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Journal of Trace Elements in Medicine and Biology 27 (2013) 302–306

Contents lists available at ScienceDirect

Journal of Trace Elements in Medicine and Biology

journa l homepage: www.e lsev ier .de / j temb

linical studies

rinary iodine and thyroid function in a population of healthyregnant women in the North of Spain

nibal Aguayoa,e,1, Gema Graua,1, Amaia Velaa,e, Angeles Aniel-Quirogab,e,ercedes Espadac, Pedro Martula,e, Luis Castanod,e, Itxaso Ricaa,e,∗

Paediatric Endocrinology Section, Cruces University Hospital, UPV/EHU, Plaza de Cruces s/n, 48903 Barakaldo-Bizkaia, SpainBiochemistry Laboratory, Cruces University Hospital, UPV/EHU, Plaza de Cruces s/n, 48903 Barakaldo-Bizkaia, SpainPublic Health Laboratory Standards, Basque Government Department of Health, Parque Tecnológico de Bizkaia, Ibaizabal Bidea, 48160 Derio-Bizkaia, SpainResearch Unit, Cruces University Hospital, UPV/EHU, Plaza de Cruces s/n, 48903 Barakaldo-Bizkaia, SpainCIBERER (Center for Biomedical Research on Rare Diseases), Instituto de Salud Carlos III, Barcelona, Spain

r t i c l e i n f o

rticle history:eceived 22 April 2013ccepted 6 July 2013

eywords:regnancyodine epidemiologyodine measurementhyroid hormonesSH

a b s t r a c t

Background: Iodine is an essential trace element for the synthesis of thyroid hormones, which are keys inmaternal metabolism during pregnancy as well as in neurological development during fetal and postnatallife. This was a prospective study on iodine status and thyroid function in women during pregnancy in theBasque country to assess whether there was any relationship among maternal urinary iodine, maternalthyroid function and thyrotropin (TSH) in newborns, and to explore any difference in women experiencingmiscarriages.Methods: We analyzed TSH, free T4 (FT4), free T3 (FT3), thyroid peroxidase antibody (TPO-Ab) titers inserum and urinary iodine concentrations (UIC) in 2104 women in the first trimester of pregnancy and in1322 of them in their second trimester. We obtained neonatal TSH levels in 1868 cases.Results: In the first (T1) and second trimesters (T2), the median UICs were 88.5 �g/L and 140 �g/L, respec-tively. No relationship was found between UIC and FT4, or maternal and neonatal TSH. In T1 and T2, 9.7%and 7.5% of women were TPO-Ab positive, respectively. The total miscarriage rate was 10%. The percent-

age of miscarriages in healthy women was 8.9%, lower than in women with overt hypothyroidism (21.2%;p < 0.001) and than in women with subclinical hypothyroidism (15.6%; p < 0.025). The miscarriage ratewas not higher in TPO-Ab-positive women.Conclusions: In this study most women had iodine deficiency during pregnancy. Neonatal TSH is notcorrelated with maternal UIC during pregnancy. Pregnant women with hypothyroidism have a higher rate of miscarriages.

ntroduction

Iodine is an essential trace element for the synthesis of thyroidormones, which have a fundamental role in maternal metabolismuring pregnancy as well as in the neurological development of theetus and the newborn [1–3]. Pregnant women have physiological

odifications in the regulation of thyroid function. Changes in theeripheral metabolism of thyroid hormones have been described,

ainly, increases in thyroxine-binding globulin (TBG), in human

horionic gonadotropin (HCG) which acts on the thyrotropin (TSH)eceptors, and in renal filtration which leads to a greater loss of

∗ Corresponding author at: Sección de Endocrinología Pediátrica, Hospital Uni-ersitario de Cruces, Plaza de Cruces s/n, 48903 Barakaldo-Bizkaia, Spain.el.: +34 946006313.

E-mail address: ITXASO.RICAECHEVARRIA@osakidetza.net (I. Rica).1 These authors contributed equally to this work.

946-672X/$ – see front matter © 2013 Elsevier GmbH. All rights reserved.ttp://dx.doi.org/10.1016/j.jtemb.2013.07.002

© 2013 Elsevier GmbH. All rights reserved.

iodine [4]. To cope with these changes and the stress of pregnancy,women must have optimal thyroid function and an adequate iodineintake.

