Iodine deficiency in pregnant women in the apparently iodine-sufficient capital city of Turkey

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1 Clinical Endocrinology (2012) 77, doi: /j x ORIGINAL ARTICLE Iodine deficiency in pregnant women in the apparently iodine-sufficient capital city of Turkey Alev Oguz Kutlu* and Cengiz Kara *Department of Pediatric Endocrinology, Dr. Sami Ulus Women s and Children s Hospital, Ankara, and Department of Pediatric Endocrinology, Ondokuz Mayis University, Samsun, Turkey Summary Objective Previous studies of the current iodine status in Turkey have yielded contradictory results. Although urinary iodine concentration (UIC) in school age children (SAC) suggests sufficient iodine status, studies on neonatal thyroid-stimulating hormone (TSH) indicate that iodine deficiency is a continuing problem. We aimed to assess the iodine nutritional status of pregnant women living in Ankara, an area that has appeared to be iodine sufficient in earlier studies. Design Hospital-based, noninterventional, prospective, crosssectional study. Methods A total of 162 pregnant women in their second trimester were examined regarding iodized salt use, UIC, presence or absence of goitre and thyroid function. Goitre status was determined by palpation. UIC was measured using colorimetric method based on Sandell Kolthoff reaction. Thyroid hormones and TSH were measured by chemiluminescence immunoassays. Results While the proportion of iodized salt use was 80 2%, UIC was below 150 μg/l in 72 8% of the women. The median UIC was 80 5 ( ) μg/l, indicating insufficient iodine intake. Total goitre rate was 15 4%. Preferential T3 secretion reflected by elevated molar ratios of FT3/FT4 was present in 89 5% of the women. 12 4% had subclinical hypothyroidism or isolated hypothyroxinaemia based on serum TSH and FT4 levels. Conclusions Our study shows that iodine deficiency is a serious problem among pregnant women in Ankara. These data confirm that iodine nutritional status among SAC does not reflect the iodine supply for pregnant women. We propose that nationwide surveillance studies should urgently be performed to directly assess and monitor the iodine status of pregnant women. We also consider that pregnant women in Turkey should be supplemented by iodine-containing preparations in addition to iodized salt. Correspondence: Cengiz Kara, Department of Pediatric Endocrinology, Ondokuz Mayıs University, Kurupelit, Samsun, Turkey. Tel.: ; Fax: ; cengizkara68@yahoo.com (Received 27 March 2012; returned for revision 10 April 2012; finally revised 24 April 2012; accepted 10 May 2012) Introduction Iodine deficiency is a global public health problem affecting nearly 2 billion people. 1 Adverse effects of iodine deficiency result from inadequate thyroid hormone production and include goitre, hypothyroidism, spontaneous abortion, stillbirth, congenital anomalies, increased perinatal and infant mortality, cretinism, impaired mental function and delayed physical development. 2 All of the adverse health consequences, which are collectively called iodine deficiency disorders (IDD), can be prevented by adequate iodine intake. To assess and monitor iodine intake in a population, four methods are recommended by World Health Organization (WHO) and International Council for Control of IDD (ICCIDD): urinary iodine concentration (UIC), goitre prevalence, serum thyroglobulin and neonatal thyroid-stimulating hormone (TSH) levels. 3 Urinary iodine excretion is the main indicator for recent iodine intake. 2,3 Traditionally, if the median UIC in school age children (SAC) is below 100 μg/l, insufficient iodine intake is considered to be a problem affecting the entire population. 4 In Turkey, before 1998 when iodization of table salt became mandatory, the median UIC in SAC was 25 5 μg/l, indicating moderate ID. 5 After salt iodization, the median UIC increased to 87 μg/l in 2002 and to 117 μg/l in In 2007, the median UIC reached 130 μg/l, suggesting sufficient iodine intake in the general population. 7 These follow-up monitoring studies demonstrated that iodine deficiency was eliminated in most urban areas, including Ankara, the capital city of Turkey. 6,7 A recent study from Turkey has found that the mean value of UIC among adolescents was 198 μg/l. 8 Taken together, these data suggest that the IDD control programme was successful in Turkey, especially in urban areas. However, several studies on neonatal TSH levels and congenital hypothyroidism (CH) have yielded conflicting results For example, in a study investigating the role of iodine deficiency in the aetiology of CH, we found that the frequency of iodine deficiency was 36% in CH patients and 88% in their mothers

