Iodine Intake and Maternal Thyroid Function During Pregnancy

ORIGINAL ARTICLE

Iodine Intake and Maternal Thyroid Function During Pregnancy Marisa Rebagliato,a,b Mario Murcia,a,c Mercedes Espada,d Mar A´lvarez-Pedrerol,a,e Francisco Bolu´mar,a,f Jesu´s Vioque,a,b Mikel Basterrechea,a,g Elizabeth Blarduni,h Rosa Ramoń,a,c Mońica Guxens,a,e Carles M. Foradada,i Ferrań Ballester,a,c Jesu´s Ibarluzea,a,g and Jordi Sunyera,e,j Background: An adequate iodine intake during pregnancy is essential for the synthesis of maternal thyroid hormones and normal brain development in the fetus. Scant evidence is available on the effects and safety of iodine supplementation during pregnancy in areas with adequate or mildly deficient iodine intake. We examined the association of maternal iodine intake and supplementation with thyroid function before 24 weeks of gestation in population-based samples from 3 different areas in Spain. Methods: A cross-sectional study of 1844 pregnant women (gestational age range 8 –23 weeks) was carried out in 3 areas in Spain (Guipu´zcoa, Sabadell, Valencia), during the period 2004 –2008. We measured levels of free thyroxine and thyroid-stimulating hormone (TSH) in serum, iodine in a spot urine sample, and questionnaire estimates of iodine intake from diet, iodized salt and supplements. Adjusted associations were assessed by multiple linear regression and logistic regression analyses. Results: There was an increased risk of TSH above 3 ␮U/mL in women who consumed 200 ␮g or more of iodine supplements daily compared with those who consumed less than 100 ␮g/day (adjusted odds ratio ⫽ 2.5 关95% confidence interval ⫽ 1.2 to 5.4兴). We Submitted 17 December 2008; accepted 15 September 2009. From the aCentro de Investigación Biomédica en Red de Epidemiología y Salud Pu´blica (CIBERESP), Barcelona, Spain; bDepartment of Public Health, Miguel Hernańdez University, Ctra Alicante-Valencia, San Juan de Alicante, Spain; cDivision of Environment and Health, Valencian School for Health Studies-EVES, Valencian Center for Research on Public Health-CSISP, Valencia, Spain; dDepartamento de Sanidad Gobierno Vasco, Laboratorio Normativo de Salud Pu´blica, María Díaz de Haro, Bilbao, Spain; eCentre for Research in Environmental Epidemiology, Barcelona, Spain; fDepartamento de Ciencias Sanitarias y MédicoSociales, Alcala´ University, Ctra Madrid-Barcelona, Alcala´ de Henares, Madrid, Spain; gDepartamento de Sanidad Gobierno Vasco, Subdireccioń de Salud Pu´blica de Guipu´zcoa, Avenida de Navarra, San Sebastiań, Spain; hDepartment of Pediatrics, Hospital Zumarraga, Osakidetza, Barrio Argixao s/n, Zuma´rraga, Spain; iDepartment of Obstetrics and Gynecology, Hospital Parc Taulí, Sabadell, Spain; and jDepartment of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain. Supported by grants from Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0041), the Spanish Ministry of Health (FIS 03/1615, FIS 04/1509, FIS 04/1436, FIS 05/1079, FIS 06/1213, FIS06/0867), Ministerio Educacioń y Ciencia (SAF2002-03508), the Generalitat de Catalunya-CIRIT 1999SGR 00241, Departamento de Sanidad-Gobierno Vasco 2005111093, and Diputacioń Foral de Gipuzkoa 06/004. Correspondence: Marisa Rebagliato, Miguel Hernańdez University, Department of Public Health, Ctra Alicante-Valencia, Km 87, 03550 San Juan de Alicante, Spain. E-mail: [email protected]. Copyright © 2009 by Lippincott Williams & Wilkins ISSN: 1044-3983/10/2101-0062 DOI: 10.1097/EDE.0b013e3181c1592b

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observed no association between urinary iodine and TSH levels. Pregnant women from the area with the highest median urinary iodine (168 ␮g/L) and highest supplement coverage (93%) showed the lowest values of serum free thyroxine. (geometric mean ⫽ 10.09 pmol/L 关9.98 to 10.19兴). Conclusions: Iodine supplement intake in the first half of pregnancy may lead to maternal thyroid dysfunction in iodine-sufficient or mildly iodine-deficient populations. (Epidemiology 2010;21: 62– 69)

