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Original article
Reference values and variability study of thyroid hormones in pregnant women from El Bierzo
Valores de referencia y estudio de la variabilidad de hormonas tiroideas en gestantes de El Bierzo
Manuel Lombardo Grifol
Corresponding author
, María Luisa Gutiérrez Menéndez, Luís García Menéndez, María Vega Valdazo Revenga
Servicio de Análisis Clínicos, Hospital del Bierzo, Ponferrada, León, Spain
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13&#46;5&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> In newborns&#44; complications include low weight and inadequate neurophysiological development&#44; which may even cause a seven-point decrease in the intelligence quotient in children aged 7&#8211;9 years&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Iodine is an essential element for the synthesis of thyroid hormones&#44; and iodination levels in pregnant women are highly variable in Spain&#46; The geographic area of El Bierzo is characterized by lower than recommended urinary iodine levels in women in the first trimester of pregnancy &#40;&#8805;150<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;L according to the World Health Organization&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> a median of 118<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;L&#44; which causes a high prevalence of thyroid dysfunction in pregnant women&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a> In one study only 15&#46;6&#37; of such women were found to be taking supplemental iodine&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Reference thyroid hormone levels in pregnant women are different from those for the general population because of physiological changes in pregnancy&#44; particularly in the first trimester&#46; Since neurological fetal development occurs during that first trimester&#44; any intervention should occur at the beginning of pregnancy to achieve a good neurological development&#46; A diagnosis of thyroid dysfunction should therefore be made during the first trimester of pregnancy&#46; For this&#44; thyroid-stimulating hormone &#40;TSH&#41; should primarily be measured&#44; and when this is altered&#44; free thyroxine &#40;FT4&#41; and free triiodothyronine &#40;FT3&#41; should also be measured&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Several scientific societies&#44; such as the American Thyroid Association &#40;ATA&#41; and the Endocrine Society&#44; have recently published new guidelines for the diagnosis and management of thyroid dysfunction in pregnancy&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;14</span></a> A consensus document of the Spanish Society of Endocrinology and Nutrition &#40;SEEN&#41; intended to improve the diagnosis of a condition which is considered to be underdiagnosed is also available&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> There is some controversy among scientific bodies as to whether universal screening of thyroid hormones should be performed in the first trimester of pregnancy&#46; The ATA and the Endocrine Society only recommend screening in high-risk patients&#44;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;14</span></a> but in its document the SEEN advocates universal screening in Spain&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> The area of El Bierzo is defined as a high-risk area because of the low iodine intake&#44; and all these societies would recommend the universal screening of pregnant women living in it&#46; To diagnose thyroid dysfunction in pregnancy&#44; all of these scientific bodies recommend verification that thyroid hormone levels are within the reference values for each trimester and area of the relevant laboratories&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#8211;15</span></a> When such reference values are not available&#44; they recommend what they consider to be adequate reference values&#46; Specifically&#44; SEEN and ATA recommend the use of 2&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL as the cut-off value&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The purpose of this study was to establish reference values for TSH&#44; FT4&#44; and FT3 in women in the first trimester of pregnancy in our area that could be used for universal screening for thyroid dysfunction in the pregnant population&#46; The study was also intended to find population factors which could explain the variability of TSH&#44; FT4&#44; and FT3 in pregnant women&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Subjects and methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">A retrospective study was conducted on 412 pregnant women consecutively attending Hospital del Bierzo from February 2011 to April 2012 for screening for chromosome diseases in the first trimester&#46; The results of TSH&#44; FT4&#44; and FT3 measurements performed on serum samples between weeks 8 and 13 of pregnancy were collected&#46; The clinical histories of the pregnant women and the database of chromosome disease screening were consulted to collect population data at the time of sampling for thyroid hormone measurement&#46; The population data collected included age&#44; weight&#44; height&#44; body mass index &#40;BMI&#41;&#44; prior and&#47;or current diseases &#40;thyroid and non thyroid&#41;&#44; and the smoking of three or more cigarettes daily&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Pregnant women with endocrine changes&#44; with no thyroid hormone data available between 8 and 13 weeks of pregnancy&#44; with no information available on population data or prior diseases&#44; and with twin and Down syndrome pregnancies were excluded from the study&#46; Endocrine causes included treatment with thyroxine or other drugs altering thyroid hormones&#44; positive anti-thyroid antibodies&#44; a prior diagnosis of hypothyroidism or hyperthyroidism&#44; or nutritional problems&#44; and a diagnosis of diabetes mellitus or gestational diabetes&#46; As smoking may alter thyroid hormone levels&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> pregnant women who smoked at least three cigarettes daily were excluded from the calculation of reference values in the first