2 616 A. Oguz Kutlu and C. Kara The median values of UIC in patients and their mothers were 110 and 40 μg/l, respectively. Another recent study on cord blood TSH has found a high frequency (28%) of elevated TSH concentrations. 13 Although the results of national CH screening, implemented by the Ministry of Health since 2007, have not yet been published, the data from several studies on regional CH screening indicate that iodine deficiency may still be a public health problem in some regions in Turkey Because an elevated TSH level in newborns is suggested as a sensitive indicator of iodine nutrition during pregnancy, 14 previous studies on neonatal TSH and CH generally imply that pregnant women in Turkey have inadequate iodine nutrition However, only a few studies directly examined iodine status in Turkish pregnant women. 15,16 Therefore, we aimed to assess the iodine nutritional status of pregnant women living in Ankara, an area appears to be iodine sufficient from earlier studies. We hypothesized that if iodine deficiency is an ongoing problem, pregnant women s iodine intake may also be insufficient. For this purpose, we examined iodized salt use, UIC, goitre prevalence and thyroid function of pregnant women in their second trimester. Subjects and methods This was a hospital-based, noninterventional, prospective, crosssectional study. The study was carried out at the gynaecology and obstetrics outpatient clinics of the Dr Sami Ulus Women s and Children s Hospital in Ankara between October and December All consecutive pregnant women in their second trimester who attended the hospital for routine antenatal care were recruited in the study. The study protocol was approved by the Hospital Ethics Committee for Human Studies. All participants provided written informed consent. Subjects with known thyroid pathologies or any other acute or chronic diseases at the time of presentation and those using medicines that might affect thyroid hormone metabolism or iodine bioavailability including iodinecontaining prenatal vitamins were excluded. After exclusion of 22 women, a total of 162 subjects were included in the study group. Participants filled out a questionnaire, which included questions regarding socio-demographic features and iodized salt consumption. A clinical neck examination was performed by the same investigator (A.O.K), and goitre was ascertained and classified according to the criteria recommended by WHO and IC- CIDD (grade 0: no goitre; grade 1: thyroid palpable but not visible; grade 2: thyroid visible with neck in normal position). When in doubt, the immediate lower grade was recorded. The sum of grades 1 and 2 provided the overall goitre rate (or prevalence) in the study population. 4 A total goitre rate above 5% was considered to be suggestive of long-term iodine deficiency. 2,3 Early-morning spot urine samples were collected in deiodized test tubes with tight lids and were immediately transported to the laboratory and stored in a lightproof box at 20 C until just before analysis. The UIC was determined with a colorimetric method based on the Sandell Kolthoff reaction as recommended by WHO and ICCIDD, 17 using Fisher reagents (Spectrum Chemicals and Laboratory Products, CA, USA), Spectronic 20 (Thermo Scientific Instruments Group, Madison, WI, USA) and Genesis autoanalyzer (McKinley Scientific, Sparta, NJ, USA). The analytical sensitivity was 2 μg/l. The coefficient of variation in the range investigated was <5%. A recent WHO/ICDIDD expert group defined epidemiological criteria for assessing iodine nutrition based on the median or range in UIC of pregnant women. 3 Based on these ranges, iodine intake was accepted as follows: insufficient, if UIC is <150 μg/l; adequate, if between 150 and 249 μg/l; more than adequate, if between 250 and 499 μg/l; and excessive, if 500 μg/l. Total triiodothyronine (T3), total thyroxine (T4), free T3 (FT3), free T4 (FT4) and TSH were measured by chemiluminescence immunoassays using Immulite 2500 analyzer (DPC, Los Angeles, CA, USA). As recently recommended, 18 trimester-specific reference intervals were used for serum FT3, FT4 and TSH. Second trimester specific reference ranges for serum FT3, FT4 and TSH were , pm and miu/l, respectively. Normal serum T3 and T4 values for nonpregnant women were nm and nm, respectively. Precision profiles showed inter- and intra-assay coefficients of variation <5% over the entire measurement range. The molar ratios of T3/T4 and FT3/FT4 were calculated to determine whether preferential T3 secretion existed as a consequence of iodine deficiency. Under conditions of normal iodine intake, the T3/T4 ratio usually ranges between 10 and , 19 and the FT3/FT4 ratio is below 0 25 in euthyroid pregnant women. 