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Iodine Prophylaxis Using Iodized Salt and Risk of Maternal Thyroid Failure in Conditions of Mild Iodine Deficiency

Dipartimento Clinico-Sperimentale di Medicina e Farmacologia (M.M., V.P.L.P., M.C.C., F.M., M.G., M.M., M.A.V., F.T., F.V.), Sezione di Endocrinologia, Dipartimento di Diagnostica di Laboratorio (G.G.), Servizio di Biochimica Clinica, and Dipartimento di Statistica (D.D.D.), University of Messina, 98125 Messina, Italy

Address all correspondence and requests for reprints to: Francesco Vermiglio M.D., Cattedra di Endocrinologia, Policlinico Universitario, Via Consolare Valeria, 98125 Messina, Italy. E-mail: francesco.vermiglio{at}unime.it.

	Abstract

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Context: Mild to moderate iodine deficiency during pregnancy can cause transient maternal hypothyroidism and impaired mental development of the progeny. These unfavorable effects are preventable by iodine supplementation. In Europe, however, less than 50% pregnant women receive iodine-containing supplements, thus representing dietary iodized salt the only carrier of iodine for most women in this life stage.

Objective/Design: This longitudinal study is aimed to investigate the effects of long-term iodized salt consumption on maternal thyroid function during gestation.

Participants/Outcome Measures: We prospectively evaluated thyroid function in 100 consecutive thyroperoxidase antibody-negative pregnant women from a mildly iodine-deficient area. Sixty-two women who had regularly used iodized salt for at least 2 yr prior to becoming pregnant and 38 who commenced iodized salt consumption upon becoming pregnant were classified as long-term (LT) and short-term (ST) iodine supplemented, respectively.

Results: Long-term iodized salt consumption resulted in a very low prevalence of maternal thyroid failure (MTF) in LT women. Conversely, short-term iodine prophylaxis does not seem to protect against the risk of MTF, the prevalence of which was almost 6-fold higher in ST than LT women (36.8% vs. 6.4%; ² 14.7, P < 0.0005; relative risk 5.7, 95% confidence interval 2.03–16.08, P < 0.001). The relative risk reduction amounted to 82.5%, this measure indicating the extent to which long-term iodine prophylaxis using iodized salt would reduce the risk of MTF in ST women.

Conclusions: Prolonged iodized salt significantly improves maternal thyroid economy and reduces the risk of maternal thyroid insufficiency during gestation, probably because of a nearly restoring intrathyroidal iodine stores.

	Introduction

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There is mounting evidence that even mild maternal thyroid underfunction may be associated with impaired fetal brain development. Over recent decades, the idea that iodine deficiency (ID) is responsible for both maternal and fetal thyroid failure has gained widespread acceptance after evidence that there is a direct correlation between the severity of ID and the seriousness of the repercussions on pregnant women and their children (1).

In previous studies, we reported a high prevalence of maternal thyroid failure (MTF) in women living in a mildly to moderately ID region (2, 3) and minor neurointellectual disorders (4) in schoolchildren from the same area. Furthermore, a 10-yr follow-up of the progeny of mildly iodine-deficient women carried out by our research group showed a high proportion (70%) of children with attention deficit and hyperactivity disorders and defective IQ scores among those born to mothers who had experienced hypothyroxinemia (but not hypothyroidism) during early gestation (5). Based on this evidence, we promoted a program of iodine prophylaxis on a voluntary basis encouraging iodized salt consumption in women of child-bearing age and pregnant women living in the ID area where the aforementioned studies had been carried out. The program was designed to monitor maternal thyroid function throughout gestation and detect/correct any maternal thyroid underfunction.

This prospective study evaluates the efficacy of iodine prophylaxis using iodized salt in preventing maternal thyroid failure over gestation.

