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ORIGINAL ARTICLE
Year : 2018  |  Volume : 15  |  Issue : 3  |  Page : 105-112

Trimester-specific thyroid hormone dynamics, iodine reserve, and pregnancy outcomes: A longitudinal study


1 Centre for Biosciences and Clinical Research, School of Biosciences, Apeejay Stya University, Gurgaon, Haryana; Department of Community Medicine, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, Uttarakhand, India
2 Centre for Biosciences and Clinical Research, School of Biosciences, Apeejay Stya University, Gurgaon, Haryana, India
3 Government Civil Hospital, Department of General Medicine, Pataudi, Haryana, India
4 Maternity Clinic and Nursing Home, Gurgaon, Haryana, India
5 Department of Endocrinology and Diabetes, Medanta, The Medicity, Gurgaon, Haryana, India

Date of Web Publication15-Nov-2018

Correspondence Address:
Dr. Asha Chandola-Saklani
Centre for Bioscience and Clinical Research, School of Bioscience, Apeejay Stya University, Sohna, Gurgaon - 122 103, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/trp.trp_23_18

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  Abstract 


Background: Iodine is an integral constituent of thyroid hormones, and the physiological changes during pregnancy affect its turnover and excretion necessitating increased intake during pregnancy. Understandably, populations with deficient iodine would have a greater prevalence of thyroid dysfunction which would also affect reference-range estimations and hence unreliable diagnosis. Despite this, there is a conspicuous lack of data on the impact of iodine deficiency on thyroid hormone dynamics and reference-intervals during pregnancy.
Objective: The aim of this study is to assess thyroid hormone ranges and pregnancy outcome in a mild-iodine-deficient population.
Methods: Survey was conducted for goiter and adverse pregnancy outcomes on rural women from 13 Government Primary Health Centers in an iodine-deficient zone. Out of this population, 340 women completed the follow-up for thyroid status (Goiter, thyroid-stimulating hormone [TSH], free thyroxine) and pregnancy outcome. Data on pregnancy outcome for the last 10 years were also retrieved from health center records.
Results: Urinary iodine concentration values re-affirmed the mild-iodine-deficient status of this population. TSH indicated relatively higher cutoffs (at 2.5th–97.5th percentile: 1.02–3.70, 1.54-4.83, 2.20–5.74 mIU/L, 1st, 2nd, and 3rd trimester) as compared to that of international guidelines imported in India, yet 98% of the population was found within normal range. Data indicated the possibility of misclassification error following imported guidelines. Survey revealed 1.1% Grade1 goiter, 0.4% miscarriages, 0.68% premature birth, and 1.59% stillbirth. Data retrieved from the past 10 years are comparable.
Conclusion: Iodine deficiency appears to enhance the upper cutoffs of TSH. Thyroid function remains unimpaired in continued mild iodine deficiency during pregnancy as a result of efficient homeostasis. The study underscores the need for indigenous population-specific ranges to avoid misclassification errors.

Keywords: Dry blood sampling, free thyroxine, iodine deficiency, micronutrient iodine, pregnancy, pregnancy outcome, thyroid function, thyroid-stimulating hormone, thyroid in pregnancy, urinary iodine excretion


How to cite this article:
Yadav N, Kathait A, Malik DS, Pasricha MK, Mishra SK, Chandola-Saklani A. Trimester-specific thyroid hormone dynamics, iodine reserve, and pregnancy outcomes: A longitudinal study. Thyroid Res Pract 2018;15:105-12

How to cite this URL:
Yadav N, Kathait A, Malik DS, Pasricha MK, Mishra SK, Chandola-Saklani A. Trimester-specific thyroid hormone dynamics, iodine reserve, and pregnancy outcomes: A longitudinal study. Thyroid Res Pract [serial online] 2018 [cited 2018 Dec 17];15:105-12. Available from: http://www.thetrp.net/text.asp?2018/15/3/105/245559




  Introduction Top


Thyroid hormones are well known for their developmental and metabolic effects with a role in reproductive and associated phenomena in vertebrates[1],[2] including humans. The micro-nutrient iodine, being an important component of the thyroid hormone molecule, assumes great physiological importance and its deficiency in the environment can produce adverse effects.[3] It is well established that during pregnancy, normal physiological changes occur concomitantly with an enhanced metabolic demand for thyroxine/iodine.[4] These changes are adjusted if dietary iodine intake is adequate. With deficient iodine intake, it is believed that the glandular machinery may not be able to attain equilibrium resulting in pathological aberrations leading to hypothyroidism, thyroxinemia, and attendant reproductive failure, for example, miscarriages, pre-term delivery, stillbirth, and neuro-developmental iodine deficiency disorders in the offspring.[5],[6],[7] Understandably, populations with inadequate iodine would have a greater chance of prevalence of thyroid dysfunction that in turn would affect normal reference ranges also. Accurate diagnosis of thyroid status is, therefore, crucial. International guidelines (the American Thyroid Association [ATA], Endocrine Society [ES], and European Thyroid Association [ETA])[8],[9],[10] specifically mandate reference ranges derived from populations with optimal iodine intake. Despite this, there is a paucity of data addressing the impact of iodine deficiency on thyroid hormone dynamics in pregnant women.

