3 - 3 1 .

99 Chapter 5

20. Kavishe FP. C a n A f r i c a meet the goal of eliminating iodine deficiency disorders by the y e a r 2 0 0 0 ? Food N u t r B u l l 1 9 9 6 ; 1 7 : 2 6 2 - 7 . 21. Stewart C , S o l o m o n s NW, M e n d o z a I, M a y S , M a b e r l y G . S a l t i o d i n e v a r i a t i o n w i t h i n an e x t e n d e d G u a t e m a l a n c o m m u n i t y : T h e f a i l u r e o f i n t u i t i v e a s s u m p t i o n s . Food N u t r Bull1 9 9 6 ; 1 7 : 2 5 8 - 6 1 . 22. Arhya, I . N . E f f e c t o ns t o r a g e a n d c o m m o n l y u s e d s p i c e s o n s t a b i l i t y of i o d i z e d s a l t i n Indonesia. I D D N e w s l e t t e r 12(2), 2 7 . 1 9 9 6 . 23. ICCIDD. T e c h n i c a l a s p e c t o f s a l t i o d i z a t i o n : a n u p d a t e . I D D N e w s l e t t e r 1995;11:26-9. 24. Boonstra A M , Rozendaal M, Rexwinkel H, et al. Determination of discretionary salt intake in rural Guatemala and Benin to determine the iodine fortification of salt required t o c o n t r o l i o d i n e d e f i c i e n c y d i s o r d e r s : s t u d i e s using l i t h i u m - l a b e l e d s a l t . Am J C l i n N u t r1 9 9 8 ; 6 8 : 6 3 6 - 4 1 .

100 Chapter 6

General d i s c u s s i o n Chapter 6

CONTROLLING I O D I N E D E F I C I E N C Y Iodized s a l to r i o d i z e do i l ? Universal s a l t i o d i z a t i o n a n d i o d i z e d o i l s u p p l e m e n t a t i o n can b o t h b e u s e d t o control iodine deficiency. Universal salt iodization is the main strategy adopted worldwide f o r e l i m i n a t i o n o f i o d i n e d e f i c i e n c y d i s o r d e r s (IDD) ( 1 ) .A l t h o u g h i o d i z a t i o n of salt has been successful in many countries in reducing the prevalence of IDD, additional s t r a t e g i e s a r e r e q u i r e d t o e r a d i c a t e IDD f o r t h e c o m i n g d e c a d e s because not a l l c o m m u n i t i e s a t - r i s k o f I D Dc o n s u m e i o d i z e d s a l t y e t . Supplementation with oral iodized oil has shown good results in many endemic areas and may become a more widely used method. The major advantages o f iodized o i l a d m i n i s t r a t i o n a r e t h a t it c a n be i m p l e m e n t e d q u i c k l y , h a s immediate impact, a n d d o e s n o t involve t h e c o m p l e x i t i e s of a l t e r i n g salt production and t r a d e . Iodized o i l h a s a r o l e in a r e a s of s i g n i f i c a n t iodine d e f i c i e n c y where s a l t iodization is u n l i k e l y t o b e s u c c e s s f u l l y implemented s o o n a n d c o r r e c t i o n is n e e d e d promptly. In m a n y s u c h a r e a s , a n i o d i z e d o i l p r o g r a m w i l l b e n e c e s s a r y f o r at leas t severaly e a r s , a n d f o r s o m e r e m o t e a r e a s i t m a y b e s e m i - p e r m a n e n t (2).A t p r e s e n t , most c o u n t r i e s d e p e n d o n a n o r a l i o d i z e d p o p p y s e e d o i l p r e p a r a t i o n , w h i c h is m a d e from a raw material derived from the opium poppy {Papaversomniferum). Since cultivation of this plant is tightly regulated, iodized oil has become relatively expensive ( 3 ) .T h e r e i s a n u r g e n t n e e d t o i n c r e a s e t h e p r o d u c t i o n of i o d i z e d o i l a n d to m a k e a v a i l a b l e a na l t e r n a t i v e p r o d u c t w h i c h i sc h e a p e r a n d e f f e c t i v e ( 4 ) .

Which i o d i z e d o i l ? Studies i n r a t s a n d m a n b y V a n d e r H e i de e t a l . (5) i n d i c a t e d t h a t i o d i n e f r o m a preparation based on ethyl oleate was retained longer in the body than a preparation b a s e d o n e t h y l l i n o l e a t e o r f r o m e t h y l e s t e r s d e r i v e d f r o m p o p p y s e e do i l . A r e p o r t o f a s t u d y b y I n g e n b l e e k et a l . ( 3 ) o nt h e e f f e c t i v e n e s s of i o d i z e d r a p e s e e d oil appeared while this study was being carried out. These authors reported that iodized rapeseed oil supplying 752 mg I gave a longer period of protection in moderate iodine deficient adults (30 wk) compared to iodized poppyseed oil supplying 729 mg I (17 w k ) when an iodine concentration in urine of 0.79 |amol/L was t a k e n as t h e cut-off point. Most of iodine in t h e rapeseed oil preparation was bound t o o l e i c a c i d w h e r e a s i nt h e p o p p y s e e d o i l p r e p a r a t i o n t h e i o d i n e is b o u n d t o linoleic a c i d .

102 General discussion

In our study (Chapter 2) we compared iodized peanut oil with iodized poppyseed o i l . P e a n u t oil c o n t a i n s t h r e e t i m e s more oleic acid a n d o n e half of t h e amount o f l i n o l e i c a c i d t h a n p o p p y s e e d o i l .T h e d u r a t i o n o f e f f e c t i v e n e s s of a s i n g l e oral d o s e o f i o d i z e d p e a n u t o i l w a s a b o u t t w i c e t h a t o f t h e i o d i z e d p o p p y s e e d o i l ( 7 7 wk vs 42 wk; both preparations contained 400 mg I) in moderate iodine deficient school children. Thus we have been able to confirm the results obtained by Ingenbleek e t a l . (3),w i t h a n o t h e r i o d i z e d o i l a l s o b a s e d o n a n o l e i c a c i d r i c h o i l a n d in a n o t h e r population and s e t t i n g . T h e r e f o r e , iodized oils prepared f r o m peanut oil and r a p e s e e d o il s h o u l d be p r e f e r r e d a b o v e t h o s e f r o m poppyseed oil in p r o g r a m s to c o n t r o l i o d i n e d e f i c i e n c y .

Efficacy o f o r a l i o d i z e d p e a n u t o i l Although experience in using oral iodized oil is limited, previous studies in Algeria (6), B o l i v i a (7), M a l a w i (8,9) a nd Z a i r e (10) h a v e d e m o n s t r a t e d t h a t a s i n g l e orald o s e o f i o d i z e d o i l c a n m e e t i o d i n e r e q u i r e m e n t s f o r o n e o rt w o y e a r s .T h e s t u d y in Algeria by Benmiloud et al. (6) showed that a single oral dose of iodized poppyseed oil p r o v i d i n g 240 mg I e f f e c t i v e l y protected iodine d e f i c i e n c y in c h i l d r en aged 6 - 1 1 y f o r 6 m o n t h s a n d a d o s e of 4 8 0 mg I f o r 12 m o n t h s . Furnee et a l . ( 9 ) found t h a t 1 ml_ o f oral iodized poppyseed (490 mg I, e t h y l esters of iodized f a t t y acids) e f f e c t i v e l y p r o t e c t e d s c h o o l c h i l d r e n f r o m m o d e r a t e l y i o d i n e d e f i c i e n c y (cut-off point 0 . 4 | i m o l / L ) f o r 13.7 w k . Our r e s u l t s s h o w e d t h a t t h e s a m e p r e p a r a t i o n of o r a l iodized p o p p y s e e d o i l s u p p l y i n g 4 0 0 m g I ,c o u l d p r o v i d e s c h o o l c h i l d r e n w i t h e n o u g h iodinef o r 4 2w k ,w h i c h w a s a b o u t t w i c e a s l o n g a st h a t r e p o r t e d b y B e n m i l o u d e ta l . (6) a n d m u c h l o n g e r t h a n t h a t f o u n d b y F u r n e e e t a l . ( 9 ) w h o u s e d a c u t - o f f p o i n t s o f urinary iodine concentration half that used by Benmiloud et al (6) and by us. O u r results a r e d i f f e r e n t f r o m t h o s e r e p o r t e d p r e v i o u s l y p r o b a b l y b e c a u s e o f t h e s e v e r i t y of i o d i n e d e f i c i e n c y . O t h e r f a c t o r s i n c l u d e , e x t e r n a l iodine i n t a k e , p o s s i b l e exposur e to g o i t r o g e n i c substances, nutritional status w i t h r e s p e c t t o o t h e r nutrients, a n d t h e indicators and cut-off points used. Our data indicate that iodized peanut oil is efficacious for controlling iodine deficiency: a single dose 200 mg I effectively protected i o d i n e d e f i c i e n t s c h o o l c h i l d r e n w h o h a v e l i m i t e d a c c e s s t o i o d i z e d s a l t f o r one y e a r (Chapter2).

103 Chapter 6

ASSESSMENT O F I O D I N E D E F I C I E N C Y A N D M E A S U R I N G I T S I M P R O V E M E N T The s t a t u s of iodine d e f i c i e n c y in a p o p u l a t i o n , a n d t h e progress t o w a r d s its elimination a f t e r intervention, c a n be a s s e s s e d t h r o u g h v a r i o u s outcome indicators. The c h o i c e o f a s i n g l e i n d i c a t o r , o r a c o m b i n a t i o n o f i n d i c a t o r s f o r s t u d i e s o r s u r v e y s , is not fully standardized but rather depends on the specific circumstances of the study. S of a r , t h e n u m b e r o f s t u d i e s c o m p a r i n g t h e r e l a t i v e s e n s i t i v i t y a n d s p e c i f i c i t y between indicators in assessing iodine status of a population is limited and have given c o n f l i c t i n g r e s u l t s ( 1 1 - 1 8 ) . The s c h o o l c h i l d r e n i nt h e p r e s e n t s t u d y w e r ej u d g e d t o b e m o d e r a t e l y iodine deficient at baseline as indicated by a p r e v a l e n c e of goiter measured by palpation and ultrasound, at 22% and 23% respectively, and a median urinary iodine concentration of 0.36 nmol/L (19). However, serum TSH and serum FT4 concentrations were in the normal range, suggesting that the population had an adequate iodine s t a t u s . O n e y e a r a f t e r treatmen t w i t h o r a l iodized peanut o i l , t h e r e were significant reductions in thyroid volume and prevalence of goiter and an increase in t h e median urinary iodine concentration of t h e population. A significant increase of serum FT4 concentration was also observed half a year after supplementation, but both t h e initial and f i n a l levels were within t h e normal range. There was no significant change in the serum TSH concentration. The results suggest that t h y r o i d volume measured by ultrasound and by p a l p a t i o n and urinary iodine c o n c e n t r a t i o n g a v e s i m i l a r i n f o r m a t i on o nt h e s e v e r i t y o f i o d i n e d e f i c i e n c y a n d all indicated an improvement in iodine status after treatment with oral iodized o i l .