20 Elevated molar ratios of T3/T4 ( ) and FT3/FT4 ( 0 25) were used as an indicator of thyroidal alterations because of iodine deficiency during pregnancy. 20,21 In assessing maternal thyroid function, we referred to FT4 and TSH levels. Accordingly, a diagnosis of overt or subclinical hypothyroidism was established in women having raised TSH (>3 1 miu/l) with or without low FT4 (<9 6 pm), respectively. A condition of normal TSH, but low FT4, was considered as isolated hypothyroxinaemia. 22 Data were analysed using SPSS software (Statistical Package for the Social Sciences, version 15.0; SPSS Inc, Chicago, IL, USA). Values in the text are presented either as means ± standard deviation (SD) or, if not normally distributed, as medians (ranges). Statistical analysis was performed using parametric (v 2 - and Student s t-tests) or nonparametric (Fisher s exact and Mann Whitney U-tests) tests, when appropriate. Values for P < 0 05 were accepted as statistically significant. Results Urinary iodine concentration A total of 162 pregnant women whose ages ranged from 16 to 41 years (25 ± 4 6) were enrolled for this study between the 12th and 18th week of gestation. The median UIC was 80 5 μg/l ( μg/l), which indicated an overall insufficient iodine intake. UIC was below 150 μg/l in 72 8% of the women (Table 1). Accordingly, only 27 8% of the pregnant women had adequate or more than adequate iodine intake.

3 Iodine deficiency in pregnant women in Turkey 617 Table 1. Distribution of urinary iodine concentrations (UIC) in the study group Reference ranges* for the median UIC Goitre prevalence Iodine intake based on the median UIC The total prevalence of goitre of any grade was 15 4% (n = 25), with a visible (grade 2) goitre in 4 3%. The high total goitre prevalence was another indicator of iodine deficiency in the study group. All of the women with goitre had insufficient iodine intake (UIC < 150 μg/l).the UIC [61 7 ( ) μg/ l] in women with goitre was significantly lower than in women without goitre [93 6 ( ) μg/l] (P = 0 019). Thyroid function parameters Number (percent) of pregnant women UIC [median (range)] <150 μg/l Insufficient 118 (72 8%) 58 5 ( ) [<50 μg/l] [54 (33 3%)] [<100 μg/l] [92 (56 8%)] μg/l Adequate 28 (17 3%) ( ) μg/l More than 16 (9 9%) ( ) adequate 500 μg/l Excessive 0 Total ( ) *Reference ranges defined by WHO/ICDIDD (Ref. 3). In accordance with the physiological changes in pregnancy, serum T3 and T4 levels were increased (Table 2). Because the increment in serum T4 level was relatively low, the T3/T4 molar ratio was found to be elevated in 44 8% (35/78) of the women. In addition, as the mean FT3 was raised and the mean FT4 remained within normal limits, the molar ratio of FT3/FT4 was remarkably increased at 0 44 ± 0 11 and was above the upper limit of normal in 89 5% of the women (Table 2). Table 2. Average values of the studied thyroid parameters Parameter n Normal range Mean ± SD Median (range) T3 (nm) * 3 37 ± ( ) T4 (nm) * ± ( ) FT3 (pm) ± ( ) FT4 (pm) ± ( ) TSH (miu/l) ± ( ) Molar ratio 78 < ± ( ) of T3/T4 Molar ratio of FT3/FT4 162 < ± ( ) TSH, thyroid-stimulating hormone. *Normal range for nonpregnant women. Trimester-specific reference range. Ref. 21. Ref. 20. Of the 162 pregnant women, 16 (10%) had raised TSH (>3 1 miu/l) with normal FT4 indicating subclinical hypothyroidism. None of our subjects had overt hypothyroidism. However, four patients (2 4%) had isolated hypothyroxinaemia, with low FT4 (<9 6 pm) and normal TSH concentrations. Among 20 women with thyroid function abnormalities, antithyroid antibodies were positive in two women with subclinical hypothyroidism. Overall, 20 women (16 subclinical hypothyroidism, four isolated hypothyroxinaemia) were given substitutive L-T4 (median T4 dose 1 65 μg/kg per day). In all of them, serum TSH and/or FT4 values returned to normal within 4 weeks and remained normal during further follow-up. Summary of questionnaire data Pregnant women in the study group were, in general, of low socioeconomic level, with a monthly household income of 402 ( ) and median education duration of 8 (5 15) years. During the enquiry, 80 2% of pregnant women declared that they used iodized salt at home. Even though the median UIC (91 8 μg/l) of women using iodized salt was significantly higher than in women using noniodized salt (54 5 μg/l) (P = 0 009), only 32 3% of iodized salt users had adequate iodine intake (UIC 150 μg/l). Iodine deficiency was diagnosed in 67 7% and 93 2% of expectant mothers with and without iodized salt use, respectively (P = 0 003). Discussion Even though the results of previous monitoring studies on the basis of sufficient urinary iodine excretion in SAC have shown the region of Ankara to be iodine-replete since 2007, 6,7 recent studies based on CH and TSH levels of neonates born in Ankara suggest that iodine deficiency is a continuing problem. 