Universal salt iodization in India was implemented in the early 60s, but reports from different parts of the country[11] have shown inadequate availability of iodine to the population. Populations inhabiting these iodine deficient zones are most vulnerable to thyroid dysfunction due to suboptimal iodine intake. Given the paucity of reference ranges in these zones, physicians have no recourse but to follow the established international guidelines derived from iodine-sufficient populations, which, understandably, would be different. This is disconcerting in view of the possibility of misclassification errors, as well as the fact that minor variations in thyroid hormone levels can have clinical implications.[12]

In this paper, we provide trimester-specific longitudinal profiles and dynamics of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) along with urinary iodine concentration (UIC) with reference to upper limits, cut-offs and distribution in a population from the known mild iodine-deficient zone. Pregnancy outcomes, derived from questionnaire-based survey, data retrieval, as well as longitudinal follow-up are also described from the same area.

These data were presented at the 38th meeting of ETA 2014, Santiago de Compostela, Spain.[13]


  Methods Top


Study site

The study was conducted in rural region of District Gurgaon Haryana (28.32°N 76.78°E) designated as mild iodine-deficient zone[14],[15] in 13 Villages (Gudhana, Hussainka, Rajpura, Jauri Khurd, Jauri Kala, Janaula, Sampka, Nurgarh, Ram Nagar, Khandewala, Bhasunda, Tripadi, Dhaboda) after approved by Ethical Committee (Ethical Committee of Centre for Biosciences and Clinical Research, Apeejay Stya University vide SBS_ASU/IEC001/2012 on 26 May 2012).

Primary Health Centers (PHC) and “Aanganwadi” Units affiliated to reproductive and child healthcare Division of State Health Department cater to the health needs of women and children through accredited social health activists.

A questionnaire-based pilot survey was conducted on pregnant healthy females (19–34 years) visiting these PHCs from 13 villages. Thus primary information was obtained on 440 pregnant women on demographic socioeconomic, physiological, and clinical features, namely, household income, age, height, body weight, blood pressure (BP), parity, gravida and hyperemesis, Inflammatory bowel disorder, occurrence of goiter (palpation), asthma, tumor, thyroid dysfunction, previous pregnancy outcomes (miscarriages, stillbirth, and premature birth), smoking habit, iodized/uniodized salt usage, and water source.

In the longitudinal follow-up study, pregnant and nonpregnant women who had a previous history of thyroid disease, use of thyroid medications, hypertension, renal disease, diabetes, hyperemesis gravidarum, miscarriages, overt hypo-hyperthyroidism, and those on medication that might affect thyroid function were excluded from the study. Anti-thyroid peroxidase (TPO Ab) was determined using Calbiotech ELISA kits. About 2.4% of subjects were found to be anti-TPO positive (>50 IU/ml) and excluded from the study. After being subjected to exclusion criterion, 340 subjects completed the study. This sample was in conformity with the estimated adequate sample size (332) calculated using G-Power software with a power of 80%. Fifty nonpregnant subjects were also enrolled from the same population with similar age group, socioeconomic and physiological characteristics to serve as an indicator of baseline pre-conception values of the pregnant women.

Pregnant women were followed and data generated in the 10th, 20th, and 30th week of gestation. Thyroid was palpated and samples of blood (finger prick, Dry blood spot, dry blood sampling [DBS]) and urine were collected at the same time (forenoon). Body mass index (BMI) and BP were also recorded. Offspring born to these women are under surveillance for neurodevelopmental studies.[16]

Data on pregnancy outcome for the past 10 years were retrieved from Government Health Records in these 13 villages. Informed consent and Institutional Ethical Clearance were obtained.

Sample collection and storage

To be least invasive with pregnant women, we resorted to finger-prick DBS. Samples were collected following universal precautions[17] on a matrix, the spots dried at room temperature for 3–4 h, sealed in zip locks and transported to the laboratory and stored in desiccators at −20°C until assayed. All hormone assays were performed together in lots, in the end to reduce inter- and intra-assay variations. Reports were blinded to reduce bias. Thus, the hormone values remained unknown until after the completion of pregnancy.

Urine samples were collected in sterile containers (5–10 ml), placed in Coolant kit (0°C–4°C) and transported to the laboratory where aliquoted and stored in a refrigerator until analysis.