SerumT S Ha n d F T 4c o n c e n t r a t i o n s d i d n o t g i v e a n y i n d i c a t i o n s o f i o d i n e d e f i c i e n c y . Although t h e p r e v a l e n c e i n d i c a t e d a g r e e m e n t , t h e s e n s i t i v i t y a n d s p e c i f i c i t y o f palpation e v a l u a t e d a g a i n s t g o i t e r m e a s u r e d b y u l t r a s o n o g r a p h y w e r e 5 5 %a n d9 0 % respectively at b a s e l i n e . T h e p o s i t i v e a n d n e g a t i v e predictive v a l u e s w e r e 6 0 % a n d 88% respectively. These data show that palpation is of limited value for use in surveys of school children to identify communities suffering from iodine deficiency and to identify changes in iodine status. Such a conclusion has been drawn by others previously (13,16,20,21). Although these data highlight the limitation of thyroid p a l p a t i o n , t h i s method s t i l l h a s a u s e f u l p l a c e in a s s e s s i n g w h e t h e r or not a problem of iodine d e f i c i e n c y exist because no s o p h i s t i c a t e d equipment is r e q u i r e d . However it i s n e c e s s a r y f o r o b s e r v e r s t o b et r a i n e d a d e q u a t e l y i nt h et e c h n i q u e .

104 General discussion

Based o no u r s t u d i e s , u r i n a r y i o d i n e c o n c e n t r a t i o n a n d t h y r o i d v o l u m e a r et h e best indicators f o r assessing iodine status a n d measuring t h e impact of iodized oil supplementation a m o n g i o d i n ed e f i c i e n t s c h o o l c h i l d r e n (Chapter3).

EFFECT OF STUNTING, IODINE DEFICIENCY AND ORAL IODIZED OIL ON COGNITIVE PERFORMANCE We found that the population studied had a low score for cognitive performance and suffered from multiple nutritional deficiencies: iodine deficiency, iron deficiency anemia and stunting. Earlier studies have shown that some improvement in cognitive performance can be achieved by appropriate supplementation (22-27). O u r r e s u l t s s h o w e dt h a t b o t h n u t r i t i o n a l a n d n o n n u t r i t i o n a l factors played a role in cognitive performance of the school children. Father's education and hemoglobin concentration were the main determinants of cognitive performance at baseline, and urinary iodine concentration and stunting were the most important determinants for improvement in cognitive performance after supplementation w i t h i o d i z e d o i l . W e d i d n o t f i n d a p o s i t i v e c o r r e l a t i o n between t h e education of m o t h e r s a n d c o g n i t i v e p e r f o r m a n c e of s c h o o l c h i l d r e n , p r o b a b l y a s t h e majority of the mothers (96%) had 6 years of education or less. The higher the education of f a t h e r , t h e higher the cognitive scores and t h e higher the educational achievement o f t h e s c h o o l c h i l d r e n a s i n d i c a t e d b y s c h o o l g r a d e s . There has been much debate about whether stunting is a harmless adaptation t o poor d i e t a r y intakes o r has a f u n c t i o n a l c o n s e q u e n c e (28). T h i s s t u d y confirmed results of previous studies (11,24,29,30) that stunting has a role in cognitive development. Stunting may not directly cause poor intellectual development in c h i l d r e n , but t h e same underlying factors that cause stunting such as s o c i o - e c o n o m i c s t a t u s o f t h e f a m i l y , m a y a l s o i m p a i r c h i l d r e n ' s i n t e l l e c t u a l g r o w t h (1). Most of t h e c h i l d r e n in t h i s s t u d y w e r e f r o m poor f a m i l i e s , a n d t h e i r d i e t s w e r e below t h e r e c o m m e n d e d d i e t a r y intakes. In a d d i t i o n , w e f o u n d a p o s i t i v e c o r r e l a t i o n between t h y r o i d v o l u m e and s t u n t i n g at a l l periods of measurement. Normal linear growth is determined by variable contributions from genetic, nutritional and endocrine f a c t o r s a n d c o n t i n u e s u n t i l b o n e m a t u r a t i o n in e a r l y a d u l t h o o d . O n e o f t h e major hormones that influence growth during childhood is triiodothyronine (31): before p u b e r t y , it m a y b e t h e major d e t e r m i n a n t f o r normal m a t u r a t i o n of b o n e ( 3 2 ) . Untreated hypothyroidism in children results in profound growth retardation and 105 Chapter 6

delayed s k e l e t a l m a t u r a t i o n . Linear growth is a l m o s t completely halted, but can be resumed quickly by replacement of t h y r o i d hormones t o produce a rapid catch-up period o f g r o w t h ( 3 3 ) . We found that 40% of the school children were anemic and the cognitive scores o f t h e a n e m i c c h i l d r e n (hemoglobin < 1 1 0 g / L ) w e r e 3 p o i n t s l o w e r t h a n t h e i r non-anemic counterparts. Our findings are in line with those earlier studies that showed i r o nd e f i c i e n c y a n e m i a i m p a i r s c o g n i t i v e d e v e l o p m e n t ( 2 2 , 2 3 ) . Previous s t u d i e s i n i o d i n e d e f i c i e n t s c h o o l c h i l d r e n h a v e s h o w n i m p a i r m e n t o f school performance and IQ when compared to similar groups from iodine-replete areas (7). I o d i n e d e f i c i e n c y results in a s h i f t of t h e d i s t r i b u t i o n of cognitive skills of the entire population to a lower level. In iodine deficient populations, mild mental impairment has b e e n s h o w n t o o c c u r f i v e t i m e s m o r e f r e q u e n t l y t h a n in p o p u l a t i o n s with n o r m a l i o d i n e s t a t u s (34) a n d t h a t t h e IQ c u r v e o f t h e p o p u l a t i o n c a n b e s h i f t e d 10 p o i n t s t o t h e left (35). A l t h o u g h a s i n g l e o r a l d o s e o f iodized o i l i m p r o v ed iodine status of our population, it d i d not result in improvement of cognitive performance compared to the placebo group. However, the changes in cognitive score were inversely correlated t o t h e urinary iodine concentration which indicates that iodine deficient children did benefit more in cognitive performance from iodine supplementation t h a n t h e i r more r e p l e t e c o u n t e r p a r t s . T h i s s u p p o r t s e a r l i e r f i n d i n g s that iodine supplementation can increase cognitive performance of school children (22). This study suggest that iodine status as measured by urinary iodine concentration at baseline and s t u n t i ng are related t o t h e improvement of cognitive performance when children are dosed with iodized oil. In addition anemia and father's education play a role in c o g n i t i o n . T h i s illustrates the role of nutrition and socialf a c t o r s i n c o g n i t i v e d e v e l o p m e n t a n d p e r f o r m a n c e i n c h i l d r e n (Chapter4).

IODIZED S A L T F O R C O N T R O L L I N G I O D I N E D E F I C I E N C Y Universal salt iodization is the major public health nutrition measure for eliminating i o d i n e d e f i c i e n c y o n a l o n g - t e r m b a s i s ( 3 6 ) . M a n y c o u n t r i e s h a v e a l r e a d y made s i g n i f i c a n t progress t o w a r d s t h e e l i m i n a t i o n of IDD, l a r g e ly as a r e s u l t of s a l t iodization (37). I n r u r a l a r e a s o f m a n y d e v e l o p i n g c o u n t r i e s , w h e r e i o d i n e d e f i c i e n c y is often most severe, populations are largely dependent on subsistence foods. Therefore, t h e main or only source of iodine in t h i s kind of area is iodized salt or 106 General discussion supplementation with iodized oil. A l t h o u g h , it is w e l l established that an adequate iodine intake prevents iodine deficiency disorders, data on the effectiveness of iodized s a l tf o r c o n t r o l l i n g i o d i n e d e f i c i e n c y a r e s t i l l s c a n t y . Duringt h e o n e y e a r o f t h e s t u d y w h e nt h e r e w a s i n c r e a s i n g a c c e s s t o i o d i z e d salt, t h e proportion of adequately iodized salt used by households increased from 2% t o 5 4 % . H o w e v e r , h o u s e h o l d s w e r e nor c o n s i s t e n t in t h e i r usage o f iodized s a l t throughout t h e y e a r , a n d t h e m a j o r i t y also u s e d n o t - a d e q u a t e l y iodized s a l t a t l e a s t once. The median value of urinary iodine concentration of the school children improved from 0.38 (imol/L t o 0.70 |amol/L a n d prevalence of goiter measured by ultrasound d e c r e a s e d f r o m 2 6 %t o 1 4 % .P r e v a l e n c e o f g o i t e r m e a s u r e d b y p a l p a t i o n remained a t 1 7 % , b u tt h i s c o u l d b e a t t r i b u t e d t o m i s c l a s s i f i c a t i o n i n g o i t e r m e a s u r e d by p a l p a t i o n c o m p a r e d t o w h e n m e a s u r e d by u l t r a s o u n d (Chapter 3), a n d p a l p a t i o n might not be sufficiently sensitive to detect small changes in thyroid volume. In addition, t h e r e w e r e no s i g n i f i c a n t differences in s e r u m c o n c e n t r a t i o n s of T S H a n d

FT4a m o n g c h i l d r e n c o n s u m i n g s a l tt h a t w a s i o d i z e d a t d i f f e r e n t levels.T h e s e r e s u l t s confirm those described above on the use of thyroid palpation and serum concentrations of TSH and FT4 f o r assessing the impact of iodine prophylaxis but with i o d i z e d o i l (Chapter2; Chapter3). Household use of iodized salt was related significantly to urinary iodine concentration and t h y r o i d volume (Chapter5). A l t h o u g h the use of iodized salt in households increased, about half of the salt available in the market was still not adequately iodized or iodized at all. T h e availability of cheaper non-iodized salt in the m a r k e t , s u b v e r t e d t h e e f f e c t i v e n e s s of t h e iodized s a l t p r o g r a m . T h e s e f i n d i n g s indicate t h a t iodine prophylaxis using iodized s a l t is n o t s i m p l y a matter of passing legislation, but should also include advocacy, education, marketing, an overall system o f q u a l i t y a s s u r a n c e a n d m o n i t o r i n g o ft h e s a l t i o d i z a t i o n p r o g r a m .