12,13 To clarify these controversial data, we carried out the first study assessing the iodine nutritional status of pregnant women in Ankara, the capital city of Turkey. Our study has shown that the median UIC in pregnant women was 80 5 μg/l, indicating insufficient iodine intake. More importantly, 72 8% of these pregnant women were iodine deficient and 15 4% had goitre. Therefore, our results demonstrate that iodine deficiency remains a serious problem for pregnant women living in Ankara, an area that appeared to be iodine sufficient in previous studies, 6,7 and are in agreement with similar reports of low iodine status in pregnant women from other regions of Turkey. 15,16,23 Our results also indicate that iodine nutritional status among SAC does not reflect the iodine supply of pregnant women and their offspring in the same region. In fact, several studies from different countries have shown marginal or deficient iodine status in pregnant women residing in iodine-sufficient areas Our findings confirm this information and further emphasize the need to monitor pregnant women directly. Older recommendations from WHO propose that a <3% frequency of neonatal TSH values >5 miu/l indicates iodine sufficiency in a population. 29 A recent study by Zimmermann et al. 14 on iodine status in pregnant women and children

4 618 A. Oguz Kutlu and C. Kara supported the notion that the frequency of neonatal TSH concentrations >5 miu/l was a sensitive indicator of iodine nutrition during pregnancy. Even though the large data set of national CH screening in Turkey has not yet been published, the current regional data showing a high prevalence of neonates with elevated TSH levels implies the presence of inadequate iodine nutrition of pregnant women. 10,11,13 The present and other studies, 15,16,23 therefore, provide direct evidence for the problem of iodine deficiency among pregnant women in Turkey. The major impact of iodine deficiency in pregnant women is on the foetus and neonate. Mild thyroid insufficiency defined by a moderate decrease in maternal FT4 concentration during pregnancy has detrimental effects on neuropsychological development of the child. 30,31 In this study, we assessed thyroid function parameters to determine whether there was any thyroid dysfunction that might reflect inadequate iodine intake. We found that the vast majority of women had relative hypothyroxinaemia and preferential T3 secretion as reflected by the elevated molar ratio of FT3/FT4 in serum. In addition, 12 4% of the women had subclinical hypothyroidism or isolated hypothyroxinaemia. These thyroid abnormalities during pregnancy suggested that the women were greatly affected by iodine deficiency. This was not an interventional study; however, the expectant mothers at risk because of a high TSH or a low FT4 were treated with L-T4. Taken together, the increased goitre rate, low UIC and thyroid function data indicate that intrathyroidal iodine stores of the women in the study group were insufficient. Consequently, our study suggests that women planning a pregnancy and pregnant women living in Ankara should be supplemented with iodine-containing preparations. On the other hand, considering that previous studies, carried out in various cities from the different regions of Turkey, have demonstrated deficient iodine status of newborns and/or pregnant women, 9 13,15,16,23 it can be concluded that iodine deficiency among pregnant women is a more widespread problem that is not restricted to those living in Ankara. For this reason, we consider that pregnant women in Turkey as a whole should receive iodine supplementation, in addition to the use of iodized salt. WHO experts recommend that universal salt iodization remains the main strategy for elimination of iodine deficiency in pregnancy. 32 However, a few countries (e.g. Switzerland) that have long-standing and well-established salt iodization programmes have achieved an adequate median UIC in pregnant women. 14 On the other hand, iodine status in pregnant women is obviously suboptimal in many other countries around the world including Australia, China, Kyrgyzstan, Pakistan and many European countries. 