A

n adequate iodine intake during pregnancy is essential for the synthesis of maternal thyroid hormones, which in turn are required for an adequate maturation of the central nervous system of the fetus and the subsequent neurodevelopment of the child.1– 4 Because fetal thyroid gland does not contribute to fetal requirements until midgestation, the fetus is totally dependent at this stage on maternal thyroid function for its normal brain development. Furthermore, an increase in maternal thyroxine production is required during pregnancy due to several metabolic changes, apart from the transfer of thyroxine to the fetus.5 Healthy pregnant women with a sufficient iodine intake before conception (150 ␮g/day) and consequently adequate store of iodine in the thyroid, are able to adjust their thyroid economy for the pregnant situation.5 In contrast, pregnant women from iodine-deficient areas may have pathologic changes in maternal thyroid function. The main consequences are a relative decrease of maternal free thyroxine levels and an increased concentration of serum thyroid-stimulating hormone (TSH). Based on a recent report by the World Health Organization (WHO),6 several European countries (including Belgium, France, Italy, and some regions in Spain) are still affected by mild iodine deficiency. In the U.S.A., the data from the National Health and Nutrition Examination Survey (NHANES) support adequate iodine nutrition in the general population, including pregnant women.7 However, recently published papers have pointed out a heightened concern about iodine nutrition during pregnancy.8 The American Thyroid Association9 recommends that in the U.S.A., women Epidemiology • Volume 21, Number 1, January 2010

Epidemiology • Volume 21, Number 1, January 2010

receive 150 ␮g iodine supplements daily during pregnancy, despite the fact that reported median urinary iodine concentrations in pregnant women7 are within the normal range established by WHO (150 –249 ␮g/L).10 There is wide consensus that the small risks of iodine excess are outweighed by the substantial hazards of iodine deficiency during pregnancy. Consequently, universal iodine supplementation programs for pregnant and lactating women have been widely advocated.9,10 However, in recent years, there has also been an increasing concern about the importance of monitoring risk of thyroid disease due to excessive consumption of iodine, given the association found in several studies between increased iodine intake and a higher prevalence of subclinical and even overt hypothyroidism in the general population and in women of reproductive age.11–14 Despite this evidence, information is limited on the effects of supplementation programs on maternal thyroid function in iodine-sufficient populations or even in mildly iodine-deficient areas.15–22 As part of the collaborative mother and child cohort study Infancia y Medio Ambiente (Environment and Childhood),23 we assessed the effect of maternal iodine nutritional status, measured by urinary iodine concentration and iodine intake from diet and supplements, on maternal thyroid function before 24 weeks of gestation in 3 areas in Spain—Valencia, Guipu´zcoa, and Sabadell— each with different supplementation practices.

METHODS Population and Study Design This analysis denotes a Spanish multicenter populationbased mother and child cohort study; details about the research protocol have been published elsewhere.23 In this paper, we analyzed the cross-sectional data obtained at baseline in pregnant women enrolled in the study in 3 areas: Valencia, Guipu´zcoa (Basque Country), and Sabadell (Catalonia). All pregnant women were recruited at their first routine antenatal care visit in the main public hospital or health center of reference for defined geographical areas. The recruitment period was from February 2004 to June 2005 in Valencia, from April 2006 to January 2008 in Guipu´zcoa, and from July 2004 to July 2006 in Sabadell. There were 2137 women who agreed to participate and met the inclusion criteria (being at least 16 years old, having a singleton pregnancy, and not following any program of assisted reproduction). We included only those women who had a serum sample available for thyroid hormone testing and questionnaire data on iodine intake before 24 weeks of gestation. Those women who reported having been diagnosed with thyroid pathology, regardless of whether or not they continued in treatment, were excluded from the analysis. Thus, the final analysis was based on 1844 pregnant women (658 in Valencia, 583 in Guipu´zcoa, and 603 in Sabadell). The study was approved by the ethical committee of the Institut Municipal d’Investigacio´ Me`dica of Barcelona © 2009 Lippincott Williams & Wilkins

Iodine Supplementation and Thyroid Function in Pregnancy

and by the ethical committees of the hospitals involved in the study.