trimester&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">TSH&#44; FT4&#44; and FT3 measurements were performed using an ADVIA CENTAUR XP analyzer from Siemens Healthcare Diagnostics<span class="elsevierStyleSup">&#174;</span>&#46; TSH was measured using a double-antibody ultrasensitive assay with a range from 0&#46;008 to 150<span class="elsevierStyleHsp" style=""></span>mIU&#47;L and with the following interassay coefficients of variation &#40;iCV&#41; for three levels&#58; level 1<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;418<span class="elsevierStyleHsp" style=""></span>mIU&#47;L&#44; iCV<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;1&#37;&#59; level 2<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#46;685<span class="elsevierStyleHsp" style=""></span>mIU&#47;L&#44; iCV<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;4&#37;&#59; level 3<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>36&#46;4<span class="elsevierStyleHsp" style=""></span>mIU&#47;L&#44; iCV<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;1&#37;&#46; FT4 was measured using a competitive assay&#44; with a range from 0&#46;1 to 12<span class="elsevierStyleHsp" style=""></span>ng&#47;dL &#40;1&#46;3&#8211;155<span class="elsevierStyleHsp" style=""></span>pmol&#47;L&#41; and iCV for three levels&#58; level 1<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;883<span class="elsevierStyleHsp" style=""></span>ng&#47;dL&#44; iCV<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#46;9&#37;&#59; level 2<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;155<span class="elsevierStyleHsp" style=""></span>ng&#47;dL&#44; iCV<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#46;1&#37;&#59; level 3<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#46;1<span class="elsevierStyleHsp" style=""></span>ng&#47;dL&#44; iCV<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#46;2&#37;&#46; FT3 was measured using a competitive assay&#44; with a range from 0&#46;2 to 20<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL &#40;0&#46;3&#8211;30&#46;8<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;L&#41; and iCV for three levels&#58; level 1<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;53<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL&#44; iCV<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;2&#37;&#59; level 2<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#46;31<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL&#44; iCV<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;2&#37;&#59; level 3<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>11&#46;24<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;mL&#44; iCV<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;4&#37;&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Statistical analysis</span><p id="par0045" class="elsevierStylePara elsevierViewall">Data were collected in Excel version 2003&#44; and CBStat version 5&#46;1 software was used to calculate reference values&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Normal thyroid hormone distribution was analyzed using an Anderson&#8211;Darling test&#44;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> and variables not normally distributed were transformed to adjust them to a parametric distribution&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> FT3 followed a parametric distribution&#44; but FT4 required transformation by natural logarithms and TSH required dual exponential and modular transformation&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;21</span></a> Potential stratification by weeks of pregnancy&#44; age&#44; and BMI were studied&#44;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> and possible outliers were analyzed to discard them or not&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Reference values were established between the 2&#46;5th and 97&#46;5th percentiles&#44; with 90&#37; confidence intervals as recommended by the International Federation of Clinical Chemistry&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Group comparison was performed using a Student&#39;s t test&#44; a Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span> test&#44; a Kruskal&#8211;Wallis <span class="elsevierStyleItalic">H</span> test&#44; or a one-factor ANOVA test as appropriate&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Thyroid hormone variability was analyzing using SPSS software &#40;PASW Statistics 18<span class="elsevierStyleSup">&#174;</span>&#41;&#46; Multivariate linear regression tests were done to obtain an approximation of significant variables&#44; followed by a comprehensive study of multifactorial covariance &#40;ANCOVA&#41; for TSH&#44; FT4&#44; and FT3&#44; in order to ascertain the main factors and interactions accounting for thyroid hormone variability&#46; The variability factors analyzed included age &#8805;30 years&#44; IMC<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#44; and smoking three or more cigarettes daily &#40;smoker&#41;&#46; TSH&#44; FT4&#44; or FT3 were introduced in the models as covariates if they were significant&#44; in order to better differentiate the variability of the factors&#46; FT4 was the covariate in the TSH model&#44; while TSH was the covariate in the FT4 model and FT4 was the covariate in the FT3 model&#46; Homogeneity and model lack-of-fit tests were performed&#44; and residuals charts were analyzed to see whether the covariance models were correct&#46; A value of <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 was considered significant for all tests&#46;</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><p id="par0055" class="elsevierStylePara elsevierViewall">A total of 412 women aged 16&#8211;43 years in the first trimester of pregnancy were studied&#46; Of these&#44; 163 were excluded from the study of reference values&#44; and 193 from the variability study&#46; The reasons for exclusion are given in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; The prevalence of anti-thyroid antibodies in pregnant women was 5&#46;1&#37;&#46; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the characteristics of the study population&#44; which were not significantly different between the pregnant women included and