20,33 37 Moreover, several recent studies have reported deficient iodine status in pregnant women from different iodine-sufficient regions including Italy, Iran, India, Thailand, Australia and the United States ,38 Similar to the results of our study, these worldwide data suggest that pregnant women may need iodine supplementation despite salt iodization. Currently, the American Thyroid Association recommends a supplement of 150 μg iodine per day during pregnancy and lactation, in addition to the use of iodized salt. 39 Thus, at present, this official recommendation appears suitable for pregnant women living in Turkey as well as in other regions of the world. Most multivitamin/mineral products that are marketed as prenatal supplements do not contain iodine, and iodine tablets are not available at this time in Turkey. The Ministry of Health has currently implemented programmes directed to prevent major nutritional problems including vitamin D, iron and iodine deficiencies ( last accessed March 2012). In the context of these programmes, children and pregnant women have been supplemented by the Ministry of Health with vitamin D and iron preparations, but not with iodine. As a result, we believe that the Ministry of Health should provide iodine supplementation to pregnant women as a part of the IDD control programme. Such iodine supplementation would be especially important for the poor and less educated women like those in our study group. The insufficient iodine nutrition of pregnant women, despite the regular use of iodized salt, might have three possible explanations: (i) inadequate iodine content of table salts, (ii) erroneous consumption of iodized salt and (iii) insufficient salt intake. We have no direct evidence on these specific topics because our study has some potential limitations. First, we did not analyse iodine content of salt samples used at home. However, the latest surveillance study by Erdoğan et al. 7 in Turkey revealed that 56 5% of salt samples at the home level had adequate (>15 ppm) iodine content. This figure demonstrates that the proportion of households using adequately iodized salt in Turkey was considerably under the target level of at least 90% recommended by WHO. 3 The second limitation of our study is that we have not gathered data on the pregnant women s knowledge, attitudes and behaviour towards the consumption of iodized salt. Nevertheless, a recent study on Turkish pregnant women of higher educational level has found that only 19 1% stored iodized salt appropriately in lightproof containers and that only 16 3% added iodized salt properly after cooking into the stewpot or their plate. 16 Based on these findings, we can speculate that insufficient iodine nutrition in pregnant women might also be related to their defective knowledge, attitude and behaviour regarding iodized salt consumption. In addition, even if the women have correctly consumed adequately iodized salts, their daily salt intake might not be enough to meet the daily iodine requirement. In fact, a person should consume approximately 6 15 g per day of adequately iodized salt to receive the 250-μg iodine recommended by WHO for pregnant women. 3 On the other hand, WHO recommends a salt intake per person of <5 g/day to reduce the risk of cardiovascular diseases. 40 Therefore, a salt intake below 5 g/day during pregnancy may cause insufficient iodine intake. Finally, another potential limitation of our study is that it was a hospital-based study with a relatively small sample size. Thus, our results may not be applicable to all pregnant women, especially to those of higher socioeconomic level, in Ankara. For confirmation of our results, nationwide, population-based, cross-sectional surveys are required. In conclusion, our study shows that iodine deficiency is a serious problem in the poor and less educated subgroup of

5 Iodine deficiency in pregnant women in Turkey 619 pregnant women living in Ankara, an area that appeared to be iodine sufficient in previous studies. These data also confirm that iodine nutritional status among SAC does not reflect the iodine supply of pregnant women in the same region. Based on the data of the present and other studies from Turkey 9 13,15,16,23, we propose that nationwide surveillance studies should urgently be performed for direct assessment and monitoring of iodine status in pregnant women. We also consider that pregnant women in Turkey should be supplemented by iodine-containing preparations in addition to iodized salt. Declaration of interest Nothing to disclose. References 1 de Benoist, B., McLean, E., Andersson, M. et al. (2008) Iodine deficiency in 2007: global progress since Food and Nutrition Bulletin, 29, Zimmermann, M.B. (2009) Iodine deficiency. 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