Assessment of Iodine Intake Variables and Other Covariates In their first visit after recruitment (gestational age range 8 –23 weeks), women were interviewed and blood and urine samples were collected. Using questionnaires administered by personal interview, we obtained information on education, socioeconomic background, demographic factors, maternal disease and obstetric history, anthropometric measures, diet, use of iodized salt and intake of vitamin/mineral preparations containing iodine. The ranges for gestational age at data collection were 9 –16 weeks in Valencia (mean 12.4 weeks), 8 –22 weeks in Guipu´zcoa (mean 14 weeks), and 8 –23 weeks in Sabadell (mean 13.4 weeks). A semi-quantitative food frequency questionnaire (FFQ) was used to assess the usual dietary intake of 100 food items and beverages from the last menstrual period to the time of interview. The questionnaire, an adapted version of the FFQ developed by Willett et al,24 has been previously used and validated in the general population in Valencia (Spain).25 Iodine values were obtained primarily from food composition tables from the US Department of Agriculture26 and from additional information available for iodized salt in Spain. The production of iodized table salt has been regulated in Spain by law since 1982, but its use is not compulsory and its availability is not accompanied by a sustained educational campaign. Women were asked, as part of the FFQ, on the frequency (from never or ⬍1 per month to 6⫹ times per day) of adding a pinch of salt (estimated as 0.4 g) to foods at the table. For women who reported consuming iodized salt, its iodine content was taken into account in the salt usually added at the table, and also in the cooking process of some meals. Because table salt is iodized in Spain at 60 mg of iodine per kg, a pinch of salt would be equivalent to 24 ␮g of iodine. Furthermore, we assumed that the same amount (24 ␮g of iodine) was added per portion to a predetermined list of 20 cooked food items, according to usual cooking practices. Iodine intake from foods and salt was then estimated and adjusted for total energy by the residual method; the results were then dichotomized as adequate or inadequate according to the estimated average requirement recommended by the Institute of Medicine27 for pregnant women (ⱖ160 ␮g/day). Information on brand names, dose and timing of consumption of specific potassium iodide supplements, or vitamin/mineral preparations containing iodine was obtained by a structured questionnaire with a reference time window from 3 months before conception until the date of the interview. The iodine content per daily dose was obtained from the composition referred to in the reference manual or in the product label information. We defined supplement consumers as those women who were taking supplements at the time of www.epidem.com | 63


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thyroid hormone testing (categorized as ⬍100, 100 –199, or 200⫹ ␮g/day). Iodine concentrations were measured in a spot urine sample by a paired-ion reversed-phase high-performance liquid chromatography with electrochemical detection and a silver working electrode.28 In Guipu´zcoa and Sabadell nonfasting urine samples were obtained, whereas in Valencia urine samples were mostly fasting. Urine samples were stored at ⫺20°C, until they were delivered to the reference laboratory (Normative Public Health Laboratory of Bilbao, Basque Country). Urinary iodine concentration were measured in most women in the Valencia and Guipu´zcoa samples (in 630 and 581 women, respectively), but only in a subsample in Sabadell (274 women). Urinary iodine concentration was categorized as ⬍50, 50 –99, 100 –149, 150 –249, and 250⫹ ␮g/L, according to the WHO recommended normal range for pregnant women (150 –249 ␮g/L).10

Thyroid Hormone Analysis Nonfasting blood samples were collected in all 3 areas. Serum samples were stored at ⫺80°C and also tested in the Normative Public Health Laboratory of Bilbao, Basque Country. TSH and free thyroxine were measured by a solidphase, time-resolved sandwich fluoroimmunoassay (AutoDELFIA, PerkinElmer Life and Analytical Sciences, Wallac Oy, Turku, Finland), using a lanthanide metal europium label. Laboratory reference values for adults ranged from 0.63 to 4.19 ␮U/mL for TSH, and 9.8 to 16.8 pmol/L for free thyroxine. Gestational age–specific TSH thresholds have been proposed, given the physiologic fall in serum TSH level during early pregnancy.5 A conservative cut-off point for TSH as low as 2.5 ␮U/mL has been proposed to define thyroid dysfunction in early pregnancy,29 but without clear

evidence of associated clinical problems. To define hyperthyrotropinemia, we chose a cut-off value of 3␮U/mL, corresponding approximately to the 97.5th percentile in the first half of pregnancy reported in a large population-based study of pregnant women aimed at establishing gestational agespecific reference intervals for TSH.30 We also repeated some analyses with a cut-off value (4 ␮U/mL) proposed by Haddow et al.29,31 The lack of trimester-specific normative data for free thyroxine makes it difficult to establish an appropriate definition of hypothyroxinaemia. We decided to compare the 3 study areas, using as an external reference the manufacturer’s normal range for nonpregnant population.