CONCLUSIONS • A s i n g l e o r a l d o s e o f i o d i z e d p e a n u t o i l c o m p a r e d t o a s i n g l e o r a l d o s e o f i o d i z e d poppyseed oil r e s u l t e d in t h r e e t i m e s higher iodine retention leading t o a p e r i o d of protection twice as long in iodine deficient school children. Peanut oil is characterized b y h a v i n g a h i g h p r o p o r t i o n o f o l e i c a c i d w h i l e p o p p y s e e d o i l i s r i c h in l i n o l e i c a c i d . T h u s t h e i o d i z e d o i l p r e p a r e d f r o m o i l s r i c h i n o l e i c a c i d , s u c h a s

107 Chapter 6

peanut o i l ,s h o u l d b eg i v e n i n p r e f e r e n c e t o p r e p a r a t i o n s b a s e d o n p o p p y s e e d o i l in p u b l i c h e a l t h n u t r i t i o n p r o g r a m s t o c o n t r o l i o d i n e d e f i c i e n c y . • A single oral dose of iodized peanut oil supplying 200 mg I was effective in protecting school children living in endemic iodine deficient area for one year against i o d i n e d e f i c i e n c y . • Urinary iodine c o n c e n t r a t i o n a n d t h y r o i d v o l u m e m e a s u r e d b y u l t r a s o u n d a r e t h e most useful indicators for assessing iodine status and measuring the impact of iodized oil supplementation in school children living in an endemic iodine deficient area. However palpation still has a useful place in assessing iodine status because no sophisticated equipment is required, but it is necessary for observerst o b ea d e q u a t e l y t r a i n e d i nt h et e c h n i q u e . • Iodine status as measured by urinary iodine concentration at baseline and stunting w e r e r e l a t e d t o t h e i m p r o v e m e n t o f c o g n i t i v e p e r f o r m a n c e w h e n c h i l d r e n were d o s e d w i t h iodized o i l . I n a d d i t i o n a n e m i a a n d f a t h e r ' s education played a role i nc o g n i t i o n .T h i s i l l u s t r a t e s t h e r o l e o f n u t r i t i o n a n d s o c i a lf a c t o r s i n c o g n i t i v e development a n d p e r f o r m a n c e i nc h i l d r e n . • The use of iodized salt was correlated with urinary iodine concentration and thyroid v o l u m e of t h e population studied. However, adequate iodine status w a s not a c h i e v e d t h r o u g h t h e i o d i z e d s a l t p r o g r a m a n d m o r e a t t e n t i o n w i l l b e r e q u i r e d to m a k e i t a s u c c e s s .

IMPLICATION FOR P O L I C I E S T O C O N T R O L I O D I N E D E F I C I E N C Y Selection o f s t r a t e g i e s Universal s a l t i o d i z a t i o n is t h e main s t r a t e g y f o r c o n t r o l l i ng iodine deficiency. Results showed t h a t iodized salt has improved t h e iodine status of t h e p o p u l a t i o n . However there is still a low awareness of the population at risk about using adequately iodized s a l t , e s p e c i a l l y w h e n n o n - i o d i z e d c h e a p e r s a l t i s a v a i l a b l e in t h e market. More intensive social marketing strategies, improved education, better quality assurance and closer process monitoring of t h e s a l t iodization program are required. Oral i o d i z e d o i l i st h e b e s t a l t e r n a t i v e a n d a n a d d i t i o n a l s t r a t e g y t o i o d i z e d s a l t for controlling iodine deficiency, especially in areas of moderate to severe iodine deficiency where iodized salt is unlikely to be successfully implemented soon and correction is n e e d e d promptly. In many such areas, an iodized oil program will be 108 General discussion necessary f o r at l e a s t s e v e r a l y e a r s , a n d f o r s o m e r e m o t e a r e a s it m a y n e e d t o be semi-permanent. A n o r a l i o d i z e d o i l p r e p a r a t i o n b a s e d o n a n o l e i c a c i d r i c h o i l s u c h as p e a n u t o i l i s m o r e e f f e c t i v e t h a n a p r e p a r a t i o n b a s e d o n p o p p y s e e d o i l . A s i n g l e dose of o r a l iodized peanut o i l g i v e n t o moderate or s e v e r e iodine d e f i c i e n t school children a n n u a l l y w i l lc o n t r o l i o d i n e d e f i c i e n c y a d e q u a t e l y .

Measuring the extent of iodine deficiency and evaluating the effect of programs A c o m m o n l y used parameter to access t h e extent of IDD i n a c o m m u n i t y is the p r e v a l e n c e o f g o i t e r a s a s s e s s e d t h r o u g h t h y r o i d p a l p a t i o n . H o w e v e r , g r a d i n g o f goiter size by palpation has large intra a n d inter-observer variability. Even though thyroid palpation has its limitations, it still has a useful place in assessing iodine status b e c a u s e n os o p h i s t i c a t e d e q u i p m e n t is r e q u i r e d .T h e r e f o r e , i t i s n e c e s s a r y f o r observers t o be t r a i n e d a d e q u a t e l y in t h e t e c h n i q u e . In a d d i t i o n , o t h e r indicators of iodine or thyroid status should be used. T h i s study suggested that urinary iodine concentration and thyroid volume measured by ultrasound are the most useful indicators f o r a s s e s s i n g i o d i n e s t a t u s a n d m e a s u r i n g t h e i m p a c t o f t r e a t m e n t a m o n g populations o f s c h o o lc h i l d r e n .

RECOMMENDATIONSF O RF U T U R ER E S E A R C H Research on t h e e f f i c a c y of d i f f e r e n t preparations of iodized oil s h o u l d f o c u s on: • The m e t a b o l i s m o f s u c h p r e p a r a t i o n s int h e b o d y t o e l u c i d a t e t h e r e l a t i v e r a t e s o f the v a r i o u s r e a c t i o n s a n d p r o c e s s i n v o l v e d .

Research o n i o d i n e i n d i c a t o r s s h o u l d f o c u so n : • Development of reliable and cost-effective indicators for measuring the iodine status o ft h e p o p u l a t i o n .

Research o nc o g n i t i v e p e r f o r m a n c e s h o u l df o c u so n : • The relative importance of iodine supplementation in improving the cognitive performance of populations with multiple nutritional problems including iodine deficiency.

109 Chapter 6

Research o ne f f i c a c y o f i o d i z e d s a l t s h o u l d f o c u so n : • Measuring t h e a v e r a g e s a l t c o n s u m p t i o n i nt h e p o p u l a t i o n . • The e f f e c t of f o o d p r e p a r a t i o n including t h e m e t h o d a n d d u r a t i o n of c o o k i n g a n d the s p i c e s u s e d ,o nt h e s t a b i l i t y o f i o d i z e d s a l t . • Determining optimal levels of fortification for controlling iodine deficiency in populations d i f f e r i n g i nt h e s e v e r i t y o f i o d i n e d e f i c i e n c y a n d o t h e r c h a r a c t e r i s t i c s .

110 Generaldiscussion

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1. UNICEF. T h e s t a t e of t h e w o r l d ' s c h i l d r e n 1998. New Y o r k : O x f o r d U n i v e r s i ty P r e s s , 1998. 2. Dunn J T . I o d i n e s u p p l e m e n t a t i o n and t h e p r e v e n t i o n of c r e t i n i s m . A n n N Y A c a d S c i 1993;678:158-68. 3. Ingenbleek Y, Jung L, Ferard G, Bordet F, Goncalves AM, Dechoux L. Iodised rapeseed o i lf o r e r a d i c a t i o n o f s e v e r e e n d e m i c g o i t r e . Lancet 1 9 9 7 ; 3 5 0 : 1 5 4 2 - 5 . 4. Dunn J T , T h i l l y C H , P r e t e l l E. I o d i z e d o i l a n d o t h e r a l t e r n a t i v e s t o i o d i z e d s a l t f o r t h e prophylaxis of e n d e m i c goiter and c r e t i n i s m . In: Dunn J T , P r e t e l l E, Daza C H , V i t e r i FE, e d s . T o w a r d s t h e e r a d i c a t i o n of e n d e m i c goiter, c r e t i n i s m , a n d i o d i n e d e f i c i e n c y (PAHO-WHO Sci Publ no 502). Washington, DC: Pan American Sanitary Bureau, 1986:170-81. 5. Van der Heide D, de Goeje MJ, van der Bent C. The effectiveness of oral administered iodized oil in rat and man. Annales d'endocrinologie 1989; 50: 116(abst). 6. Benmiloud M, Chaouki ML, G u t e k u n s t R, Teichert HM, W o o d WG, Dunn JT. Oral iodized oil for correcting iodine deficiency: optimal dosing and outcome indicator selection. J C l i n E n d o c r i n o l M e t a b 1 9 9 4 ; 7 9 : 2 0 - 4 . 7. Bautista A , Barker PA, Dunn J T , S a n c h e z M, K a i s e r DL. T h e e f f e c t s of o r a l iodized oil o n i n t e l l i g e n c e , t h y r o i d s t a t u s , a n d s o m a t i c growth in s c h o o l - a g e c h i l d r e n f r o m a n area o f e n d e m i c g o i t e r . Am J C l i n N u t r 1 9 8 2 ; 3 5 : 1 2 7 - 3 4 . 8. Furnee CA, v a n der Haar F, W e s t C E , H a u t v a s t J G A J . A c r i t i c a l a p p r a i s a l of goiter assessment a n d t h e ratio of urinary iodine t o c r e a t i n i n e f o r evaluating iodine s t a t u s . Am J C l i n N u t r 1 9 9 4 ; 5 9 : 1 4 1 5 - 7 . 9. Furnee C A , P f a n n G A , W e s t C E , v a n d e r Haar F, v a n d e r H e i d e D., H a u t v a st J G A J . New m o d e l f o r d e s c r i b i n g u r i n a r y i o d i n e e x c r e t i o n : i t s u s e f o r c o m p a r i n g d i f f e r e n t o r a l preparations of i o d i z e d o i l . Am J C l i n N u t r 1 9 9 5 ; 6 1 : 1 2 5 7 - 6 2 . 10. Tonglet R, Bourdoux P, Minga T , Ermans A M . E f f i c a c y of low o r a l d o s e s of iodized oil i nt h e c o n t r o l o f i o d i n e d e f i c i e n c y i nZ a i r e . NE n g lJ M e d 1 9 9 2 ; 3 2 6 : 2 3 6 - 4 1 . 11. Pardede LVH, H a r d j o w a s i t o W, G r o s s R, et a l . Urinary iodine excretion is t h e most appropriate o u t c o m e i n d i c a t o r f o r iodine d e f i c i e n c y a t f i e l d c o n d i t i o n s a t d i s t r i c t l e v e l . J N u t r 1 9 9 8 ; 1 2 8 : 1 1 2 2 - 6 . 12. Gerasimov GA, Gutekunst R. [Comparison of the data of palpation and ultrasonic examination in assessing the dimensions of the thyroid gland] Sopostavlenie dannykh pal'patsii i ul'trazvukogo obsledovaniia pri opredelenii razmerov s h c h i t o v i d n o i z h e l e z y . Probl E n d o k r i n o l M o s k 1 9 9 2 ; 3 8 : 2 6 - 7. 13. Gutekunst R, Chaouki ML, Dunn JT, Benmiloud M. Field assessment of goiter: comparison of palpation, surfac e outline and ultrasonography. Int Symp on Iodine andt h e T h y r o i d 1 9 9 0 ; ( a b s t ) . 14. Hintze G, W i n d e l e r J, Baumert J , S t e i n H, Kobberling J. T h y r o i d v o l u m e a n d goitre prevalence in the elderly as determined by ultrasound and their relationships to laboratory i n d i c e s . Acta E n d o c r i n o l C o p e n h 1 9 9 1 ; 1 2 4 : 1 2 - 8 . 15. Nordmeyer J P , S i m o n s M, W e n z e l C, S c h o l t e n T. How a c c u r a t e is t h e assessment of thyroid volume by palpation? A prospective study of 316 patients. Exp Clin Endocrinol D i a b e t e s 1 9 9 7 ; 1 0 5 : 3 6 6 - 7 1 . 16. Vitti P, Martino E, A g h i n i LF, e t al. T h y r o i d volume measurement by ultrasound in children as a t o o l for the assessment of mild iodine deficiency. J Clin Endocrinol Metab 1 9 9 4 ; 7 9 : 6 0 0 - 3 . 111 Chapter6