Assessment of thyroid status

Palpation

Each pregnant patient was clinically examined for the enlargement of the thyroid (goiter) by palpation method[18] (Grade 0: no goiter; Grade 1: nonvisible palpable; and Grade 2: Thyroid visible with the neck in normal position).

Urinary iodine content

UIC was measured using Sanger-Kolthoff reaction spectro-photometrically using the prescribed standard protocol.[3] The intra- and inter-assay coefficient of variation was 4.8% and 5.3%, respectively.

Dry blood sampling extraction and hormone assay

We used pre-coated TLC silica gel matrix (60F254, Merck 20 cm × 20 cm) which was subjected to validation for optimum working conditions.[19],[20],[21] Drying time (0.5, 1.5, 2.5, 3.5, 4.5, 5.5 h), elution time (1.0, 3.0, 5.0–16 h), percent recovery (83%–98%) and linearity at varying dilutions were determined. Stability studies for TSH samples were conducted at variable temperatures, and half-life found to be temperature dependent viz., 24.54 days, RT; 180.45, 4°C; 206.25 days, −20°C. Standards and controls were prepared with 30% hematocrit. Blood with known hematocrit was prepared by collecting human K2EDTA whole blood, followed by centrifugation at 4°C for 10 min at 1000 g. Erythrocyte pellet was washed and suspended in 0.9% NaCl. The suspension was gently rotated and then re-centrifuged at 1000 g for 10 min at room temp. Pellet was resuspended and the step repeated thrice.

Different dilutions of the calibrator solution from TSH ELISA kit (calbiotech) were added to the washed erythrocyte, vortexed and spotted on matrices and dried at room temperature for 3.30 h.

After drying, 4 mm diameter spot were punched out and placed in a micro-centrifuge tube containing elution solvent (110 μL milliQ water), vortexed and incubated at 4°C for 5 h. A volume of 50 μL eluate was added to wells pre-coated with anti-TSH antibodies followed by secondary antibody-enzyme conjugate and kept for 60 min at room temperature. After incubation and washing, TMB substrate was added, and absorbance was measured at 450 nm. Calibration curves were constructed at different concentrations in triplicate, i.e., 0.25–20.0 mIU/L TSH and 5.7–25.0 pMol/L FT4. Samples were done in duplicates.

The assay characteristics of calibration curves were as follows: correlation coefficient 0.976, slope 0.068, coefficient of variation 0.40%–0.85%, sensitivity 0.0286 mIU/L, interassay variation 0.50 and for FT4 correlation coefficient 0.926, slope 0.094, coefficient of variation 0.84%–4.12%, and interassay variation 3.03%.

Hematocrit correction experiments were performed to convert DBS results into serum equivalent.[22] TSH values obtained from DBS samples after hematocrit correction were compared with those simultaneously obtained from serum from the same blood samples (P not significant). A significant correlation was found between serum-TSH and DBS-TSH values (Spearman correlation coefficient 0.9492, P < 0.0001 and slope and intercept were 1.013 and 0.256 respectively). The present TSH and FT4 levels are in accordance with previously published reports using DBS sampling method.[19]

Statistical analyses

Data for TSH and FT4 were expressed as mean ± standard deviation, median, and 2.5th–97.5th percentiles. UIC data were expressed in median and 2.5th–97.5th percentiles. All hormonal values were calculated and compared among trimesters. Student's t-test, followed by Bonferroni post hoc analysis and Pearson correlation analysis were the Statistical tests performed for comparisons.


  Results Top


Results are summarized in [Table 1], [Table 2], [Table 3] and [Figure 1], [Figure 2], [Figure 3].
Table 1: Urinary iodine concentration (urinary iodine concentration, median values) in longitudinal follow-up population

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Table 2: Survey of goiter and pregnancy outcome in 13 villages of Haryana

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Table 3: Thyroid-stimulating hormone and free thyroxine ranges in pregnant and nonpregnant subjects

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Figure 1: Distribution of serum thyroid-stimulating hormone values within the normal percentile intervals (2.5th–97.5th) in a mild iodine-deficient population of 340 healthy rural young Indian women who completed the follow-up longitudinal study after exclusion criteria.Note approximately 98% population lies within upper limit thyroid-stimulating hormone cut-offs i.e., 3.7, 4.8 and 5.74 mIU/L in 1st, 2nd, 3rd trimester respectively. Any women falling beyond these cut offs (2%–4% of population) would require treatment. Whereas according to the cut-offs in practice in India (following International guidelines) a much higher segment of population would be potential candidates for treatment, and thus stand the risk of misclassification

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Figure 2: Boxplot. Value for thyroid-stimulating hormone and free thyroxine in different trimester of pregnancy. The stars represent outliers in every trimester

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Figure 3: Correlation of thyroid-stimulating hormone and free thyroxine in pregnant subjects over trimesters I, II and III

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During longitudinal follow-up of 340 subjects who completed the study, eight developed goiter (Grade1 nonvisible palpable) having normal TSH and FT4. Twenty-five women developed hypertension during the study, tracked separately, but data were included.