excluded&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows the reference values obtained in the first trimester of pregnancy for TSH&#44; FT4&#44; and FT3&#44; with their corresponding confidence intervals&#46; Upon stratification between weeks 8 and 13 of pregnancy&#44; no significant differences were found between pregnancy weeks in TSH &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;502&#41;&#44; FT4 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;979&#41;&#44; and FT3 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;564&#41;&#44; applying one-factor ANOVA taking into account the means of these parameters in each week &#40;data not shown&#41;&#46; A significant age-related decrease in TSH was seen &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> also shows TSH reference values for pregnant women aged &#60;30 years and &#8805;30 years&#46; A significant BMI-related increase in FT3 was also seen &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; but no stratification was made because of the small number of cases with BMI<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span> &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>24&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">The ANCOVA test showed that TSH decreased with age&#44; mainly in pregnant women &#8805;30 years &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; but that TSH levels in pregnant smokers did not differ from those in non-smokers &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;471&#41;&#46; However&#44; an interaction was seen to exist between the two variables&#44; so that women &#8805;30 years of age who smoked had the lowest TSH levels &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> shows a profile plot of the marginal means estimated by the TSH model&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Age&#44; BMI&#44; or smoking had no influence on FT4 variability&#46; As regards FT3&#44; ANCOVA showed that FT3 increased with BMI&#44; mainly in pregnant women with BMI<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span> &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; Smoking also increased FT3 levels in pregnant women &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; An interaction was also seen between BMI<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span> and smoking&#44; so that pregnant women who smoked and had BMIs<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span> &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; had higher FT3 levels&#46; This interaction is better seen in the profile plot &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Discussion</span><p id="par0075" class="elsevierStylePara elsevierViewall">The issue of the various recommendations made by scientific bodies and the lack of reference values for TSH&#44; FT4&#44; and FT3 in El Bierzo&#44; an area where a high proportion of pregnant women have iodine deficiency&#44; led us to calculate more precisely the reference values for those hormones in the first trimester of pregnancy&#46; Although this was a retrospective study&#44; maximum precautions were taken in our exclusion criteria&#46; Any pregnant woman in whom there was the least doubt as to whether a treatment or disease would influence thyroid function was excluded from the study&#46; This explains the high proportion of women excluded &#40;39&#46;6&#37;&#41;&#46; However&#44; as shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#44; pregnant women included in and excluded from the study did not differ in the population data&#44; and a homogeneous population could be assumed&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">To calculate reference values&#44; distributions were normalized to obtain reference values with confidence intervals as adjusted as possible&#44; which made the number of individuals less relevant&#46; The upper TSH reference value &#40;97&#46;5th percentile<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;595<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL&#41; was somewhat higher than 2&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;mL&#44; the value recommended by the guidelines if no local reference values are available&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#8211;15</span></a> Some authors relate this higher value to a low iodine intake in the population&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> but others think that no association exists between urinary iodine and TSH levels in the first trimester of pregnancy&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Despite the stratification by age of pregnant women for subsequent use in screening for thyroid dysfunction in the first trimester of pregnancy&#44; we think that it would be advisable to define the reference values of the total population&#44; with no stratification by age&#44; because it is more practical&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Since TSH and FT4 and FT3 levels did not differ between weeks 8 and 13 of pregnancy&#44; a differentiation of reference values by week is not required&#44; and they are grouped as reference values for the first trimester&#46; Some reports provide reference values by weeks of pregnancy&#44;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;28</span></a> while others do not&#44;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;30</span></a> but even Garc&#237;a de Guadiana Romualdo et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> who give values according to gestational age&#44; state that there are no significant differences in TSH by gestational week in the first trimester&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">A direct comparison of reference values found in this and other studies&#44; even with the same procedures&#44; is very difficult for several reasons&#46; Many retrospective population studies use positive anti-thyroid antibodies as the only criterion&#44; but as suggested by Spencer et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> this procedure biases the upper reference TSH value due to other occult thyroid dysfunctions&#46; Other studies used populations that were not comparable to ours both with regard to race<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> and