Statistical Analysis We computed descriptive statistics for thyroid hormone levels, iodine-intake-related variables (urinary iodine concentration, iodized salt consumption, adequate intake from diet and iodized salt, dose of iodine supplement consumption), and other maternal characteristics (maternal age, country of origin, educational level, prepregnancy body mass index, parity, and gestational age at serum sampling). To control for confounding and to assess effect modification, multiple linear regression analysis was applied to evaluate the association of serum concentrations of TSH and free thyroxine with iodine intake variables, and multiple logistic regression analysis to evaluate the risk of elevated TSH (⬎3 and ⬎4 ␮U/mL). Values of TSH and free thyroxine were transformed by natural logarithm to obtain a normally distributed variable in the multiple linear regression analyses. Because some TSH observations were close to zero, we added a constant value to TSH before transformation to avoid a left-skewed distribution after transformation. Two models were constructed: Model 1 contained urinary iodine concentration as an overall measure of iodine intake, and Model 2 included the questionnaire

TABLE 1. Percentile Distribution of Serum Thyroid-stimulating Hormone (TSH), Free Thyroxine, and Urinary Iodine Concentrations, by Trimester of Pregnancy and Geographic Area TSH (␮U/mL)

Urinary Iodine (␮g/L)

% >3 ␮U/mL (95% CI)

2.5th

50th

97.5th

% 3 (95% CI)

Free Thyroxine (pmol/L) Geometric Mean (95% CI)

TABLE 4. Adjusted Association of Serum Thyroid-stimulating Hormone (TSH) Levels and Hyperthyrotropinemia (TSH ⬎3 ␮U/mL) With Urinary Iodine Concentrations (Model 1), and Iodine-intake Variables (Model 2) Ln TSHa Models

All women 1844 6.0 (4.9 to 7.1) Geographic Area Valencia 658 6.1 (4.2 to 8.0) Guipúzcoa 583 6.7 (4.6 to 8.8) Sabadell 603 5.3 (3.4 to 7.2) Gestational age at serum sampling (weeks) ⬍12 203 3.4 (0.7 to 6.2) 12–13 1207 6.6 (5.2 to 8.1) ⱖ14 434 5.5 (3.3 to 7.8) Urinary iodine concentration (␮g/L) ⬍50 137 4.4 (0.6 to 8.2) 50–99 343 6.4 (3.7 to 9.2) 100–149 321 5.9 (3.2 to 8.7) 150–249 367 7.6 (4.8 to 10.5) ⱖ250 317 3.8 (1.5 to 6.0) Iodized salt consumption No 1040 6.3 (4.7 to 7.8) Yes 804 5.7 (4.1 to 7.4) Iodine intake (␮g/day) from diet and iodized salta ⬍160 656 6.4 (4.5 to 8.4) ⬎160 1188 5.8 (4.4 to 7.2) Iodine intake from supplements (␮g/day) 0–99 945 4.9 (3.4 to 6.3) 100–199 298 6.7 (3.7 to 9.7) ⱖ200 601 7.5 (5.3 to 9.7)

10.55 (10.48 to 10.61) 10.91 (10.80 to 11.01) 10.09 (9.98 to 10.19) 10.62 (10.50 to 10.73) 11.31 (11.10 to 11.53) 10.64 (10.57 to 10.72) 9.95 (9.83 to 10.08) 10.36 (10.14 to 10.59) 10.61 (10.44 to 10.77) 10.64 (10.49 to 10.79) 10.40 (10.26 to 10.54) 10.43 (10.27 to 10.59) 10.51 (10.43 to 10.60) 10.59 (10.49 to 10.69) 10.50 (10.39 to 10.61) 10.58 (10.50 to 10.66) 10.72 (10.63 to 10.81) 10.85 (10.69 to 11.02) 10.14 (10.03 to 10.24)

a Average daily iodine intake from foods and iodized salt adjusted for total energy, and defined as adequate according to the estimated average requirement (EAR) recommended by the Institute of Medicine27 for pregnant women (ⱖ160 ␮g/day).