Even within the same country, iodine intake may vary amongthe population by age, season, geographical location and eatinghabits. For these reasons, iodine deficiency may be underestimatedor hidden [5–7]. In an epidemiological setting, the indicators thathave historically been considered to assess the iodine status are:thyroid gland volume, urinary iodine, serum thyroglobulin, andneonatal TSH levels. On the other hand, newborn TSH level solelyis not included among the indicators in the latest recommenda-tions of the World Health Organization (WHO), the United NationsChildren’s Fund (UNICEF), and the International Council for IodineDeficiency Disorders (ICCIDD) [8].

For pregnant women, WHO, UNICEF, and ICCIDD consider that aurinary iodine concentration (UIC) ≥ 150 �g/L [8] reflects adequateintake of this trace element. Iodine deficiency during pregnancymay cause a wide range of iodine deficiency disorders in both

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centrations below what it is considered adequate and 5.7% hadconcentrations above the normal range. In the second trimester, themedian UIC was 140 �g/L (range: 21–880 �g/L), with 54.4% of thewomen continuing to have UICs below 150 �g/L, while 18.8% had

Table 1Distribution of UIC in pregnant women during the first and second trimesters ofpregnancy.

Range (�g/L)a 1st trimester 2nd trimester

n (%) n (%)

<100 1224 58.2 428 32.4100–149 455 21.6 291 22150–249 304 14.4 354 26.8250–499 105 5 214 16.2

A. Aguayo et al. / Journal of Trace Elemen

he mother and the child [7,9]. In geographical areas with chronicevere iodine deficiency, women may have low blood levels of thy-oid hormones from the beginning of pregnancy with potentialffects on the neurological and intellectual development of theirffspring. On the other hand, in areas with mild or moderate iodineeficiency it is not clear whether children will suffer from cognitive

mpairment, hence more long term studies are required [7].The objective of this study was to assess prospectively iodine

tatus and maternal thyroid function through pregnancy in a sam-le of pregnant women in the Basque Country (North of Spain). Theecondary objectives were:

. To assess the relationships between UIC, maternal thyroid func-tion and TSH at birth in the newborns.

. To assess whether there were any differences in the subset ofwomen who had miscarriages.

opulation and methods

We conducted a prospective observational study of UIC and thy-oid function in pregnant women attending obstetric outpatientppointments in the catchment area of Cruces Hospital (Biscay,he Basque Country, Spain) between April 2002 and October 2004.regnant women received the usual obstetric monitoring and weid not intervene in the dietary measures and/or vitamin supple-ents prescribed. We obtained informed consent and the studyas approved by the Clinical Research Ethics Committee of Crucesospital. We excluded women with any kind of disease (included

hyroid pathology), those receiving any pharmacological agent andultiple pregnancies. At the end of the gestation a random sub-

roup of women (n = 539) were asked if they had received vitaminupplements containing iodine during pregnancy by indication ofheir obstetricians.

The sample included 2104 women in the first trimester of preg-ancy and 1322 were tested again in their second trimester. Bloodamples were taken during routine tests in both trimesters, andhe following parameters were analyzed: TSH, free T4 (FT4) andree T3 (FT3) and anti-thyroid peroxidase antibodies (TPO-Ab). Theame day of the blood test, a morning urine sample was collectedor measuring UIC. Serum samples were stored at −80 ◦C and urineamples at −20 ◦C until processing, the analysis being carried outfter completion of the pregnancy.

We assessed the levels of iodine in urine on the basis of UICeasured in a spot urine sample using paired-ion, reversed-phase,

igh-performance liquid chromatography with electrochemicaletection at silver working electrodes [10] (Waters Chromatogra-hy, Milford, MA). UIC was expressed in micrograms of iodine per000 ml of urine (�g/L).

We determined serum FT3, FT4 and TSH levels by chemilu-iniscence with an automated immunoassay system (IMMULITE

000, Siemens-Healthcare Diagnostic, Los Angeles, CA). TSH lev-ls were measured using a third generation, solid-phase, two-sitemmunometric assay, with a reference range of 0.4–4.5 mU/LIMMULITE 2000 Third Generation TSH, Siemens-Healthcare Diag-ostic). FT4 and FT3 were measured using solid-phase competitivenalog chemiluminiscence immunoassays, with reference rangesf 10.3–24.5 pmol/L and 2.8–6.5 pmol/L, respectively (IMMULITE000 Free T4 and IMMULITE 2000 Free T3, Siemens-Healthcareiagnostic). Lastly, TPO-Ab titers were conducted using a solid-hase enzyme-labeled chemiluminiscent sequential immunoassayith 35 IU/ml cut-off for normal (IMMULITE 2000 Anti-TPO Ab,

iemens-Healthcare Diagnostic).The iodine status of the women was classified according to the

HO/UNICEF/ICCIDD guidelines [8]. Specifically, iodine intake wasefined as insufficient for UICs < 150 �g/L; adequate for UICs of

edicine and Biology 27 (2013) 302–306 303

150–249 �g/L; above the requirements for UICs of 250–499 �g/L;and excessive for UICs ≥ 500 �g/L.