	Subjects and Methods

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Study design and iodine prophylaxis program

This prospective cohort study was designed primarily to prevent ID-related MTF over gestation. It was carried out in a mild [median urinary iodine excretion (UIE) 67.0 µg/liter; goiter prevalence in schoolchildren 16.3%] ID area in northeastern Sicily; this area had previously been classified as moderately severely (1976–1980: UIE 25.5 ± 23.6 µg per 24 h; prevalence of goiter in schoolchildren 65%) or moderately (1989–1991: UIE 48.1 ± 38.2 µg per 24 h; prevalence of goiter in schoolchildren 31.7%) iodine deficient (2, 6).

For the purposes of our program, all women were asked about their dietary habits, particularly about iodized salt consumption, and advised to commence or continue regular use of commercially available iodine-fortified salt (30 ppm as KIO₃). The women were recruited between wk 6 and 9 of gestation and sampled twice at each trimester of gestation for serum T₃, T₄, free T₃ (FT3), free T₄ (FT4), TSH, and T₄ binding globulin (TBG). At initial observation antithyroperoxidase antibodies (TPO-Ab), thyroglobulin (Tg), and UIE were also determined.

The study was approved by the Ethical Committee of the "G. Martino" Polyclinic, Messina. Informed consent was obtained from all the women recruited.

Participants

Three hundred ninety-five consecutive pregnant women were screened at early gestation for thyroid function and invited to participate in our prevention program. At initial observation, 141 women proved ineligible for the study because they were affected variously with autoimmune thyroiditis (14 of 395), diagnosed before becoming pregnant; nodular goiter (79 of 395); postsurgical hypothyroidism (16 of 395), treated by levothyroxine (L-T4) replacement; or either subclinical or overt thyroid dysfunction (32 of 395, seven of whom had antithyroid antibodies), the treatment of which could not be postponed.

A further 154 of 395 women were excluded either because they did not fulfill the study criteria for discontinuous use of iodized salt during gestation (73 of 395) or incomplete follow-up (81 of 395). The remaining 100 women, who were euthyroid and TPO-Ab negative, made up our study sample.

For the purposes of our investigation, the women were divided into two groups according to their iodized salt consumption habits:

The first was a long-term iodine supplementation (LT) group of 62 women who had regularly used iodized salt for at least 24 months (mean 60.6 ± 28.2 months; median 60 months; range 24–120 months) before becoming pregnant; the period of 24 months was arbitrarily assumed to be sufficient time to guarantee intrathyroidal iodine store repletion.

The second was a short-term iodine supplementation (ST) group of 38 women who commenced iodized salt consumption upon becoming pregnant.

All women found to be either hypothyroid or hypothyroxinemic throughout gestation were given substitutive L-T4 and included in statistical analyses until L-T4 replacement was started. In particular, serum mean values for thyroid parameters were calculated for all members of both groups at first trimester, for 35 ST and 61 LT women at second trimester and for 28 ST and 61 LT women at third trimester.

Measurements

Maternal circulating total T₄ and T₃ (RIA), TSH (immunoradiometric assay), FT3, and FT4 (Amerlex-MAB, a one-step radiolabeld analog RIA) were determined using commercial kits supplied by Kodak Clinical Diagnostic Ltd. (Amersham, UK). Precision profiles showed inter- and intraassay coefficients of variation not exceeding 5% over the entire measurement range for both free thyroid hormones. Serum TPO-Abs were measured using a two-step immunoenzymometric assay supplied by Tosoh Corp. (Tokyo, Japan; AIA-PACK TPO-Ab). TBG concentrations were measured using a commercial RIA kit (Behring, Marburg, Germany). Serum Tg was measured using an ultrasensitive immunoradiometric assay [Radim Diagnostics, Pomezia (Roma), Italy]. Urinary iodine excretion was assessed colorimetrically, using an automated analyzer (AutoAnalyzer 3; Bran+Luebbe, Norderstedt, Germany).