(CI ⫽ 1.2 to 5.4). The same model but with the more extreme cut-off level (TSH ⬎4 ␮U/mL) yielded a similar, although less precise, result (adjusted OR for iodine supplements of 200 ␮g/day or more ⫽ 2.6, 关CI ⫽ 0.85 to 7.88兴). Heterogeneity between effect estimates for each area was examined by using standard methods for random-effects meta-analysis. The association between iodine supplement intake and TSH levels was homogeneous among the areas, as shown in Figure 1 for the logistic model (P value for heterogeneity ⫽ 0.71). We carried out a multiple linear regression analysis to assess the effects of iodine intake from the various sources on free thyroxine levels. Results stratified by area showed that iodine-related variables were not associated with free thyroxine, except in Sabadell where an association between supplement intake and free thyroxine was found. Figure 2 shows the meta-analysis results: P value for heterogeneity was 0.003. Iodine supplement consumption of 200 ␮g/day or more in Sabadell was related to an 11% decrease in free thyroxine (CI ⫽ 5% to 16%), while no effect was observed in the other 2 areas or in the pooled estimate. 66 | www.epidem.com

␤

(95% CI)

Model 1 Urinary iodine concentration (␮g/L) ⬍50c Reference 50–99 0.021 (⫺0.068 to 0.110) 100–149 ⫺0.053 (⫺0.144 to 0.037) 150–249 ⫺0.019 (⫺0.108 to 0.070) ⱖ250 ⫺0.056 (⫺0.148 to 0.036) Model 2 Iodized salt consumption Noc Reference Yes ⫺0.014 (⫺0.059 to 0.030) Iodine intake from diet (␮g/day)d ⬍160c Reference ⱖ160 0.013 (⫺0.029 to 0.055) Iodine intake from supplements (␮g/day) 0–99c Reference 100–199 0.042 (⫺0.024 to 0.109) ⱖ200 0.090 (0.003 to 0.177)

TSH >3 ␮U/mLb Adjusted OR (95% CI)

1.00 1.39 (0.55 to 3.53) 1.20 (0.46 to 3.11) 1.55 (0.62 to 3.89) 0.69 (0.25 to 1.91)

1.00 0.85 (0.56 to 1.29) 1.00 1.04 (0.70 to 1.55) 1.00 1.47 (0.78 to 2.79) 2.51 (1.16 to 5.43)

a Linear regression analysis. Model 1 adjusted for Area, Country of origin, Educational level, Parity, and Gestational age at serum sampling. Model 2 adjusted for the iodine intake variables shown in the table and for the same covariables of Model 1. b Logistic regression analysis. Model 1 adjusted for Area, Educational level, and Gestational age at serum sampling. Model 2 adjusted for the iodine intake variables shown in the table and for Area, Country of origin, and Gestational age at serum sampling. c Reference category. d Average daily iodine intake from foods adjusted for total energy, and defined as adequate according to the estimated average requirement recommended by the Institute of Medicine27 for pregnant women (⬎160 ␮g/day).

DISCUSSION We examined the relationship between maternal indicators of iodine nutritional status and biochemical markers of thyroid function during the first half of gestation. Consumption of iodine supplements at doses of 200 ␮g/day or more was associated with an increased risk of hyperthyrotropinemia (TSH ⬎3 and ⬎4 ␮U/mL), according to TSH cut-off values being used for detecting thyroid deficiency in the first half of pregnancy.30,31 Furthermore, free thyroxine values were lower in pregnant women from Guipu´zcoa—an area where most women were supplemented—than in the other 2 areas, and these differences persisted after allowing for gestational age at serum sampling and other maternal characteristics. Serum TSH concentrations were not associated with urinary iodine concentration in either area. These results are consistent with those reported among 15- to 44-year-old women in the NHANES III, including pregnant women.8,33 In the last few years, several studies in other countries have shown that a high iodine intake may be associated with a higher prevalence of subclinical and even overt hypothy© 2009 Lippincott Williams & Wilkins


FIGURE 1. Pooled estimate of OR and 95% CI for Hyperthyrotropinemia (TSH ⬎3 ␮U/mL) associated with increasing supplement intake (⬍100/100 –199/ⱖ200 ␮g/day analyzed as continuous variable). Confidence intervals for the effect from each study area are shown. Center of boxes represents the effect per region, where the area of the box is proportional to the weight of each region in the summary estimate, represented by the middle of a diamond whose left and right extremes correspond to the confidence interval. Models are adjusted for country of origin, gestational age at serum sampling, iodized salt consumption, and iodine intake from diet.