We used the criteria proposed by the American Thyroid Associa-tion [11] to define overt and subclinical hypothyroidism in pregnantwomen. We considered the participants to have: overt hypothy-roidism when TSH levels were above 10 mU/L, or 2.5–10 mU/Lwith FT4 below the fifth percentile; and subclinical hypothyroidismwhen TSH levels were 2.5–10 mU/L with normal FT4 levels. Hyper-thyroidism was diagnosed if TSH was <0.1 mU/L with an FT4 level>25.7 pmol/L.

We used neonatal TSH screening for detecting iodine defi-ciency as it is one of the methods previously proposed byWHO/UNICEF/ICCIDD [12]. They suggest that the level of deficiencyin a population could be characterized as a function of frequencyof neonatal TSH concentrations >5 mU/L: mild deficiency for fre-quencies of 3–19.9%, moderate deficiency for 20–39.9% and severedeficiency for ≥40%. We evaluated the TSH results of 1868 livenewborns of the women participating in this study, through thelocal screening program for congenital metabolic disorders. Totalblood samples were obtained from newborns between the 2nd and3rd day after birth by lancet puncture of the heel, spotted on fil-ter paper and delivered to the reference laboratory (NormativePublic Health Laboratory of Bilbao, Basque Country). Blood TSHwas measured by a solid-phase, time-resolved sandwich fluoroim-munoassay (AutoDELFIA, PerkinElmer Life and Analytical Sciences,Wallac Oy, Turku, Finland) using a lanthanide metal (europium)label.

Statistical analysis was performed using the Statistical Packagefor Social Sciences SPSS® (version 18 for Windows; Chicago,IL). Quantitative variables that followed a normal distributionwere analyzed using the Student’s t-tests, while non-parametricWilcoxon test and Spearman correlation coefficients were used fornon-normally distributed quantitative variables. Qualitative vari-ables were analyzed using the McNemar tests, �2 or Fisher exacttests. We selected a level of significance of p < 0.05.

Results

Results were obtained from 2104 women in the first trimester ofpregnancy and from 1322 of them, in the second one. Their meanage at delivery was 32.6 ± 4.2 years. We did not find statisticallysignificant differences between women who completed the studyand those who did not, with regards to TSH, FT4, or FT3 levels, UICor age.

Maternal urinary iodine: Table 1 lists the results of urinaryiodine. In the first trimester of pregnancy, the median UIC was88.5 �g/L (range: 16–875 �g/L). Of all the women, 79.8% had con-

≥500 16 0.7 35 2.6Total 2104 1322

UIC: urinary iodine concentration.a Range of urinary iodine concentration.

304 A. Aguayo et al. / Journal of Trace Elements in M

Table 2Comparison of urine and blood parameters in the first and second trimesters(n = 1322).

1st trimester 2nd trimester pb

UIC (�g/L) 108.9 ± 88.1 171.3 ± 121.9 <0.001TSH (mU/L) 1.78 ± 8.9 2.06 ± 3.5 <0.001FT4 (pmol/L) 17.26 ± 3.1 14.32 ± 1.9 <0.001FT3 (pmol/L) 6 ± 1.3 6.23 ± 1.3 <0.001TPO-Ab + (%)a 9.7 7.5 <0.001

Values are expressed as mean ± SD or proportion. UIC: urinary iodine concentration.Note to convert pmol/L to ng/dl: FT4 divide by 12.87; to convert pmol/L to pg/ml:FT3 divide by 1.536.

a McNemar test.b Wilcoxon test.

Table 3Relationship between UIC and thyroid function in TPO-Ab-negative women.

1st trimester FT4 FT3 TSH

FT3 0.103*

TSH −0.283* −0.034UIC 0.001 −0.069* 0.001

2nd trimester FT4 FT3 TSH

FT3 0.002TSH −0.117* 0.034UIC 0.005 −0.120* 0.042*

Spearman “r” correlation coefficient; statistical significance. UIC: urinary iodinec

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hypothyroidism or hyperthyrotropinemia, they have not found

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oncentration.* p < 0.01.

oncentrations above the recommended levels. Comparing womenor which we had data for both trimesters, we observed a sig-ificant increase in UIC in the second trimester (108 ± 88.1 �g/Ls. 171 ± 121.9 �g/L; p < 0.001). In the random subgroup of 539omen, 80% had received iodine supplements prescribed by their

bstetricians after the first analysis (blood and urine samples) hadeen collected.