17. Gutekunst R, Smolarek H, Hasenpusch U, et al. Goitre epidemiology: thyroid volume, iodine excretion, thyroglobulin and thyrotropin in Germany and Sweden. Acta E n d o c r i n o l C o p e n h 1 9 8 6 ; 1 1 2 : 4 9 4 - 5 0 1 . 18. Berghout A, Wiersinga WM, Smits NJ, Touber JL. The value of thyroid volume measured by ultrasonography in the diagnosis of goitre. Clin Endocrinol Oxf 1988;28:409-14. 19. WHO/UNICEF/ICCIDD. I n d i c a t o r s f o r a s s e s s i n g i o d i n e d e f i c i e n c y d i s o r d e r s a n d t h e i r control p r o g r a m s . G e n e v a : W H O , 1 9 9 4 . 20. Berghout A , W i e r s i n g a W M , S m i t s N J ,T o u b e r J L . D e t e r m i n a n t s of t h y r o i d v o l u m e a s measured by ultrasonography in healthy adults in a n o n - i o d i n e deficient area. Clin Endocrinol O x f 1 9 8 7 ; 2 6 : 2 7 3 - 8 0 . 21. Hegedus L, Perrild H, Poulsen LR, et al. The determination of thyroid volume by ultrasound and its relationship to body w e i g h t , age, and sex in normal subjects. J Clin E n d o c r i n o l M e t a b 1 9 8 3 ; 5 6 : 2 6 0 - 3 . 22. Shresta RM, West CE, Bleichrodt N, van de Vijver FJR, Hautvast JGAJ. Supplementation with iodine and iron improves mental development in Malawian children. Submitted f o r p u b l i c a t i o n . 23. Idjradinata, P. and Pollitt, E. Reversal of developmental delays in iron-deficient anaemic i n f a n t s t r e a t e d w i t h i r o n . L a n c e t 1993; 3 4 1 : 1-4. 24. Grantham MS, Powell C, Walker S. Nutritional supplements, stunting, and child development [ l e t t e r ] . Lancet 1 9 8 9 ; 2 : 8 0 9 - 1 0 . 25. Grantham MS, Walker SP, Himes JH, Powell CA. The effect of nutritional supplementation and stunting on morbidity in young children: t h e Jamaican study. Trans R S o c T r o p M e d H y g 1 9 9 3 ; 8 7 : 1 0 9 - 1 3 . 26. Grantham MS, Powell CA, Walker SP, Himes JH. Nutritional supplementation, psychosocial s t i m u l a t i o n , a n d m e n t a l d e v e l o p m e n t of s t u n t e d c h i l d r e n : t h e J a m a i c a n Study. Lancet 1 9 9 1 ; 3 3 8 : 1 - 5 . 27. Walker SP, Powell CA, Grantham MS, Himes JH, Chang SM. Nutritional supplementation, psychosocial stimulation, and growth of stunted children: the Jamaican s t u d y . Am J C l i n N u t r 1991 ; 5 4 : 6 4 2 - 8 . 28. Waterlow JC. What do we mean by adaptation? In: Blaxter K, Waterlow JC, eds. Nutritional a d a p t a t i o n i n m a n . L o n d o n :J o h n L i b b e y , 1 9 8 5 : 1 - 1 2 . 29. Grantham MS, Powell C, Fletcher P. Stunting, severe malnutrition and mental development i n y o u n g c h i l d r e n . Eur J C l i n N u t r 1 9 8 9 ; 4 3 : 4 0 3 - 9 . 30. Vermiglio F, Sidoti M, Finocchiaro MD, et al. Defective neuromotor and cognitive ability in i o d i n e - d e f i c i e n t schoolchildren of a n e n d e m i c goiter region in S i c i l y . J C l i n Endocrinol M e t a b 1 9 9 0 ; 7 0 : 3 7 9 - 8 4 . 31. Williams G R , R o b s o n H, S h a l e t S M .T h y r o i d h o r m o n e a c t i o n s o n c a r t i l a g e a n d b o n e : interactions w i t h o t h e r h o r m o n e s a tt h e e p i p h y s e a l p l a t e a n d e f f e c t s o n l i n e a r g r o w t h . J E n d o c r i n o l 1 9 9 8 ; 1 5 7 : 3 9 1 - 4 0 3 . 32. Underwood L E ,V a n W y k J J . N o r m a l a n d a b e r r a n t g r o w t h . I n : W i l s o n J D , F o s t e r D W , eds. Williams Textbook of Endocrinology. Philadelphia, PA: W.B. Saunders Company, 1992:1079-138. 33. Boersma B , W i t J M . C a t c h - u p g r o w t h . Endocr Rev 1 9 9 7 ; 1 8 : 6 4 6 - 6 1 . 34. Boyages SC, Collins JK, Maberly GF, Jupp JJ, Morris J, Eastman CJ. Iodine deficiency impairs intellectual and neuromotor development in apparently-normal persons. A study of rural inhabitants of north-central China. Med J Aust 1989;150:676-82.

112 Generaldiscussion

35. Bleichrodt N, E s c o b a r del Rey F, Moreale de Escobar G, Garcia I, Rubio C. Iodine deficiency, implications for mental and psychomotor in children. In: Delong GR, Robbins J , C o n d l i f f e PG, eds. Iodine and the brain. New Y o r k : Plenum Publishing Corporation, 1 9 8 9 : 2 6 9 - 8 6 . 36. UNICEF. Micronutriets: Mid-decade goals. CF/PROG/IC/93-070 24/11/1993. New York, U N I C E F . 1 9 9 3 . 37. UNICEF/PAMM/MI/ICCIDD/WHO. Monitoring universal salt iodization programmes. Atlanta, G . A . : P A M M / M I / I C C I D D , 1 9 9 5 .

113 Annex 1

Efficacy o fd i f f e r e n t t y p e s o f iodized o i l

Lancet 1 9 9 8 ; 3 5 1 : 7 5 2 - 7 5 3 (Letter)

Juliawati Untoro, Werner Schultink, Rainer Gross, Clive E West, Joseph G A J Hautvast Annex 1

Sir--Y Ingenbleek and colleagues(l) describe the preparation and use in severe endemic goitre of a n e w t y p e of iodized oil based on rapeseed oil w h i c h is better than previously available preparations based on poppyseed oil. Iodized oil based o n p e a n u t o i lw a s i n t r o d u c e d i n I n d o n e s i a i n 1 9 9 3 . T h e c o m p o s i t i o n o f p e a n u t oil ( 5 6 %o l e i c a c i d a n d 2 6 %l i n o l e i c a c i d ) is s i m i l a r t o t h a t o f r a p e s e e d o i l ( 6 0 %o l e i c acid and 20% l i n o l e i c acid), as reported by Ingenbleek. Apart f r o m t h e scarcity of poppyseed o i l , i t s h i g h p r o p o r t i o n of p o l y u n s a t u r a t e d f a t t y acids (73%) was a n o t h e r reason f o r s e e k i n g a n e w b a s i s f o r iodized o i l . I o d i n e f r o m s u c h o i l s is r e t a i n e d f o r a shorter time t h a n iodine from oils with a high proportion of monounsaturated f a t t y acids ( 2 ) . We compared t h e efficacy of t w o iodized oils: o i l A (ethyl esters of iodized fatty a c i d s f r o m p o p p y s e e d o i l ; L i p i o d o l ® , Laboratoire G u e r b e t , R o i s s y , F r a n c e ) a n d oil B (iodized peanut oil; Yodiol®, PT Kimia Farma, Jakarta, Indonesia), under community conditions in a r a n d o m i z e d , s i n g l e - b l i n d , p l a c e b o - c o n t r o l l ed trial among 250, 8-10-year-old, Indonesian school children from Cilacap district, Central-Java, which i sa na r e ae n d e m i c f o r i o d i n e d e f i c i e n c y d i s o r d e r s . Children were de-wormed with 400 mg albendazole (SmithKline Beecham, Indonesia) 1 week before being supplemented. A urine sample was collected between 08.00 h a n d 12.00 h o n 2 c o n s e c u t i v e days at baseline and at 4 a n d 12 weeks' f o l l o w - u p . Further s a m p l e s w i l l b e t a k e n a t 2 5 a n d 5 0 w e e k s . U r i n a r y iodine excretion w a s m e a s u r e d i n d u p l i c a t e a n d t h e a v e r a g e c a l c u l a t e d f o r e a c h c h i l d . T h e table s h o w s d e t a i l s a b o u t t r e a t m e n t a n d p r e l i m i n a r y r e s u l t s . U r i n a r y i o d i n e e x c r e t i o n at baseline was closely similar between groups. A t 4 a n d 12 w e e k s urinary iodine excretion of all supplemented groups was significantly higher than in t h e placebo group (Mann-Whitney; P<0.001). Urinary iodine excretion of the group supplemented w i t h o i l A w a s s i m i l a r t o t h e u r i n a r y i o d i n e e x c r e t i o n o f t h e 2 0 0 m g o i l B group, and significantly lower than urinary iodine excretion of the 400 mg oil B group ( P< 0 . 0 0 1 ) a t b o t h 4 a n d 1 2w e e k s .

116 Preliminaryreport on efficacy of oral iodized oils

Table 1. M e d i a n urinary iodine excretion at the baseline and at 4 and 12 w e e k s after oral supplementation o f s c h o o l c h i l d r e n w i t hd i f f e r e n t t y p e s o f i o d i z e do i l .

Treatment* n Median urinary i o d i n e e x c r e t i o n [ r a n g e ] ,n g / L§

Baseline 4w e e k 12w e e k

Iodized o i lA 49 43.0 465.0 *H 239.0 *! 400m g [8.0-195.5] [51.5-1450.0] [72.5-840.0]

Iodized o i lB 50 46.5 533.0 * H 347.5 *U 200m g [20.0-157.0] [124.5-3625.0] [95.5-1797.0]

Iodized o i lB 51 43.5 925.0 t# 555.0 t # 400m g [13.0-143.5] [147.5-3700.0] [115.0-1626.0]

Iodized o i lB 50 46.3 1517.5*** 1119.0*** 800m g [12.0-212.5] [430.0-6450.0] [355.0-2590.0]

Placebo 51 47.5 67.0 § t t 82.5 § t t [6.5-132.5] [15.5-385.0] [14.0-199.0]

* Iodized oil A , iodized fatty acid ethyl esters from poppy-seed oil; iodized oil B, iodized peanut o i l ; p l a c e b o , p e a n u to i l . t Based o nt h e a v e r a g e u r i n a r y i o d i n e e x c r e t i o n o f t w o c o n s e c u t i v e d a y s f o r e a c h p e r s o n Within-group c h a n g e s c o m p a r e d t o b a s e l i n e :$, P < 0 . 0 0 1 ; § ,P < 0 . 0 5 ( W i l c o x o n M a t c h e d - P a i r s ) Different letters (11, # , **, t t j indicate significant differences between groups of treatment (P<0.0001, K r u s k a l W a l l i s )

These results indicate h i g h e r iodine retention f r o m iodized peanut oil t h a n w i t h ethyl esters of iodized f a t t y a c i d s prepared f r o m p o p p y s e e d oil. T h e s h o r t - t e r m efficacy of iodized peanut oil, having a fairly high percentage of monosaturated fatty acid, is greater t h a n t h a t of t h e p o p p y s e e d oil p r e p a r a t i o n . T h i s f i n d i n g is i n a c c o r d w i t h t h a t of Ingenbleek et a l . (1). T h e c o n t i n u e d f o l l o w - u p w i l l s h o w w h e t h e r iodized p e a n u t oil will allow less f r e q u e n t supplementation while maintaining a median urinary iodine excretion higher than 100 ug/L. Iodized oil capsules based on oils with a high percentage of monounsaturated fatty acids would allow eradication of iodine deficiency in a r e a s in w h i c h i m m e d i a t e a c t i o n is r e q u i r e d .