Trimester-specific FT4 and TSH reference intervals and definition of isolated hypothyroxinemia

As recently recommended (7, 8, 9, 10, 11), both serum FT4 and TSH trimester-specific reference intervals were calculated. In particular, the first 500 serum samples were collected from as many consecutive healthy and antibody-negative pregnant women at different stages of pregnancy. Five women diagnosed with transient gestational hyperthyroidism were excluded, so the final reference ranges were derived from 495 serum specimens (n = 143, first trimester; n = 215, second trimester; and n = 137, third trimester). Gestational ages and medical histories were obtained from women’s obstetrical records. In particular, no woman with a personal history of autoimmune disease or a current or past history of thyroid disorder was included. The women all lived in a borderline iodine-sufficient area. Individual iodine intake was calculated in most of them on the basis of urinary iodine determination on sporadic samples using an automated analyzer. Median urinary excretion was 135 µg/liter (range 93–312, mean ± SD 158.2 ± 54.9), which is consistent with an estimated daily iodine intake of more than 200 µg/d. Normal serum FT4 values were 11.9–20.8 pmol/liter (mean ± SD, 16.5 ± 2.3 pmol/liter; median 16.4 pmol/liter), 10.4–18.7 pmol/liter (mean ± SD, 14.3 ± 2.1 pmol/liter; median 14.2 pmol/liter), and 10.3–16.4 pmol/liter (mean ± SD, 13.2 ± 1.7 pmol/liter; median 13.1 pmol/liter) at first, second, and third trimester, respectively.

Analogously, trimester-specific reference ranges for TSH were 0.03–2.3 mIU/liter (mean ± SD, 0.85 ± 0.62 mIU/liter, median 0.71 mIU/liter), 0.29–2.8 mIU/liter (mean ± SD, 1.15 ± 0.68 mIU/liter, median 1.0 mIU/liter), and 0.34–3.0 mIU/liter (mean ± SD, 1.21 ± 0.65 mIU/liter, median 1.2 mIU/liter) at first, second, and third trimester, respectively.

Accordingly, isolated hypothyroxinemia refers to a condition characterized by normal (within the trimester-specific reference range) TSH concentrations but maternal serum FT4 values that are below the lower limit of the trimester-specific reference range.

Statistical analysis

Unless otherwise specified data are expressed as mean ± SD.

Statistical analysis was performed using the following statistical tests: ² or Fisher exact tests when appropriate (categorical data); t test (normally distributed paired and unpaired data); Wilcoxon signed rank test (nonnormally distributed paired data); Mann-Whitney test (nonnormally distributed unpaired data); and one-way ANOVA test for repeated measures.

	Results

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Maternal thyroid function

Table 1 shows the epidemiological and biochemical features of both LT and ST women at enrollment (6–9 wk of gestation). There was no difference in age and parity between the two groups. Conversely, median UIE and serum Tg concentrations were different and consistent with a more adequate dietary iodine intake in LT women, which was, however, still below the recommended intake for pregnancy (12).

According to the total thyroid hormone changes observed, the T₃ to T₄ molar ratio was higher in ST women (t = 2.8, P < 0.005) at first trimester only (Fig. 1A).

View larger version (12K): [in this window] [in a new window]   FIG. 1. Average values of maternal T3 to T4 molar ratio, FT4, and TSH at first, second, and third trimester of gestation in both LT and ST groups. *, P < 0.05; **, P < 0.001; ***, P < 0.0001.

Serum FT4 concentrations were consistently higher and TSH values lower in LT women over the whole period.