Maternal thyroid function: Among the women with measure-ents in both trimesters, TSH and FT3 levels increased in the second

rimester, while FT4 levels and the rate of positive TPO-Ab titersecreased, as can be seen in Table 2. When we assessed the relation-hip between UIC and thyroid function in TPO-Ab-negative women,e found a weak correlation between UIC and FT3 levels in therst trimester and between UIC, FT3 and TSH levels in the secondrimester, as shown in Table 3.

We analyzed the TPO-Ab-positive subgroup; these were 9.7% ofhe women in the first and 7.5% of those in the second trimester.s reported in Table 4, this subgroup had higher TSH levels in both

rimesters, although no differences were found with regards to UIC.When we assessed thyroid function of pregnant women in

he first trimester, we found that 13.7%, 1.6% and 1% of womenad subclinical hypothyroidism, overt hypothyroidism and hyper-

hyroidism, respectively. In these subgroups, the mean FT4 levelsere 16.61 ± 1.9, 11.84 ± 1.8 and 32.36 ± 7.4 pmol/L, respectively,

ompared to 17.29 ± 2.5 pmol/L in healthy women (p < 0.001). The

able 4omparison as a function of auto-immunity in the 1st and 2nd trimesters.

1st trimester

TPO-Ab (−) n = 1900 TPO-Ab (+) n = 204 pa

TSH (mU/L) 1.42 ± 1.1 4.77 ± 22.5 <0.FT4(pmol/L) 17.33 ± 2.9 16.73 ± 4 <0.FT3(pmol/L) 5.92 ± 1.27 5.86 ± 1.9 0.0UIC (�g/L) 111 ± 85 106 ± 87 ns

alues are expressed as mean ± SD. UIC: urinary iodine concentration. Note to convert pma Mann–Whitney U test.

edicine and Biology 27 (2013) 302–306

mean values of UIC were not significantly different in womenwith subclinical or overt hypothyroidism compared with healthywomen (110. 3 ± 91.7 and 107.1 ± 73.4 vs. 111.4 ± 84.8), butwere lower in women with hyperthyroidism (71.8 ± 29.6 �g/L vs.111.4 ± 84.8 �g/L; p = 0.014).

Neonatal TSH: Neonatal TSH measurements were not correlatedwith maternal UIC in any of the trimesters analyzed. The prevalenceof newborn TSH levels >5 mU/L was 2.9%. We did not find any sig-nificant differences between their mother and the rest of the groupin the variables studied (thyroid function and UIC).

Miscarriages: In the total sample, there were 210 miscarriages(10%). In healthy women the percentage of miscarriages was 8.9%,while in women with overt hypothyroidism it was 21.2% and inwomen with subclinical hypothyroidism 15.6% [(p < 0.001) and(p = 0.025)]. There was not, however, a higher rate of miscarriagesin women with hyperthyroidism or those who were TPO-Ab posi-tive.

Discussion

We found a generalized iodine deficiency in the sample ofpregnant women studied. In both trimesters, the median UIC wasbelow the recommended levels for considering pregnant womento have an adequate intake of iodine [8]. Comparing this find-ing to what has been reported for other geographical areas acrossSpain, our levels of iodine deficiency status can be consideredintermediate [13–16]. When we followed UIC through pregnancy,we observed a significant increase in the second trimester. It iswell known that the physiological levels of urinary iodine duringpregnancy tend to decrease as the demands of mother and fetusincrease, in areas with mild and moderate iodine deficiency [17,18].In our study, the observed increase in UIC in the second trimestermay be explained by the practice, of the obstetricians to prescribevitamin supplements with iodine (100–150 �g/day) during preg-nancy because most of the women had received it.