117 Annex 1

REFERENCES

1. Ingenbleek Y, Jung L, Ferard G, Bordet F, Goncalves AM, Dechoux L. Iodised rapeseed o i lf o r e r a d i c a t i o n o f s e v e r e e n d e m i c g o i t r e . L a n c e t 1 9 9 7 ; 3 5 0 : 1 5 4 2 - 5 . 2. Van d e r H e i d e D , d e G o e j e M J ,v a n d e r B e n t C . T h e e f f e c t i v e n e s s of o r a l a d m i n i s t e r e d iodized o i l i n r a t a n d m a n . Annales d ' e n d o c r i n o l o g i e 1989; 5 0 : 116 ( a b s t ) .

118 Summary

The r e s e a r c h d e s c r i b e d int h i s t h e s i s f o c u s e d o n t h e u s e o f o r a l i o d i z e d o i l t o control i o d i n e d e f i c i e n c y in s c h o o l c h i l d r e n l i v i n g in a n e n d e m i c iodine d e f i c i e n t a r e a in Indonesia. Iodine deficiency is responsible for a series of disabilities which are collectively known a s i o d i n e d e f i c i e n c y disorders (IDD). A l t h o u g h goiter is t h e most manifest s i g n , i o d i n e d e f i c i e n c y results in i r r e v e r s i b l e brain d a m a g e in t h e f e t u s a n d infant, retarded mental and psycho-motor development in the child, and also impaired reproductive function. T h e World Summit for Children i n 1990 committed governments to eradicate iodine deficiency by the year 2000. Universal salt iodization has been set as the main strategy employed to eradicate iodine deficiency, a n d a b o u t 6 0 %o f a l l e d i b l e s a l tw o r l d w i d e i si o d i z e d . Various s t r a t e g i e s h a v e b e e n used i n I n d o n e s i a t o c o m b a t iodine d e f i c i e n c y . The prevalence of goiter among school children decreased during the 1980s and adequately i o d i z e d s a l t u s e d i n h o u s e h o l d s i n c r e a s e d f r o m o n et h i r d i n 1 9 8 3 - 1 9 8 4t o nearly one half in 1995. Legislation was promulgated in 1994 t o bring about salt iodization with a m i n i m u m level of f o r t i f i c a t i o n set at 30 mg l / k g s a l t . A l t h o u g h the production and use of iodized salt to control iodine deficiency is now w i d e s p r e a d , additional s t r a t e g i e s a r e r e q u i r e d w h e r e i o d i z e d s a l t c a n n o t b e m a d e a v a i l a b l e int h e short t e r m o r o n l y w i t h d i f f i c u l t y int h e l o n g t e r m .T h e b e s t a l t e r n a t i v e i s p r o b a b l y o r a l iodized o i l w h i c h i st h e s u b j e c t o f t h i st h e s i s . There is e v i d e n c e f r o m p r e v i o u s s t u d i e s t h a t a s i n g l e o r a l d o s e o f i o d i z e d o i l is effective in controlling iodine deficiency for one to two years. T h e most widely available p r e p a r a t i o n i s i o d i z e d p o p p y s e e d o i l . P r e v i o u s w o r k has s h o w n t h a t iodine from i o d i z e d o i l p r e p a r e d f r o m e t h y l o l e a t e w a s r e t a i n e d l o n g e r in b o t h m a n a n d r a t s than t h a t p r e p a r e d f r o m e t h y l l i n o l e a t e o r e t h y l e s t e r s o f f a t t y a c i d s f r o m poppyseed oilw h i c h h a s a h i g h p r o p o r t i o n o f l i n o l e i c a c i d a n d a l o w p r o p o r t i o n o f o l e i c a c i d . O i l s rich i n o l e i c a c i d , s u c h a s p e a n u t oil,a l s o h a v e t h e a d v a n t a g e t h a t t h e y a r e c h e a p e r than p o p p y s e e do i l . Thus t h e e f f i c a c y of o r a l l y a d m i n i s t e r e d i o d i z e d p e a n u t o i l w a s c o m p a r e d w i t h that of iodized poppyseed oil among school children aged 8-10 years living in an endemic iodine d e f i c i e n t a r e a in I n d o n e s i a . In a d d i t i o n , t h e p e r f o r m a n c e of different outcome indicators of iodine deficiency, the impact of nutritional status and iodine supplementation on cognitive performance, as well as the effectiveness of introduction o f s a l t i o d i z a t i o n i nt h e p o p u l a t i o n w e r e i n v e s t i g a t e d . A s i n g l e oral dose of iodized peanut oil compared t o a s i n g le oral dose of iodized poppyseed oil resulted in t h r e e times higher iodine retention leading to a Summary period of protection twice as long. While this study was being carried out, similar results w e r e o b t a i n e d b y o t h e r s u s i n g i o d i z e d o i l p r e p a r e d f r o m r a p e s e e d o i lw h i c h i s also rich in o l e i c acid. T h u s iodized oil prepared f r o m oleic acid rich oils, such as peanut oil and rapeseed oil, should be given preference to poppyseed oil in programs t o c o n t r o l i o d i n e d e f i c i e n c y . Iodine status and the effect of intervention in the population, can be measured using various outcome indicators. The selection of an indicator is dependent o nt h e a c c e p t a n c e o f t h e i n d i c a t o r by t h e t a r g e t p o p u l a t i o n a n d f i e l d s t a f f performing the assessment, on the ease of use in field conditions, and on the available resources in t e r m s of money, laboratory equipment and staff. Above a l l , the indicator must be valid. So far, the number of studies comparing the relative sensitivity a n d s p e c i f i c i t y of i n d i c a t o r s f o r a s s e s s i n g iodine s t a t u s of a p o p u l a t i o n is limited and they have given conflicting results. We evaluated different outcome indicators for assessing iodine status and measuring the effect of oral iodized oil treatment. W e f o u n d t h a t u r i n a r y i o d i n e c o n c e n t r a t i o n a n d t h y r o i d v o l u m e m e a s u r e d by ultrasound are the most useful indicators for assessing iodine status and measuring t h e impact of iodized o i l s u p p l e m e n t a t i o n among iodine d e f i c i e n t school children. The other indicators, i.e.: palpation and serum concentrations of thyroid stimulating hormone (TSH) and f r e e t h y r o x i n e (FT4), d i d not s h o w concordance f o r assessing iodine deficiency or the impact of treatment. Serum concentrations of thyroglobulin were also shown to be of limited value in assessing iodine status. Although t h e s e d a t a h i g h l i g h t t h e l i m i t a t i o n s o f t h y r o i d p a l p a t i o n ,t h i s m e t h o d s t i l l h a s a useful place in assessing iodine status because no sophisticated equipment is required. H o w e v e r it i s n e c e s s a r y f o r o b s e r v e r s t o b et r a i n e d i nt h et e c h n i q u e . Nutritional supplementation of undernourished children is known to have a beneficial effect on their intellectual capacity. The factors related to cognitive performance and the effect of oral dosing with iodized oil were examined using Cattell's c u l t u r a l l y f a i r i n t e l l i g e n c e t e s t . M e d i a n c o g n i t i v e performance w a s l o w ,3 2 % of the children were underweight, 58% w e r e stunted, 3% were wasted, and 4 0 % were anemic. Father's education and hemoglobin concentration were the main determinants o f c o g n i t i v e p e r f o r m a n c e a t b a s e l i n e , and u r i n a r y i o d i n e c o n c e n t r a t i o n and stunting were the most important determinants for improvement in cognitive performance after supplementation with iodized o i l . T h e s e results illustrate t h e role of n u t r i t i o n a n d s o c i a lf a c t o r s i nc o g n i t i v e d e v e l o p m e n t a n d p e r f o r m a n c e i nc h i l d r e n . Data o nt h e e f f e c t i v e n e s s o f i o d i z e d s a l tf o r c o n t r o l l i n g i o d i n e d e f i c i e n c y i s s t i l l 120 Summary scanty. A f t e r o n e y e a r o f i n t r o d u c t i o n o f s a l t i o d i z a t i o n ,t h e p r o p o r t i o n of h o u s e h o l d s using a d e q u a t e l y iodized s a l t i n c r e a s e d s i g n i f i c a n t l y , f r o m 2 %t o 5 4 % , b u t t h e r e w a s inconsistency in its use within households during the study period. The use of iodized s a l t w a s r e l a t e dt o u r i n a r y i o d i n e c o n c e n t r a t i o n a n dt h y r o i d v o l u m e . H o w e v e r the prevalence of goiter measured by palpation remained at 17% and serum concentrations of T S H a n d FT 4 d i d n o t r e s p o n d t o t h e s a l t iodization, i n d i c a t i n g t h e poor performance of t h e s e indicators as mentioned above. T h e s e f i n d i n g s indicate that iodine prophylaxis using iodized salt is not only simply a matter of passing legislation, but should also include advocacy, education, marketing, an overall system o f q u a l i t y a s s u r a n c e a n d m o n i t o r i n g o ft h e s a l t i o d i z a t i o n p r o g r a m .