Individual data and risk of maternal thyroid failure

At presentation (6–9 wk of gestation), all the women in both groups were euthyroid. However, by the end of the first trimester (between wk 11 and 13), one of 38 ST women (2.6%) was found to be affected with subclinical hypothyroidism (TSH, 5.0 mIU/liter; FT4, 12.1 pmol/liter), whereas two of 38 ST (5.3%) and one of 62 LT women (1.6%) had developed isolated hypothyroxinemia. During the second trimester, seven of the remaining 35 ST women (20%) developed MTF (overt hypothyroidism in one of seven and isolated hypothyroxinemia in six of seven), whereas the remaining 61 LT women were consistently euthyroid over the same period. Finally, over the course of the third trimester, four of the remaining 28 ST (14.3%) and three of 61 LT women (4.9%) became hypothyroxinemic. All women of both groups found to be either hypothyroid or hypothyroxinemic at any time over gestation (four of 62 LT and 14 of 38 ST) were given substitutive L-T4 therapy and excluded from further follow-up. They all normalized their thyroid parameters within a few weeks of treatment being started.

It is noteworthy that, of the women (from both LT and ST groups) who experienced MTF throughout gestation, 16 of 18 (88.9%) were affected with isolated hypothyroxinemia, their serum TSH concentrations never exceeding the upper trimester-specific limit (Fig. 2).

View larger version (13K): [in this window] [in a new window]   FIG. 2. The three graphs show individual serum FT4 and TSH values at first (A), second (B), and third (C) trimester of pregnancy of the four of 62 LT and 14 of 38 ST women who experienced maternal thyroid failure during gestation. The number of symbols depicted in the graphs progressively decrease from A (n = 4 LT and n = 14 ST) to B (n = 3 LT and n = 11 ST) and C (n = 3 LT and n = 4 ST) due to the fact that women found to be affected with MTF were given substitutive L-T4 and consequently ruled out from the further follow-up. More in detail, of the four LT women, one of four became hypothyroxinemic during the first trimester and the remaining three by the end of the third trimester, whereas of the 14 ST women, three of 14 and seven of 14 became either hypothyroxinemic or hypothyroid during the first trimester and the second trimester, respectively, and four of 14 were found to be hypothyroxinemic at the third trimester. The vertical dotted lines indicate the highest normal trimester-specific TSH value (2.3, 2.8, and 3.0 mIU/liter at first, second, and third trimester, respectively). The horizontal dotted lines indicate the lowest normal trimester-specific FT4 value (11.9, 10.4, and 10.3 pmol/liter at the first, second, and third trimester, respectively).

View larger version (11K): [in this window] [in a new window]   FIG. 3. Prevalence of maternal thyroid failure at the first, second, and third trimester or whole gestation in both LT and ST groups.

	Discussion

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At present, in most countries in Western Europe, discretionary salt is the only approved source of iodine in the daily diet because the use of iodine-fortified salt in the food industry is not permitted (16). In 2005 Italy introduced legislation requiring retailers to sell only iodized salt (30 ppm as either KI or KIO₃) unless consumers specifically request otherwise. Before the approval of this legislation and in the absence of a national iodine prophylaxis strategy, we promoted a program of voluntary iodine prophylaxis using iodized salt in a mildly ID area in northeastern Sicily where ID disorders had been extensively investigated and monitored over a number of years (2, 3, 4, 5, 6, 17, 18, 19, 20). This program, mainly targeted at women of child-bearing age and pregnant women, also included the monitoring of thyroid function over gestation and was aimed at early detection/correction of maternal thyroid underfunction and ultimate prevention of neurointellectual disorders in children.

So far, the efficacy of iodine prophylaxis (120–180 µg daily) using iodized salt in pregnancy has been evaluated in terms of thyroid volume changes only (21). To our knowledge, this is the first study investigating the effects of long-term iodized salt consumption on maternal thyroid failure. It should be stressed that our investigation focused mainly on individual participant outcomes in terms of maternal thyroid failure occurrence, rather than on longitudinal changes in mean serum maternal thyroid parameters. The latter could only be partially evaluated due to the fact that women who became either hypothyroid or hypothyroxinemic during pregnancy were promptly treated with L-T4 and, consequently, excluded from further statistical analysis.