because the nutritional iodine status of the population had not been studied&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Moreover&#44; there is no recognized reference method for the standardization of free thyroid hormone tests&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">The ANCOVA test showed that TSH levels of pregnant women are influenced by age and by interaction between age and smoking&#46; As in some studies&#44; smoking alone did not result in different TSH levels&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> although differences were found in other studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;33</span></a> As regards age as an isolated factor&#44; there are no reports in the literature suggesting that TSH levels decrease with an increase in the age of pregnant women&#44; in particular from 30 years of age&#46; Age-related increases<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> or decreases<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> in TSH levels have however been seen in the general population&#46; Specifically&#44; V&#246;lzke et al&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> hypothesized that an inverse relationship between TSH and age is seen in iodine-deficient populations&#44; presumably due to prevailing nodular disease and increased thyroid autonomy with age&#46; No references suggesting a potential interaction between age and smoking that causes pregnant women aged &#8805;30 years who are smokers to have lower TSH levels have been found either&#46; This is a new finding which should be investigated in other studies so as to confirm it with a greater number of cases&#46; If this finding is confirmed&#44; TSH reference values in the first trimester of pregnancy for thyroid dysfunction screening will have to be stratified according to the age and smoking status of the women&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">As regards FT4 levels&#44; they were not influenced by age &#8805;30 years&#44; BMI<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#44; or smoking&#46; Other studies also reached the same conclusion with regard to smoking&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">As regards FT3 levels&#44; other studies suggested that they increase with BMI<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;36</span></a> and also with smoking&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> but independently&#46; No study reported an interaction between BMI<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span> and smoking&#44; as seen in this study&#46; This interaction may be due to increased peripheral metabolism induced by smoking<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> and increased by the greater body surface area&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">We conclude that the reference values obtained for TSH&#44; FT4&#44; and FT3 may be used for thyroid dysfunction screening in the first trimester of pregnancy in El Bierzo&#46; TSH levels in the first trimester of pregnancy are influenced by the age of the mother and by the interaction between age and smoking&#46; FT3 levels in the first trimester of pregnancy depend on BMI and the smoking status of the mother&#44; and an interaction between both factors also exists&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflicts of interest</span><p id="par0115" class="elsevierStylePara elsevierViewall">The authors state that they have no conflicts of interest&#46;</p></span></span>"
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            1 => "Free thyroxine"
            2 => "Free triiodothyronine"
            3 => "Pregnancy"
            4 => "Body mass index"
            5 => "Smoking"
            6 => "Age"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec294346"
          "palabras" => array:7 [
            0 => "Tirotropina"
            1 => "Tiroxina libre"
            2 => "Triyodotironina libre"
            3 => "Embarazo"
            4 => "&#205;ndice de masa corporal"
            5 => "Fumar"
            6 => "Edad"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Background and objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">El Bierzo area is characterized by low urinary iodine levels in the pregnant population&#46; Guidelines recommend that local reference values are established for the diagnosis of thyroid dysfunction in pregnancy&#46; Our objectives were to establish reference values for thyroid-stimulating hormone &#40;TSH&#41;&#44; free thyroxine &#40;FT4&#41; and free triiodothyronine &#40;FT3&#41; in women in the first trimester of pregnancy and to explore the factors influencing variability in these hormones&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Patients and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A retrospective study of 412 women in the first trimester of pregnancy who were measured serum levels of TSH&#44; FT4&#44; and FT3&#59; 163 women with conditions with a potential influence on thyroid function were excluded&#46; Thirty smoking pregnant women were also excluded from the study of reference values&#46; Factors examined in the variability study included age&#44; body mass index &#40;BMI&#41;&#44; and smoking&#46; A multifactorial analysis of covariance was performed&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Reference values in first-trimester pregnant women were&#58; TSH&#58; 0&#46;497&#8211;3&#46;595<span class="elsevierStyleHsp" style=""></span>mIU&#47;L&#59; FT4&#58; 0&#46;90&#8211;1&#46;42<span class="elsevierStyleHsp" style=""></span>ng&#47;dL&#59; FT3&#58; 2&#46;49&#8211;3&#46;56<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#46; TSH levels depended on mother age and on interaction between age and smoking&#46; FT3 levels depended on the mother&#39;s BMI and smoking&#44; and there was also an interaction between both factors&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The reference values found may be used to assess thyroid dysfunction in pregnant women from El Bierzo&#46; TSH and FT3 levels are influenced by age and BMI of the mother and by smoking&#44; in addition to the interaction of these factors&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes y objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La zona de El Bierzo se caracteriza por una baja yoduria en la poblaci&#243;n gestante&#46; Las gu&#237;as recomiendan establecer valores de referencia locales para el diagn&#243;stico de la disfunci&#243;n tiroidea en el embarazo&#46; Los objetivos fueron obtener valores de referencia de tirotropina &#40;TSH&#41;&#44; tiroxina libre &#40;T4L&#41; y triyodotironina libre &#40;T3L&#41; en gestantes de primer trimestre y estudiar los factores que intervienen en la variabilidad de estas hormonas&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0040">Pacientes y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio retrospectivo de 412 gestantes con determinaciones en suero de TSH&#44; T4L y T3L en el primer trimestre&#59; se excluyeron 163 por condiciones con posible influencia sobre la funci&#243;n tiroidea&#46; Para el estudio de los valores de referencia se excluyeron adem&#225;s 30 mujeres fumadoras&#46; El estudio de la variabilidad se realiz&#243; para los factores edad&#44; &#237;ndice de masa corporal &#40;IMC&#41; y fumar&#44; mediante an&#225;lisis de la covarianza multifactorial&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Los valores de referencia en gestantes de primer trimestre fueron&#58; TSH&#58; 0&#44;497&#8211;3&#44;595<span class="elsevierStyleHsp" style=""></span>mUI&#47;l&#59; T4L&#58; 0&#44;90&#8211;1&#44;42<span class="elsevierStyleHsp" style=""></span>ng&#47;dl&#59; T3L&#58; 2&#44;49&#8211;3&#44;56<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#46; La TSH depende de la edad de la madre y de la interacci&#243;n entre la edad y fumar&#46; La T3L depende del IMC de la madre y de fumar&#44; existiendo adem&#225;s una interacci&#243;n entre ambos factores&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Los valores de referencia obtenidos pueden utilizarse para valorar la disfunci&#243;n tiroidea en mujeres gestantes de El Bierzo&#46; Los valores de TSH y T3L est&#225;n influidos por la edad de la madre&#44; el IMC y fumar&#44; adem&#225;s de por las interacciones entre estos factores&#46;</p>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as&#58; Lombardo Grifol M&#44; Guti&#233;rrez Men&#233;ndez ML&#44; Garc&#237;a Men&#233;ndez L&#44; Valdazo Revenga MV&#46; Valores de referencia y estudio de la variabilidad de hormonas tiroideas en gestantes de El Bierzo&#46; Endocrinol Nutr&#46; 2013&#59;60&#58;549&#8211;554&#46;</p>"
      ]
    ]
    "multimedia" => array:5 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1519
            "Ancho" => 1669
            "Tamanyo" => 79175
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">TSH profile plots&#46; Covariate FT4 assessed at 1&#46;1391<span class="elsevierStyleHsp" style=""></span>ng&#47;mL to eliminate its significant effect &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; on TSH&#46; TSH&#58; thyroid-stimulating hormone&#59; FT4&#58; free thyroxine&#46; Significance&#58; age <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; smoking <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;471&#59; interaction between age and smoking <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 1350
            "Ancho" => 1682
            "Tamanyo" => 79333
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">FT3 profile plots&#46; Covariate FT4 assessed at 1&#46;1391<span class="elsevierStyleHsp" style=""></span>ng&#47;mL to eliminate its significant effect &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; on FT3&#46; BMI&#44; body mass index&#59; FT3&#44; free triiodothyronine&#59; FT4&#44; free thyroxine&#46; Significance&#58; BMI <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; smoking <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#59; interaction between BMI and smoking <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>412&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Reason for exclusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Number of cases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Excluded</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive anti-thyroid antibodies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Other endocrine causes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">79&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No hormone data in first trimester &#40;weeks 8&#8211;13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No data on prior diseases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Other diseases that may affect thyroid hormones&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Twin and Down syndrome pregnancies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Excluded from the variability study</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">163&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Excluded&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Smokers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Excluded from the study of reference values</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">193&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">46&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Description of reasons for study exclusion&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">BMI&#44; body mass index&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Study &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>249&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Excluded &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>163&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age &#40;mean&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                      "titulo" => "Thyroid disorders during pregnancy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "C&#46;F&#46; Yazbeck"
                            1 => "S&#46;D&#46; Sullivan"
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                      "doi" => "10.1016/j.mcna.2012.01.004"
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                        "tituloSerie" => "Med Clin N Am"
                        "fecha" => "2012"
                        "volumen" => "96"
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es en pt

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