121 Samenvatting

Het onderzoek dat in dit proefschrift beschreven wordt, was gericht op het gebruik van gejodeerde olie om jodiumtekort te bestrijden bij schoolkinderen woonachtig in e e n e n d e m i s c h j o d i u m d e f i c i e n t g e b i e d in I n d o n e s i e . J o d i u m t e k o r t is verantwoordelijk voor een aantal aandoeningen die bekend staan als het jodiumtekort syndroom (IDD). Hoewel struma het meest zichtbare symptoom is, geeft jodiumtekort ook onomkeerbare hersenschade in de foetus en zuigeling, vertraagde mentale en psycho-motorische ontwikkeling van het kind en ook een verminderde voortplantingsfunctie. Tijdens de World Summit for Children in 1990 verplichtten regeringen z i c h o m j o d i u m t e k o r t v o o r het j a a r 2000 uit te b a n n e n . H e t joderen van z o u t is d e b e l a n g r i j k s t e strategie om het j o d i u m t e k o r t te bestrijden en wereldwijd i so n g e v e e r 6 0 %v a n h e t c o n s u m p t i e z o u tg e j o d e e r d . In I n d o n e s i e z i j n d i v e r s e s t r a t e g i e e n t o e g e p a s t omj o d i u m t e k o r t te b e s t r i j d e n . De prevalence van struma onder schoolkinderen is gedurende de jaren tachtig gedaald. B o v e n d i e n s t e e g h e t g e b r u i k v a n z o u t d a t v o l d o e n d e g e j o d e e r d i s . I n 1 9 8 3 - 1984 g e b r u i k t e slechts een derde van de huishoudens dit zout terwijl dit in 1995 gestegen was tot bijna de helft van de huishoudens. In 1994 werd in de Indonesische wet v a s t g e l e g d dat a l h e t zout t e n minste 3 0 m g j o d i u m per kg m o e t bevatten. H o e w e l d e p r o d u c t i e e n h e t g e b r u i k v a n g e j o d e e r d z o u t t e r b e s t r i j d i n g v a n jodiumtekort nu w i j d v e r s p r e id is, z i j n aanvullende strategieen nodig als gejodeerd zout n i e t s n e l b e s c h i k b a a r is o f a l l e e n met m o e i t e o p l a n g e t e r m i j n b e s c h i k b a a r kan worden. Het b e s t e a l t e r n a t i e f is w a a r s c h i j n l i j k orale t o e d i e n i n g v a n g e j o d e e r d e o l i e , het o n d e r w e r p v a n d i t p r o e f s c h r i f t . Uit eerdere studies is gebleken dat een eenmalige dosis gejodeerde olie effectief is in het bestrijden van j o d i u m t e k o r t e n voor een p e r i o d e v a n 1t o t 2 j a a r . Het m e e s t b e s c h i k b a r e p r e p a r a a t is g e j o d e e r d e p a p a v e r z a a d o l i e . Eerder w e r k h e e f t laten z i e n d a tj o d i u m a f k o m s t i g v a n g e j o d e e r d e o l i e g e m a a k t v a n e t h y l o l e a a t l a n g e r beschikbaar bleef i n d e m e n s e n i n r a t t e n v e r g e l e k e n met o l i e v a n e t h y l l i n o l e a a t o f ethyl e s t e r s v a n v e t z u r e n van p a p a v e r z a a d o l i e met e e n h o o g g e h a l t e a a n l i n o l z u u r en een laag g e h a l t e a an oliezuur. Olien rijk aan oliezuur, zoals pindaolie, hebben ook a l sv o o r d e e l d a t z e g o e d k o p e r z i j n d a n p a p a v e r z a a d o l i e . De doeltreffendheid van oraal toegediende gejodeerde pindaolie werd vergeleken met dat van gejodeerde papaverzaadolie in schoolkinderen van 8-10 jaar woonachtig in een endemisch jodium deficient gebied in Indonesie. Verder werden v e r s c h i l l e n d e indicatoren v a n j o d i u m t e k o r t , het e f f e c t v a n v o e d i n g s s t a t u s e n Samenvatting jodiumsuppletie o pd e c o g n i t i e v e v e r r i c h t i n ga l s o o k d e e f f e c t i v i t e i t v a n d e i n t r o d u c t i e van h e tj o d e r e n v a n z o u t i n d e p o p u l a t i e ,b e s t u d e e r d . Eene e n m a l i g eo r a l e d o s i s g e j o d e e r d e p i n d a o l i e r e s u l t e e r d e i n e e n 3 m a a lz o hoge retentie van j o d i u m met als gevolg een twee maal zo lange beschermende periode. Terwijl deze studie werd uitgevoerd, werden door anderen vergelijkbare resultaten met gejodeerde olie gemaakt van raapzaadolie, wat ook rijk is aan oliezuur. In programma's om jodiumtekort tegen te gaan, zou dus de voorkeur gegeven moeten worden aan gejodeerde olie bereid met oliezuurrijke olien, zoals pindaolie e n r a a p z a a d o l i e , b o v e n g e j o d e e r d e p a p a v e r z a a d o l i e . De jodiumstatus en het effect van interventies kan worden bepaald met verschillende indicatoren. De selectie van een indicator is afhankelijk van de acceptatie van de doelgroep en het personeel dat de meting moet uitvoeren, de bruikbaarheid van de indicator onder onderzoeksomstandigheden en de beschikbare bronnen in termen van geld, laboratoriumuitrusting en personeel. Bovenal m o e t d e i n d i c a t o r v a l i d e z i j n . T o t z o v e r is h e t a a n t a l s t u d i e s beperkt w e l k e de s e n s i t i v i t e i t en s p e c i f i c i t e i t v a n i n d i c a t o r e n v o o r d e b e p a l i n g v a n d e j o d i u m s t a t u s van een populatie onderzoeken. Bovendien zijn de resultaten tegenstrijdig. We hebben v e r s c h i l l e n d e i n d i c a t o r e n g e e v a l u e e r d v o o r d e b e p a l i n g v a n d e j o d i u m s t a t u s en v o o r het m e t e n v a n h e t effect van inname v a n g e j o d e e r d e olie. W e v o n d e n d a t de j o d i u m c o n c e n t r a t i e in de urine en de grootte van de schildklier gemeten door ultrasound d e m e e s t b r u i k b a r e indicatoren z i j n v o o r het meten v a n d e j o d i u m s t a t u s en h e t m e t e nv a n d e u i t w e r k i n g v a n s u p p l e t i e m e t g e j o d e e r d e o l i e b i j s c h o o l k i n d e r e n met e e nj o d i u m t e k o r t . De andere indicatoren, zijnde: palpatie en serum concentraties van het schildklier stimulerend h o r m o o n (TSH) en v r i j t h y r o x i n e (FT4) s t e m d e n n i e t overeen wat betreft het meten van jodiumtekort.of de uitwerking van de behandeling. Serumconcentraties v a n t h y r o g l o b u l i n e bleken o o k e e n b e p e r k t e w a a r d e te hebben voor d e b e p a l i n g v a n d e j o d i u m s t a t u s . Hoewel d e z e g e g e v e n s d e b e p e r k i n g e n v a n schildklierpalpaties benadrukken, heeft deze methode nog steeds een bruikbare plaats i n d e b e p a l i n g v a n d ej o d i u m s t a t u s , o m d a t e r g e e n g e a v a n c e e r d e apparatuur voor n o d i g i s . H e t i se c h t e r b e l a n g r i j k d a t d e w a a r n e m e r s d et e c h n i e k g o e d o n d e r d e knieh e b b e n . Het is bekend dat de aanvulling van de voeding van ondervoede kinderen een g u n s t i g effect heeft op hun intellectuele mogelijkheden. De a a n de cognitieve verrichtingen g e r e l a t e e r d e f a c t o r e n e n h e t e f f e c t v a n o r a l e d o s e r i n g v a n g e j o d e e r d e 124 Samenvatting

olie w e r d e n b e s t u d e e r d met b e h u l p v a n d e ' C a t t e l l ' s culturally f a i r intelligency t e s t ' . Uit de test bleek dat de mediaan van de cognitieve verrichtingen laag was. Bovendien bleek 32% v a n d e k i n d e r e n t e licht t e z i j n v o o r hun l e e f t i j d , 5 8 % w a s te klein voor hun leeftijd, 3% had een t e laag gewicht voor hun lengte en 4 0 % had ijzergebreksanemie. De o p l e i d i n g v a n d e v a d e r e n d e hemoglobineconcentrati e van het kind w a r e n de b e l a n g r i j k s t e determinanten v a n de c o g n i t i e v e v e r r i c h t i n g e n aan het b e g i n v a n d e s t u d i e . D ej o d i u m c o n c e n t r a t i e in d e u r i n e e n e e n te g e r i n g e l e n g t e voor de leeftijd waren de belangrijkste determinanten voor verbetering in de cognitieve verrichting na s u p p l e t i e met gejodeerde olie. Deze resultaten illustreren de r o lv a n v o e d i n g e ns o c i a l e f a c t o r e n in d e c o g n i t i e v e o n t w i k k e l i n g e n v e r r i c h t i n g e n vank i n d e r e n . Gegevens over de effectiviteit van gejodeerd zout voor de bestrijding van jodiumtekort zijn s c h a a r s . Een j a a r na d e introductie v a n gejodeerd zout s t e e g het deel v a n d e h u i s h o u d e n s dat z o u t g e b r u i k t e dat v o l d o e n d e gejodeerd is s i g n i f i c a n t van 2% naar 54%. Het werd echter niet consequent gebruikt binnen huishoudens gedurende d e s t u d i e p e r i o d e . De jodiumconcentrati e in de urine en de grootte van de schildklier waren gerelateerd a a n h e t g e b r u i k van g e j o d e e r d z o u t . E c h t e r , d e p r e v a l e n c e v a n s t r u m a ,

zoals g e m e t e n m e t p a l p a t i e bleef o p 17%. D e s e r u m c o n c e n t r a t i e s v a n T S H e n F T 4 reageerden niet o p d e j o d e r i n g v a n het z o u t . Dit g e e f t aan d a t , z o a l s reeds eerder vermeld, dit geen goede indicatoren zijn. Deze bevindingen duiden aan dat het gebruik van jodiumprofylaxe met behulp van gejodeerd zout niet slechts een aanpassing van de wetgeving vereist, maar daarnaast kan het zoutjoderingsprogramma ook niet zonder promotie, v o o r l i c h t i n g , marketing en een allesomvattends y s t e e mv a n k w a l i t e i t s c o n t r o l e .