The monitoring of maternal thyroid function over gestation demonstrated that long-term (2 yr) use of iodized salt (LT group) significantly improves maternal thyroid economy. Indeed, at recruitment, median UIE was higher (115 µg/liter), consistent with an estimated daily iodine intake of about 190 µg/d (22), and both Tg serum concentration and T₃ to T₄ molar ratio were lower in the LT women than the women who had commenced iodized salt consumption upon becoming pregnant (ST group). Furthermore, mean serum FT4 concentrations were consistently higher and within the normal trimester-specific range in the vast majority of LT women. This resulted in a very low prevalence of maternal thyroid failure over gestation, which manifested solely as isolated hypothyroxinemia and occurred almost exclusively in late gestation. The latter finding, along with the nonappearance of major forms of maternal thyroid failure, may be assumed to be attributable to the restoration of intrathyroidal iodine stores as a result of constant and prolonged use of iodized salt. Conversely, short-term iodine prophylaxis using iodized salt does not seem to protect against the risk of maternal thyroid failure, the prevalence of which was almost 6-fold higher (36.8%) in the ST than the LT group (6.4%). The effect size of long-term iodine prophylaxis, calculated in terms of relative risk reduction, amounted to 82.5%, this measure indicating the extent to which the risk of suffering MTF was reduced in the experimental (LT) group, compared with the control (ST) group, in other words the extent to which exposure to the protective factor (long-term iodized salt consumption) would reduce the risk of maternal thyroid failure in the control group. Overall, these data seem to indicate the timing of introduction of iodine supplementation, rather than the daily dosage, to play the key role in preventing MTF during gestation. Indeed, when introduced during gestation, higher doses of iodine than those reported in our study have proven to be effective in terms of Tg and thyroid volume changes but not in terms of maternal FT4 and TSH changes (23, 24).

It is worth noting that in our series of pregnant women, isolated hypothyroxinemia was, by far, the most frequent sign of gestational thyroid insufficiency. Several clinical studies have indicated that even mild isolated maternal hypothyroxinemia is potentially responsible for neurobehavioral and intellective disorders in progeny (5, 15, 25, 26, 27). Moreover, experimental data demonstrate that the fetal brain is exposed to biologically significant levels of maternal T₄, the reduction of which in early pregnancy leads to irreversible damage to the cortical cytoarchitecture of the fetal brain (28, 29, 30). However, at what point in the course of gestation and to what extent FT4 levels should be considered harmful to the fetus is still a matter of debate. Until this question is answered and USI put into effect worldwide (and its effectiveness proven beyond question), every effort should be made to prevent maternal thyroid failure by providing pregnant women with iodine supplements. However, women living in countries in which iodine intake is lower than that recommended for pregnant and lactating women should be screened and their FT4 values monitored to identify those affected with (or at risk of) hypothyroxinemia as early in pregnancy as possible. This approach would permit the prompt and timely institution of the L-T4 therapy needed to guarantee that maternal FT4 concentrations were sufficient to prevent neurodevelopmental defects in offspring.

	Footnotes

 
Disclosure Statement: The authors have nothing to disclose.

First Published Online April 15,2008

For editorial see page 2466

Abbreviations: FT3, Free T₃; FT4, free T₄; ID, iodine deficiency; LT, long-term iodine supplementation; L-T4, levothyroxine; MTF, maternal thyroid failure; ST, short-term iodine supplementation; TBG, T₄ binding globulin; Tg, thyroglobulin; TPO-Ab, thyroperoxidase antibody; UIE, urinary iodine excretion; USI, universal salt iodization.

Received February 13, 2008.