In our study, we observed a decrease in TSH and increasein FT4 levels during the first trimester of pregnancy, consistentwith physiological changes secondary to HCG stimulus [13,19,20].We did not find any correlation between UIC and TSH or FT4, asreported by most authors [21–25]. This lack of correlation couldbe attributed to pregnancy changes and to the previous amountof iodine storage in the thyroid gland in a population who do nothave persistent iodine deficiency, so the thyroid hormone syn-thesis would be guaranteed [19,20,26]. Other researchers [27,28],have described a positive correlation between UIC and FT4 lev-els in pregnant women who belong to populations with moderateiodine deficiency and suggested that the fetal neurological devel-opment may be compromised by maternal hypothyroxinemia [28].A recent paper has shown the results of a randomized interven-tion study using levothyroxine treatment in pregnant women with

any improvement in cognitive function of offspring at 3 years ofage [29]. We think that there should be more long-term studiesto assess the potential impact of iodine deficiency and maternal

2nd trimester

TPO-Ab (−) n = 1223 TPO-Ab (+) n = 99 pa

001 1.93 ± 1.1 3.74 ± 12.2 <0.001001 14.31 ± 1.9 14.42 ± 2.2 ns22 6.22 ± 1.3 6.32 ± 1.3 ns

172 ± 119 162 ± 142 ns

ol/L to ng/dl: FT4 divide by 12.87; to convert pmol/L to pg/ml: FT3 divide by 1.536.

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A. Aguayo et al. / Journal of Trace Elemen

ypothyroxinemia on the neurological and intellectual develop-ent of school children in areas with mild or moderate iodine

eficiency. In line with this, we are now testing the offspring (cur-ently 7–8 years old) of the women who participated in this study.he prevalence of pregnant women with thyroid autoimmunityuring pregnancy was similar to data published on other womenf child-bearing age [13,30]. This prevalence decreases throughoutregnancy, and this may be related to the attenuation of the general

mmune response [31].The rate of women with overt hypothyroidism, not diagnosed

reviously in this population of women, was intermediate com-ared to other series reported in the literature [11,32,33]. The broadange of prevalence published to date may be explained by theiverse methods used as well as differences in the cut-off pointspplied to define hypothyroidism and subclinical hypothyroidism.f we included the women with subclinical hypothyroidism therevalence increases to 15.3%, but we do not consider it appropriateo combine the groups.

When we use TSH of the newborn >5 mU/L in the neonatalcreening as an indicator of iodine deficiency, we did not reachhe established percentage to define a population as having iodineeficiency. These results differ from those found by directly mea-uring UICs in pregnant women. Further, we did not observeny relationship between neonatal TSH and UIC in any of therimesters of the pregnancy studied, consistent with other authors23,33–35]. For this reason, we support the current recommenda-ions of WHO/UNICEF/ICCDD on neonatal TSH as an indicator ofodine status [8].

Focusing on the subgroup of women who had a miscarriage, weonfirm that there is an association between the levels of mater-al TSH and miscarriage, as found in other studies [36,37]. Variousuthors have also found an association between positive TPO-Abnd an increase in the rate of miscarriages, but we did not find thisn our study [11,38]. Further, considering the subgroup of pregnant

omen with hypothyroidism or subclinical hypothyroidism and ingreement with data in the literature [39], we found a higher ratef miscarriages in this subgroup than in pregnant women with nohyroid dysfunction.

Currently there is no consensus on the need to screen forhyroid dysfunction during pregnancy. A study group of themerican Thyroid Association did not find sufficient evidence

o recommend in favor or against the undertaking of this typef screening [11]. We do believe, however, that it is necessaryo screen for thyroid dysfunction in pregnant women to diag-ose and treat thyroid disorders, given the high percentage ofiscarriages observed in pregnant women with thyroid hypofunc-

ion.

onclusions

The majority of pregnant women in the geographical locationtudied had iodine deficiency during pregnancy. The UIC increasebserved in the second trimester may be due to the intake of sup-lements containing iodine, prescribed by obstetricians. The resultsf thyroid function and autoimmunity were not related to UIC inhese pregnant women. We confirm that the level of neonatal TSHs not associated with maternal urinary iodine or maternal thy-oid function in either of the two trimester studied. Miscarriagesre more common in women with overt and subclinical hypothy-

oidism.

onflict of interest

No authors have competing financial interests disclosure.

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edicine and Biology 27 (2013) 302–306 305

Acknowledgements

We would like to thank the pregnant women, nurses, labora-tory technicians and obstetricians who made this study possible.We extend our gratitude to Juan Carlos Vitoria, Maria Angeles Bus-turia, Iratxe Ocerin and Ramon Bilbao for their clinical and technicalhelp; to Jose Ignacio Pijoan and Lorea Martínez for statistical analy-sis; to Alejandro Urberuaga for correction of the English translationand to all the members implied in the Basque Country neonatalscreening program. The study was financially supported by theDepartment of Health and Department of Education of the Gov-ernment of the Basque Country (research grant: 200211011 andIT-472-07), Fundación Salud 2000, and Fundación IKERTU.

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