125 Ringkasan

Penelitian ini berfokus pada penggunaan kapsul minyak beryodium untuk menanggulangi kekurangan yodium pada anak sekolah di daerah endemik kekurangan y o d i u m d i I n d o n e s i a . Kekurangan y o d i u m b e r p e r a n a n d a l a m s u a t u s e r i bermacam gangguan yang secara keseluruhan disebut gangguan akibat kekurangan y o d i u m (GAKI). M e s k i p u n g o n d o k a d a l a h g a n g g u a n y a n g p a l i n g n y a t a , kekurangan y o d i u m j u g a d a p a t m e n y e b a b k a n g a n g g u a n perkembangan s a r a f p a d a fetus dan bayi, keterlambatan perkembangan mental dan psikomotor pada anak- anak d a n g a n g g u a n s i s t e m r e p r o d u k s i . K o n f e r e n s i WorldSummit for Childrent a h u n 1990 m e n c e t u s k a n k o m i t m e n t p e m e r i n t a h u n t u k m e n g e n t a s k a n k e k u r a n g a n y o d i u m pada tahun 2000. Program iodisasi garam merupakan strategi utama dalam penanggulangan GAKI, dan sekitar 60% g a r a m konsumsi y a n g t e r s e d i a d i s e l u r u h dunia,t e l a hd i i o d i s a s i . Berbagai s t r a t e g i d i g u n a k a n d i Indonesia, untuk menanggulangi kekurangan yodium. Prevalensi g o n d o k dari a n a k sekolah menunjukkan p e n u r u n a n pada t a h u n 1980 a n d a n p e n g g u n a a n g a r a m b e r y o d i u m d i t i n g k a t r u m a ht a n g g a m e n i n g k a t d a r i sepertiga di tahun 1983-1984 menjadi hampir setengah di tahun 1995. Kebijaksanaan pemerintah tentang penggunaan garam beryodium dituangkan dalam Keputusan Presiden pada tahun 1994, yang menetapkan iodisasi garam pada konsentrasi minimal 30 mg l/kg g a r a m . Meskipun produksi dan penggunaan garam b e r y o d i u m u n t u k m e n g a n g g u l a n g iG A K It e l a h m e l u a s , s t r a t e g i l a i n d i p e r l u k a n untuk d a e r a h - d a e r a h d i m a n a g a r a m b e r y o d i u m t i d a k d a p a t d i t e r a p k a n d a l a m j a n g k a waktu pendek atau hanya dapat diterapkan pada jangka waktu panjang dengan tingkat kesulitan yang cukup tinggi. Alternatif yang terbaik kemungkinan adalah kapsul m i n y a k b e r y o d i u m y a n g m e r u p a k a n t o p i k d a r it h e s i s i n i . Hasil penelitian-penelitian terdahulu menunjukkan bahwa pemberian dosis tunggal kapsul beryodium dapat secara efektif menanggulangi kekurangan yodium untuk j a n g k a w a k t u s a t u s a m p a i d u a t a h u n . P r o d u k minyak beryodium yang p a l i n g banyak tersedia saat ini adalah minyak beryodium dari poppyseed. Penelitian terdahulu menunjukkan bahwa yodium dari minyak beryodium dari preparasi ethyl oleat memiliki daya retensi dalam tubuh manusia maupun tikus, lebih lama dari preparasi ethyl oleate atau ethyl esters asam lemak dari minyak poppyseed yang memiliki p r o p o r s i k a n d u n g a n a s a m l i n o l e a t y a n gt i n g g i d a n p r o p o r s i a s a m o l e a t y a n g relatif rendah. Minyak yang kaya kandungan asam oleat, seperti minyak kacang, juga memiliki keunggulan bahwa harganya relatif lebih murah dari minyak poppyseed. Ringkasan

Oleh karena itu, penelitian ini bertujuan untuk membandingkan efikasi dari kapsul m i n y a k k a c a n g d e n g a n k a p s u l m i n y a k poppyseedp a d a a n a k s e k o l a h u s i a8 - 10 t a h u n . Selain itu, penggunaan berbagai indikator dari status yodium, dampak suplementasi yodium terhadap fungsi kognitif juga efektifitas dari iodisasi garam pada m a s y a r a k a t d i t e l i t i l e b i h l a n j u t . Dosis tunggal kapsul yodium minyak kacang menunjukkan retensi yodium tiga kali lebih tinggi dan menghasilkan masa proteksi dua kali lebih lama dibandingkan dengan dosis tunggal kapsul yodium minyak poppyseed. Pada saat studi ini dilakukan, hasil yang sama didapatkan pada preparasi yodium minyak rapeseed, yang juga kaya kandungan asam oleatnya. Oleh karena itu, kapsul minyak beryodium y a n g kaya kandungan asam oleat, seperti minyak kacang dan minyak rapeseed, adalah merupakan produk yang akan lebih disukai dibanding dengan p r e p a r a s i m i n y a k b e r y o d i u mpoppyseed, d a l a m m e n a n g g u l a n g i G A K I . Status yodium dan dampak dari intervensi pada masyarakat, dapat diukur dengan berbagai indikator. Pemilihan indikator adalah t e r g a n t u n g dari penerimaan indikator tersebut oleh populasi yang diukur dan petugas lapang yang melakukan pengukuran, kemudahan melakukan pengukuran tersebut di lapangan, dan ketersediaan s u m b e r d a y a d a l a m p e n g e r t i a n d a n a , p e r a l a t a n l a b o r a t o r i u m d a n s t a f f . Selain i t u ,y a n g p a l i n g u t a m a a d a l a h i n d i k a t o r t e r s e b u t harus v a l i d . H i n g g a s a a t i n i , berbagai penelitian dengan membandingkan sensitifitas and spesifisitas dari bermacam indikator untuk mengukur status yodium pada masyarakat sangat terbatas dan hasilnya saling bertentangan. Penelitian ini mengevaluasi berbagai macam i n d i k a t o r untuk mengukur status y o d i u m d a n d a m p a k d a r i p e r l a k u a n kapsul beryodium. Hasil penelitian ini menunjukkan bahwa konsentrasi yodium urin dan volume tiroid merupakan indikator-indikator yang terbaik untuk mengukur status yodium d a n d a m p a k d a r i p e r l a k u a n k a p s u l b e r y o d i u m p a d a a n a k s e k o l a h . I n d i k a t o r - indikator yang lain, yaitu: palpasi tiroid, konsentrasi serum thyroid stimulating hormone (TSH) dan thyroxine bebas (FT4), tidak menunjukkan hasil yang seiring dalam mengukur status kekurangan yodium dan dampak dari perlakuan. Konsentrasi serum thyroglobulinj u g a menunjukkan hasil y a n g kurang memuaskan dalam mengukur status yodium. Meskipun data menunjukkan bahwa palpasi t i r o id memiliki k e k u r a n g a n , n a m u n p a l p a s i t i r o i d t e t a p m e m i l i k i p e r a n a n dalam mengukur status yodium, karena tidak diperlukan peralatan yang canggih. Akan tetapi, dibutuhkan t r a i n i n g y a n g c u k u p d a l a m t e k n i k p a l p a s i . Suplementasi zat gizi t e r t e n t u pada a n a k - a n a k kekurangan zat gizi t e r s e b u t 128 Ringkasan menunjukkan hasil yang positif bagi perkembangan kapasitas intelektual mereka. Penelitian ini juga bertujuan untuk menginvestigasi faktor-faktor yang berkaitan dengan fungsi kognitif dan dampak dari penggunaan kapsul minyak beryodium terhadap perkembangan fungsi kognitif yang diukur dengan Cattell's culturallyfair intelligence test. Nilai median dari fungsi kognitif anak-anak dalam penelitian ini adalah relatif rendah, selain itu 32% dari populasi memiliki berat badan kurang (berat badan menurut usia), 58% memiliki tinggi badan kurang (tinggi badan menurut usia), 3% menderita berat menurut tinggi badan kurang, dan 40% menderita anemia gizi. Penelitian ini menunjukkan bahwa pendidikan ayah dan status hemoglobin darah memiliki peranan dalam fungsi kognitif, sementara konsentrasi yodium urin dan tinggi badan menurut usia merupakan faktor yang paling menentukan perkembangan fungsi kognitif setelah suplementasi dengan kapsul minyak beryodium. Hasil penelitian ini mengilustrasikan peranan dari f a k t o r gizi d a nf a k t o r s o s i a l d a l a m p e r k e m b a n g a n f u n g s i k o g n i t i f p a d a a n a k - a n a k . Data t e n t a n g efektifitas garam b e r y o d i u m d a l a m m e n a n g g u l a n g i k e k u r a n g a n yodium masih sangat terbatas. Setelah satu tahun penerapan iodisasi garam, proporsi rumah t a n g g a yang menggunakan garam beryodium dengan konsentrasi yang m e m e n u h i p e r s y a r a t a n , m e n i n g k a t d a r i 2 % k e 5 4 % , n a m u n d i t e m u k a n a d a n y a ketidak konsistenan dalam penggunaan garam beryodium di rumah tangga. Penelitian ini m e n u n j u k k a n bahwa p e n g g u n a a n g a r a m b e r y o d i u m b e r k a i t a n d e n g a n status y o d i u m y a n g d i i n d i k a s i k a n d e n g a n k o n s e n t r a s i y o d i u m u r i n d a n v o l u m et i r o i d . Namun prevalensi g o n d o k menurut palpasi t e t a p pada 17% d a n k o n s e n t r a s i serum

TSH dan FT4 t i d a k menunjukkan respon terhadap penggunaan garam beryodium, hal i n i m e n u n j u k k a n k e l e m a h a n p e r f o r m a n d a r i i n d i k a t o r t e r s e b u t s e p e r t i y a n g t e l a h dipaparkan t e r d a h u l u . H a s i l p e n e l i t i a n ini m e n g i n d i k a s i k a n b a h w a d a l a m penerapan penggunaan garam beryodium selain peraturan, dibutuhkan pula promosi, pendidikan, pemasaran, dan sistem yang menyeluruh dalam pengendalian mutu dan p e m o n i t o r a n p r o g r a m i o d i s a s ig a r a m .