Accepted April 8, 2008.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Morreale de Escobar G, Obregon MJ, Escobar del Rey F 2004 Role of thyroid hormone during early brain development. Eur J Endocrinol 151(Suppl 3):U25–U37
2. Vermiglio F, Lo Presti VP, Scaffidi Argentina G, Finocchiaro MD, Gullo D, Squatrito S, Trimarchi F 1995 Maternal hypothyroxinemia during the first half of gestation in an iodine deficient area with endemic cretinism and related disorders. Clin Endocrinol (Oxf) 42:409–415[Medline]
3. Vermiglio F, Lo Presti VP, Castagna MG, Violi MA, Moleti M, Finocchiaro MD, Mattina F, Artemisia A, Trimarchi F 1999 Increased risk of maternal thyroid failure with pregnancy progression in an iodine deficient area with major iodine deficiency disorders. Thyroid 9:19–24[Medline]
4. Vermiglio F, Sidoti M, Finocchiaro MD, Battiato S, Lo Presti VP, Benvenga S, Trimarchi F 1990 Defective neuromotor and cognitive ability in iodine-deficient schoolchildren of an endemic goiter region in Sicily. J Clin Endocrinol Metab 70:379–384[Abstract/Free Full Text]
5. Vermiglio F, Lo Presti VP, Moleti M, Sidoti M, Tortorella G, Scaffidi G, Castagna MG, Mattina F, Violi MA, Crisà A, Artemisia A, Trimarchi F 2004 Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate iodine deficiency: a possible novel iodine deficiency disorder in developed countries. J Clin Endocrinol Metab 89:6054–6060[Abstract/Free Full Text]
6. Trimarchi F, Vermiglio F, Finocchiaro MD, Battiato S, Lo Presti VP, La Torre N, Calaciura F, Regalbuto C, Sava L, Vigneri R 1990 Epidemiology and clinical characteristics of endemic cretinism in Sicily. J Endocrinol Invest 13:543–548[Medline]
7. Demers LM, Spencer CA 2003 Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol (Oxf) 58:138–140[CrossRef][Medline]
8. Sapin R, D’Herbomez M, Schlienger JL 2004 Free thyroxine measured with equilibrium dialysis and nine immunoassays decreases in late pregnancy. Clin Lab 50:581–584[Medline]
9. Soldin OP, Tractenberg RE, Hollowell JG, Jonklaas J, Janicic N, Soldin SJ 2004 Trimester-specific changes in maternal thyroid hormone, thyrotropin and thyroglobulin concentrations during gestation: trends and associations across trimesters in iodine sufficiency. Thyroid 14:1084–1090[CrossRef][Medline]
10. Panesar NS, Li CY, Rogers MS 2001 Reference intervals for thyroid hormones in pregnant Chinese women. Ann Clin Biochem 38:329–332[Abstract/Free Full Text]
11. Stricker RT, Echenard M, Eberhart R, Chevailler MC, Perez V, Quinn FA, Stricker Rn 2007 Evaluation of maternal thyroid function during pregnancy: the importance of using gestational age-specific reference intervals. Eur J Endocrinol 157:509–514[Abstract/Free Full Text]
12. WHO Secretariat on behalf of the participants to the Consultation; Andersson M, de Benoist B, Delange F, Zupan J 2007 Prevention and control of iodine deficiency in pregnant and lactating women and in children less than 2-years-old: conclusions and recommendations of the Technical Consultation. Public Health Nutrition 102:1606–1611
13. Glinoer D, Delange F 2000 The potential repercussions of maternal, fetal and neonatal hypothyroxinemia on the progeny. Thyroid 10:871–887[Medline]
14. Glinoer D 2007 Clinical and biological consequences of iodine deficiency during pregnancy. Endocr Dev 10:62–85[Medline]
15. Morreale de Escobar G, Obregon MJ, Escobar del Rey F 2000 Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab 85:3975–3987[Abstract/Free Full Text]