FIGURE 2. Pooled estimate of effect of iodine supplement intake (ⱖ200 vs. ⬍200 ␮g/day) on free thyroxine levels. Confidence intervals for the effect from each study area are shown. Center of boxes represents the effect per region, where the area of the box is proportional to the weight of each region in the summary estimate, represented by the middle of a diamond whose left and right extremes correspond to the confidence interval. Models are adjusted for age, country of origin, BMI before pregnancy, parity, gestational age at serum sampling, iodized salt, and iodine intake from foods.

roidism in the general population.11–14 The tolerable upper intake level for iodine proposed by the European Commission’s Scientific Committee for Food34 is 600 ␮g/day for adults and pregnant women. The WHO recently recommended an iodine intake for pregnant and lactating women of 250 ␮g/day10 and suggested that the total daily intake should preferably not exceed 500 ␮g/day, as higher intake might be associated with impaired thyroid function. It is unclear whether the major mechanism is iodine triggering thyroid autoimmunity or a direct inhibitory effect on thyroid hormone production and secretion.35 Nonetheless, the risk of iodineinduced hypothyroidism appears to be greater in formerly © 2009 Lippincott Williams & Wilkins


iodine-deficient populations and in some susceptible subjects such as those suffering from autoimmune thyroid disease.27,34 In our study, women who consumed 200 ␮g/day or more of iodine supplements had a higher risk of hyperthyrotropinemia, suggesting that the extra dose of iodine from supplements might result in an iodine excess that induces thyroid dysfunction. The relatively lower values of free thyroxine observed in Guipu´zcoa may be partly explained by an excessive iodine intake, given that almost all pregnant women were supplemented during pregnancy. There might also be genetic or environmental factors that may account for the differences between areas. The higher risk of hypothyroxinemia in pregnant women who consumed supplements in Sabadell should be taken with caution, given the small sample size in this category. Nevertheless, even in a mildly iodine deficient area such as Sabadell, with low iodized salt coverage, a sudden iodine load through supplements during early pregnancy did not appear to improve the maternal thyroid function. This is presumably because only a long-term steadystate of adequate iodine nutrition significantly improves maternal thyroid economy.5,22 Most published studies of iodine supplementation during pregnancy have focused on the safety and efficacy in mild to moderate iodine-deficient areas.15–22 In Europe, 6 randomized controlled trials16 –21 of iodine supplementation with pharmaceutical preparations have been reported involving pregnant women with mild-to-moderate iodine deficiency. Supplementation was associated in most studies with reduced maternal thyroid size and (although less consistently) with lower TSH values; little or no impact was observed on maternal total or free thyroxine levels. Iodine supplements appeared to be safe in these studies, but their sample sizes were small (the largest of the 6 clinical trials had 180 subjects), which limited the detection of subtle adverse effects. Furthermore, the degree of previous iodine deficiency in those populations appeared to be higher than in our study population. Although we do not have data on the iodine nutritional status of our women before pregnancy, recent studies carried out in the adult population in Catalonia36 and in schoolchildren in the Community of Valencia37 found urinary iodine concentration within the normal range for the general population. A recently reported longitudinal study22 found that long-term iodized salt consumption before conception resulted in a very low prevalence of maternal thyroid dysfunction during pregnancy, while short-term iodized salt prophylaxis did not protect against this risk. These results also support the relative importance of an adequate baseline iodine nutritional status, rather than sudden increases of iodine intake during pregnancy. The WHO consultation proposed the median urinary iodine concentration as the best indicator to assess the iodine nutrition of pregnant women in population surveys, although recognizing that “further studies are required to provide better www.epidem.com | 67