129 Acknowledgments

It h a st a k e n m e a b o u t t h r e e y e a r s t o a c c o m p l i s h t h i s w o r k , a n d t h i s w o u l d n o t have b e e n p o s s i b l e w i t h o u t t h e h e l p o f o t h e r s . F i r s t o f a l l , Iw o u l d l i k et o e x p r e s s m y sincere gratitude t o my p r o m o t o r s , Professor Joseph Hautvast and Professor Clive West a n dt o m yc o - p r o m o t o r Dr Werner S c h u l t i n k . Professor Hautvast, t h a n k y o u f o r y o u r v a l u a b l e g u i d a n c e , u s e f u l i n s i g h t s a n d strong s u p p o r t d u r i n g m yw o r k . Y o u r v i s i t s i n I n d o n e s i a a l w a y s g a v e m et h e i m p e t u s to keep my study going. Clive, thank you so much for your ideas, guidance and support t o c a r r y o u t t h i s s t u d y . Y o u r g u i d a n c e g a v e m e a l o t o f i n s i g h t i n t ot h e r e a l m of s c i e n t i f i c w r i t i n g . M a n yt h a n k s f o r s p a r i n g a l o t o f t i m e i ny o u r e v e n i n g s , w e e k e n d s and h o l i d a y s t o r e a d , t o c h a l l e n g e my i d e a s a n d t o c o r r e c t my ' i n d l i s h ' (indonesian- english) of the 'constantly changing' drafts. It was nice to work with you, I am impressed with your combination of hard work and great sense of humor. I w o u l d like a l s ot ot h a n k y o u r f a m i l y f o r a l l o w i n g m et o ' s t e a l 'y o u r t i m e w h i c h w a s s u p p o s e d to have been spent with them. Werner, lots of sincere thanks to you! Your continuous and intensive guidance and encouragement not only made this study happen! b u t a l s o l e dt o t h i s P h D .T h a n k y o u f o r y o u r c o m m i t m e n t t o m y w o r k . M a n y thanks a r e d u e t o Dr Rainer Gross (GTZ/SEAMEO J a k a r t a ) for your s u p p o r t t o t h i s project from the early stages of the proposal writing, during the field work and through the writing period. Your never-failing optimism encouraged me to keep going. I w o u l d a l s o l i k e t o t h a n k Professor Darwin Karyadi a n d P r o f e s s o r S o e m i l a h Sastroamidjojo (SEAMEO Tropmed, University of Indonesia, Jakarta) for their guidance a n ds u p p o r t a n da l s o a l lo f m yc o l l e a g u e s i nS E A M E O / G T Z f o r t h e i r h e l p . Special t h a n k s a r e a l s o d u e t o G T Z f o r f u n d i n g t h e research, t h e Division o f Human Nutrition and Epidemiology, Wageningen Agricultural University for additional funding, and PT Kimia Farma Indonesia for supplying the iodized oil (Yodiol®) a n d i t s p l a c e b o . For h e l p i n o b t a i n i n g p e r m i s s i o n t o c a r r y o u t t h e r e s e a r c h a n d i n s e l e c t i n g t h e research area, I would like to thank Professor R. Djokomoeljanto (Diponegoro University, Semarang) and Dr. Dini Latief (Ministry of Health, Indonesia). Vielen Dank Sandra Lohmann, f o r help with t h e preliminary survey which enabled me t o find a s u i t a b l e a r e a , f o r f r u i t f u l d i s c u s s i o n s , f u n a n d f o r designing t he cover of t h i s thesis. D u r i n g t h ef i e l d w o r k i n C i l a c a p , I n d o n e s i a , I r e c e i v e d a l o t o f a s s i s t a n c e f r o m different institutions and people. I w o u l d like t o t h a n k Dr Sumali, Bang Ramiun o f Dinas K e s e h a t a n C i l a c a p ; Dr S u p r i h a d i y o n o of Puskesmas K a r a n g P u c u n g ; a n d D r Yohannes T r i of Puskesmas Jeruk Legi f o r granting t h e necessary permission and Acknowledgments_ for supporting this study. I would like to express my gratitude to all the field assistants who w o r k e d t i r e l e s s l y and f o r their commitment to t h e i r work, making it possible for me t o complete this study on t i m e . T h a n k s to ibu Kusmalasari, Kuat, Sugiyo, Baryono, Yeni and Darsih. Many thanks to Ibu Oemi, for your help in calming down t h e children and t h e i r parents during taking the blood samples and your kind hospitality during my stay in Cilacap. T h a n k s are also due to Dra Reni Kusumawardhanif o r c o n d u c t i n g t h e p s y c h o l o g i c a l t e s t s . Special gratitude to the head & teachers of SD Pamulihan 1,2 & 3, SD Karang Kemiri 1 & 2 f o r a l l of t h e i r cooperation and f o r a l l o w i n g us t o interfere w i t h their school routine. V e r y special t h a n k s are due t o all of t h e school children who participated in t h i s study. It was obviously a very strange experience for them to donatet h e i r u r i n e a n d " v a m p i r e " b l o o d . I f u l l y u n d e r s t a n d h o w d i f f i c u l t itw a sf o r a l lo f yout o p r o v i d e b l o o d .T e r i m a k a s i h b a n y a k a t a s s e m u a n y a . For t h e u l t r a s o u n d measurements, Dr I v a n M e n d o z a (CeSSIAM, G u a t e m a l a ) provided me with extensive training in using the equipment: thanks Ivan for your patience d u r i n g h u n d r e d o ft r i a l s a n d m a n y p o o r r e a d i n g s . M a n y t h a n k s a r e a l s o d u e to Siti f o r sharing her experience with t h e ultrasound equipment and f o r help with supplementing of the children in the study. Thanks also to Ibu Ance Murdiana (Nutrition Research and Development Center, Bogor) and Dr. Mike Weight and Emma (National Research Programme for Nutritional Intervention of the Medical Research Council, C a p e T o w n , S o u t h A f r i c a ) for the laboratory analysis of urinary iodine c o n c e n t r a t i o n , a n d Dr Muhilal (Nutrition Research and Development Center, Bogor) for valuable inputs on t h e analysis. Many t h a n k s t o Professor Jan J.M. d e Vijlder, PhD a n d Drs Erik Endert at t h e Academic Medical Center, Amsterdam for analyzingt h et h y r o i d h o r m o n e s a n a l y s i s a n df o r p r o v i d i n g v a l u a b l e s u g g e s t i o n s . Many t h a n k s are d u e t o Drs J a n Burema f o r statistical advice specifically in chapters 2 , 3 a n d 5 , a n d t o G r i e t j e v a n der Z e e f o r organizing my a c c o m m o d a t i o n , visa a n d s u p p l i e s . W h i l e i nt h e N e t h e r l a n d s , m a n y p e o p l e c o n t r i b u t e d in o n e w a y o r another in making me feel at home. I w o u l d like to thank my room mates Tiny, Lisette, Hilda, Marie-Francoise and Lisbeth for their friendship, fun and heartfelt helps whenever I needed. Many thanks are also due to Alida, Annelies, Dewan, Elvina, I n g e b o r g , J a c q u e l i n e , Lidwien, L o u s , M a c h t e l d , N a n i , N i c o l e , P a t e r Didacus, Rianne, T i n a , Johan and Heleen for your warm hospitality, showing and sharing 'Dutch life-style', and extending a helpful hand. Lots of thanks are also for other AlO/PhD students for fruitful discussion and kind hospitality. Tiny and Ingeborg, 132 Acknowledgments thanks a lot for converting the summary into a 'samenvatting' in one evening. Special thanks are due to Kerstin, Hilda and Danny for letting me stay in their homes. Papa a n d Mama, I o w e s o m u c h t o y o u : t h a n k s a l o t , duo xie f o r y o u r never ending s u p p o r t a n d m a k i n g me a l w a y s f e e l s o g o o d . I w i s h I c o u l d d o t h e s a m e f o r you, j u s t by letting y o u know how m u c h y o u mean t o me. Many t h a n k s a l s o t o my brothers and sisters for all of your support and daily e-mail greetings and update stories d u r i n g m ys t a y i n H o l l a n d :i t r e a l l y m a d e m ef e e l a th o m e .

With t r u e appreciation

133 Aboutt h ea u t h o r

Juliawati Untoro was born on 4 July 1967 in Magelang, Indonesia. She completed her s e c o n d a r y high s c h o o l (SMA 1- Teladan, Y o g y a k a r t a , I n d o n e s i a ) in 1986 a n d g r a d u a t e d f r o m G a d j a h Mada U n i v e r s i t y (UGM), Indonesia in 1991 w i t h an Ingenieur (BSc) degree in Food T e c h n o l o g y & N u t r i t i o n Science. From 1991 t o 1992, s h e j o i n e d PT A s t r a International Inc, a s a c o r p o r a t e research analyst in t h e Service Q u a l i t y M a n a g e m e n t a n d M a n a g e m e n t Development D i v i s i o n . F r o m 1 9 9 2t o 1994, she studied for her MSc in Nutrition at the South East Asian Ministries of Education Organization - T r o p i c a l Medicine (SEAMEO Tropmed), Regional Center for Community Nutrition, a t t h e University of Indonesia. On g r a d u a t i o n , s h e j o i n e d the SEAMEO T r o p m e d Center as a member of t h e teaching staff with the role of coordinator of t h e regional post graduate trainin g program in Community Nutrition and was also involved in several nutrition research projects. From 1996 to early 1999, she carried out the work described in this thesis, within the framework of collaboration between SEAMEO Tropmed, GTZ (German Technical Cooperation) and the Division of Human Nutrition and Epidemiology, Wageningen Agricultural University.

PUBLICATIONS

Research p a p e r s

UntoroJ, G r o s s R, S c h u l t i n k W , S e d i a o e t a m a D . T h e a s s o c i a t i o n b e t w e e n B M I a n d haemoglobin a n d w o r k p r o d u c t i v i t y a m o n g I n d o n e s i a n f e m a l e f a c t o r y w o r k e r s . Eur J Clin N u t r 1 9 9 8 ; 5 2 : 1 3 1 - 1 3 5 .

Pardede L V H , H a r d j o w a s i t o W , G r o s s R, D i l l o n D H S ,T o t o p r a j o g o O S , Y o s o p r a w o t o M, Waskito S and Untoro J. Urinary iodine excretion is the most appropriate outcome indicator for iodine deficiency at field conditions at district level. J Nutr 1998;128:1122-1126.

UntoroJ, Ruz M, G r o s s R. Low e n v i r o n m e n t a l selenium a v a i l a b i l i t y as a n a d d i t i o n a l determinant f o r g o i t e r in E a s t J a v a , I n d o n e s i a ? . B i o l o g i c a l T r a c e E l e m e nt R e s e a r c h . Inp r e s s .

UntoroJ, Schultink W, W e s t CE, G r o s s R, Hautvast JGAJ. E f f i c a c y of oral iodized peanut oil is greater than that of iodized poppyseed oil among Indonesian school children. Submitted f o r p u b l i c a t i o n . About theAuthor

UntoroJ, W e s t C E , S c h u l t i n k W , G r o s s R , H a u t v a s t J G A J . C o m p a r i s o n o f i n d i c a t o r s to a s s e s s iodine status and its improvement through supplementation with iodized oil. Submittedf o r p u b l i c a t i o n .

UntoroJ, W e s t C E , S c h u l t i n k W , G r o s s R, H a u t v a s t J G A J . E f f e c t of s t u n t i n g , i o d i n e deficiency and o r a l iodized o i l s u p p l e m e n t a t i o n on c o g n i t i v e performance of school children i na ne n d e m i c i o d i n e d e f i c i e n t a r e a o f I n d o n e s i a . Submittedf o r p u b l i c a t i o n .

UntoroJ, W e s t C E , S c h u l t i n k W, G r o s s R, H a u t v a s t J G A J . I m p a c t o f s a l t iodization on i o d i n e s t a t u s o f I n d o n e s i a n s c h o o l c h i l d r e n l i v i n g i n a m o d e r a t e l y i o d i n e d e f i c i e n t area. Submitted f o r p u b l i c a t i o n .

Other s c i e n t i f i c p u b l i c a t i o n s

Gross R, Schultink W and Juliawati. Treatment of anaemia with weekly iron supplementation [ l e t t e r ] . L a n c e t 1 9 9 4 ,3 4 4 ;8 9 2 5 : 8 2 1 .

Untoro J, S c h u l t i n k W , G r o s s R, W e s t C E , H a u t v a s t J G A J . E f f i c a c y o f d i f f e r e n t t y p e s of i o d i s e d o i l [ l e t t e r ] . Lancet 1 9 9 8 ; 3 5 1 : 7 5 2 - 7 5 3 .

Juliawati,G r o s s R, S c h u l t i n k W , S e d i a o e t a m a D . L o w B M I a n d h e m o g l o b i n reduced productivity o f I n d o n e s i a n f e m a l e w o r k e r s . Symposium: N u t r i t i o n a n d p e r f o r m a n c e , exercise and f i t n e s s . Proceedings of the 7th Asian Congress of Nutrition. B e i j i n g , October 7 - 1 1 , 1995 ( A b s t r a c t ) .

Juguan JA, Lukito W , Schultink W, UntoroJ. Micronutrient status of elderly people living in an urban subdistrict of Jakarta. Proceedings of the 16th International Congress o f N u t r i t i o n . M o n t r e a l ,J u l y 2 7 - A u g u s t 1, 1 9 9 7 ; 6 0 ( A b s t r a c t ) .

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