16. Zimmermann M, Delange F 2004 Iodine supplementation of pregnant women in Europe: a review and recommendations. Eur J Clin Nutr 58:979–984[CrossRef][Medline]
17. Vermiglio F, Lo Presti VP, Finocchiaro MD, Battiato S, Grasso L, Ardita FV, Mancuso A, Trimarchi F 1992 Enhanced iodine concentrating capacity by the mammary gland in iodine deficient lactating women of an endemic goiter region in Sicily. J Endocrinol Invest 15:137–142[Medline]
18. Vermiglio F, Finocchiaro MD, Lo Presti VP, La Torre N, Nucifora M, Trimarchi F 1989 Partial beneficial effects of the so-called "silent iodine prophylaxis" on iodine deficiency disorders (IDD) in northeastern Sicily endemia. J Endocrinol Invest 12:123–126[Medline]
19. Vermiglio F, Benvenga S, Melluso R, Catalfamo S, Princi Jr P, Battiato S, Consolo F, Trimarchi F 1986 Increased serum thyroglobulin concentrations and impaired thyrotropin response to thyrotropin-releasing hormone in euthyroid subjects with endemic goiter in Sicily: their relation to goiter size and nodularity. J Endocrinol Invest 9:389–396[Medline]
20. Squatrito S, Delange F, Trimarchi F, Lisi E, Vigneri R 1981 Endemic cretinism in Sicily. J Endocrinol Invest 4:295–302[Medline]
21. Romano R, Jannini EA, Pepe M, Grimaldi A, Olivieri M, Spennati P, Cappa F, D’Armiento M 1991 The effects of iodoprophylaxis on thyroid size during pregnancy. Am J Obstet Gynecol 164:482–485[Medline]
22. Zimmermann MB 2007 The impact of iodised salt or iodine supplements on iodine status during pregnancy, lactation and infancy. Public Health Nutr 10:1584–1595[Medline]
23. Glinoer D, De Nayer P, Delange F, Lemone M, Toppet V, Spehl M, Grun JP, Kinthaert J, Lejeune B 1995 A randomized trial for the treatment of mild iodine deficiency during pregnancy: maternal and neonatal effects. J Clin Endocrinol Metab 80:258–269[Abstract]
24. Pedersen KM, Laurberg P, Iversen E, Knudsen PR, Gregersen HE, Rasmussen OS, Larsen KR, Eiksen, Johannesen PL 1993 Amelioration of some pregnancy-associated variations in thyroid function by iodine supplementation. J Clin Endocrinol Metab 77:1078–1083[Abstract]
25. Pop VJ, Kuijpens JL, van Baar AL, Verkerk G, van Son MM, de Vijlder JJ, Vulsma T, Wiersinga WM, Drexhage HA, Vader HL 1999 Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf) 50:149–155[CrossRef][Medline]
26. Pop VJ, Brouwers EP, Vader HL, Vulsma T, van Baar AL, de Vijlder JJ 2003 Maternal hypothyroxinemia during early pregnancy and subsequent child development: a 3-year follow up study. Clin Endocrinol (Oxf) 59:282–288[CrossRef][Medline]
27. Kooistra L, Crawford S, van Baar AL, Brouwers EP, Pop VJ 2006 Neonatal effects of maternal hypothyroxinemia during early pregnancy. Pediatrics 117:161–167[Abstract/Free Full Text]
28. Lavado-Autric R, Auso E, Garcia-Velasco JV, Arufe Mdel C, Escobar del Rey F, Berbel P, Morreale de Escobar G 2003 Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J Clin Invest 111:1073–1082[CrossRef][Medline]
29. Calvo RM, Jauniaux E, Gulbis B, Asuncion M, Gervy C, Contempre B, Morreale de Escobar G 2002 Foetal tissues are exposed to biologically relevant free thyroxine concentration during early phases of development. J Clin Endocrinol Metab 87:1768–1777[Abstract/Free Full Text]
30. Auso E, Lavado Autric R, Cuevas E, Escobar del Rey F, Morreale de Escobar G, Berbel P 2004 A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration. Endocrinology 145:4037–4044[Abstract/Free Full Text]

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