Rebagliato et al

support for this statement.”10 The fact that the median urinary iodine concentration observed in our study was under the recommended range of 150 –249 ␮g/L suggests the possibility of iodine deficiency during pregnancy in these areas. However, urinary iodine concentration should be interpreted with caution, as spot samples tend to overestimate low intakes in a population, especially when fasting morning urine samples are used.38 Apart from that, almost all studies of urinary iodine concentration during pregnancy have shown that, in a given environment, the excretion of iodide is almost the same in pregnant women and in the general population, irrespective of the status of iodine nutrition in each area, and therefore it is uncertain whether pregnancy per se markedly increases the urinary iodine concentration.39 One strength of our study was the opportunity to assess different indicators of iodine nutritional status and supplementation. Also, we were able to include large sample size of pregnant women from iodine sufficient or mildly deficient areas. The cross-sectional design of our study is a major limitation. The measurements at a single point in time preclude determining the time-order of the effect of iodine status, and reverse causation bias is possible. Nevertheless, no thyroid disorder was suspected in these women before thyroid function testing, and therefore it is unlikely that supplement prescription and dose were determined by a woman’s thyroid condition. No systematic screening was undertaken in antenatal care to detect women at a higher risk of iodine deficiency, and therefore it is unlikely that iodine supplements were prescribed for this reason. Moreover, in Guipu´zcoa and Sabadell, the main source of iodine supplementation was specific potassium iodide preparations given as part of a universal iodine deficiency prevention program, whereas in Sabadell, it was started at the end of the recruitment period. In Valencia, all iodine supplements came from vitamin/mineral preparations, since no specific potassium iodide supplement was commercialized in Spain at the time of its recruitment period, and these multivitamins were not given to prevent iodine deficiency but as part of a common antenatal care practice. Another limitation of the study is the likelihood of measurement error in the estimate of dietary iodine and iodized salt intake from the FFQ. This type of questionnaire has been shown to provide an appropriate measure of diet in pregnant women.40 The questionnaire used had been validated in the Spanish general population,25 but iodine was not one of the nutrients specifically validated. Estimates of iodine intake are affected by specific sources of variability, such as the varying iodine content of foods and drinking water, the difficulty of quantifying iodized salt consumption, and the degradation of iodine content from iodized salt. For logistic reasons, we could not carry out a validity study using urinary iodine concentration in 24-hour urine samples or other reference measures, such as short-term dietary records. Neverthe68 | www.epidem.com


less, and despite these drawbacks, the questionnaire estimate of total iodine intake showed a good correlation and concordance with UIC levels (data not shown), with values similar to that reported in validity studies among pregnant women.40 Furthermore, we did not use absolute levels of iodine intake in our analyses, but other categorical data according to consumption of iodized salt, supplement dose, or the dietary iodine intake dichotomized according to the estimated average requirement for pregnant women. We could not assess the evolution of the maternal thyroid function throughout pregnancy and the postpartum period, or whether the thyroid dysfunction we observed was transitory or persistent. Nevertheless, the thyroid function during the first half of pregnancy is important due to the known role of maternal thyroid hormones on the fetal brain at this stage.1 Furthermore, and as part of the ongoing cohort study, we will be able to assess the effect of iodine intake and maternal thyroid function indicators on perinatal outcomes and long-term child development. In conclusion, there is a tendency to defend the implementation of iodine supplementation programs with pharmaceutical preparations in pregnant women, irrespective of the status of iodine nutrition in each population. However, supplementation programs should be adapted to the particular region not only for the general population but also for pregnant women.5 Further research is needed to confirm the efficacy and safety of iodine supplementation during pregnancy in mildly iodine-deficient areas and in areas with adequate iodine intake. From a public health point of view, it would be advisable to enhance universal iodization of salt and educational programs to ensure an adequate iodine intake long before pregnancy. It might also be useful to establish a monitoring system on dietary habits and on urinary iodine concentration in the general population and in women at childbearing age. Finally, it is essential to set up a monitoring program of pregnant women to register whether any side effects are occurring in areas where supplementation programs have been implemented.

ACKNOWLEDGMENTS We thank parents for their generous contribution, as well as Dolors Serrano from Hospital de Terrassa; Silvia Folchs, Nuria Pey and Anna Sańchez for their support in the field work of Sabadell; Alfredo Perales and Maria Antonia Martín from the Obstetrics Department of Hospital La Fe, Valencia; Amparo Quiles and Amparo Cases for their support in the field work of Valencia; Haizea Begiristain, María Jesu´s Arroyo, Lourdes Arteche y Mercedes Maiztegi from the Hospital of Zumarraga. A full roster of the INMA Study Investigators can be found at http://www.infanciaymedioambiente.org/. REFERENCES 1. de Escobar GM, Obregoń MJ, del Rey FE. Iodine deficiency and brain development in the first half of pregnancy. Public Health Nutr. 2007; 10:1554 –1570.

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