Urinary iodine concentration

Median values of UIE (μg/L): Tri I 146, Tri II 128, Tri III 113.

Range UIE (μg/L) Tri I: 104–195, Tri II 86–173, Trim III 85–175.

Mean levels of UIE (μg/L): Tri I147 ± 1.21, Tri II127 ± 0.97, Tri III118 ± 1.03.

UIE was distributed in pregnant subjects as follows: Tri I 56% <150 μg/L, Tri II 89% <150 μg/L, and Tri III 91% μg/L indicating a progressive decline in iodine sufficiency.

According to the WHO Guideline (2007) Pregnant women, Iodine sufficiency = 150–249 μg/L, Iodine deficiency = <150 μg/L. In our study, the figures for insufficient iodine n status increased from 56% in the first trimester to 89% in the second trimester and to 91% in in the third trimester.

Overall 91% pregnant females were iodine deficient with 9% iodine sufficient in the third trimester.

Approximately 50% of nonpregnant women were iodine deficient 56–99 μg/L (as per the WHO norms) [Table 1].

Reference ranges[Table 3] and [Figure 2]

TSH: Overall trimester ranges in pregnant subjects were TSH (mIU/L/) Tri I: 1.02–3.70, Tri II 1.54–4.83, Tri III 2.20–5.74 and mean levels of TSH (mIU/L): Tri I 2.30 ± 0.04, Tri II 2.99 ± 0.05, Tri III 3.72 ± 0.04.

TSH level in 70% pregnant subjects lies in >0.67–4.0 mIU/L with 30% in >4.0–5.8 mIU/L [Figure 1].

FT4: FT4 (pmol/L) Tri I: 10.38–18.63, Tri II 9.00–17.60, Tri III 8.20–16.09.

Mean levels of FT4 (pmol/L): Tri I 15.06 ± 0.14, Tri II 13.49 ± 0.13, Tri III 11.82 ± 0.11.

FT4 level in 81% of subjects lies in >10–20 pmol/L across the pregnancy. Only 19% subjects having FT4 level >8.20–10.0 pmol/L [Figure 1].

The significant negative linear correlation was observed between TSH and FT4 in pregnant subjects [Figure 2]. Tri I, TSH versus FT4 r = −0.7137, Tri II, TSH versus FT4 r = −0.7302, Tri III, TSH versus FT4 r = 0.7435 (P < 0.0001 all Trimesters).


  Discussion Top


Our study area District Gurgaon comes under International direct dialing Endemic zone.[14],[15] Despite the intake of iodized salt, (as evident from questionnaire survey) urinary content reflected mild iodine-deficient status as per the WHO norms. Present UIC values reaffirm a mild iodine-deficient status of this population. Median UIC values in our study population decline across the trimesters i.e., 56%, 89%, and 91% subjects being iodine-deficient in the 1st, 2nd, and 3rd trimester (as per the WHO norms) reflecting the increased need for iodine [Table 1].

Given the alterations in thyroid physiology in pregnancy, it is important to define “normal” thyroid function during pregnancy. This issue is further complicated in iodine deficient population. The international Guidelines evolved by ES, ETA, ATA, recommend that trimester-specific normative reference ranges be established in populations on optimal iodine intake. However, limited information is available on how iodine status affects TSH reference intervals. Present data indicate a significant, consistent rise in TSH throughout trimesters resulting in higher TSH thresholds [Table 3]. Given the increasing prevalence of iodine deficiency in pregnancy in II and III Trimester [as indicated by UIC values, [Table 1], the rise in TSH values may well be a consequence of iodine deficiency.

Following The International Federation of Clinical Chemistry stipulation,[23] thyroid dysfunction is mostly defined according to population-based cutoffs at 2.5–97.5 percentile, and occasionally, 5–95 percentile. By that virtue, in current study at 97.5 percentile approximately 98% population (333 subjects) lies within upper limit TSH cut-offs, i.e., 3.7, 4.8, and 5.74 mIU/L in 1st, 2nd, and 3rd trimester, respectively. About 2% population constitutes outliers in all trimesters, i.e., six subjects in 1st and 2nd trimesterand 7 in the 3rd trimester. At 95 percentile approx 96% (326 subjects) population lies within TSH cutoffs 3.59 (1st trimester), 4.76 (2nd tri), 5.60 mIU/L (3rd trimester), and 4% (14 subjects) constitutes outliers. Therefore, any women falling beyond above cut-offs (2%–4% of the population) may require further evaluation for treatment. Whereas in this given population according to the cut-offs in practice in India (international guidelines) a much higher segment of the population would be potential candidates for treatment and hence stand the risk of misclassification.

This underscores the importance of treatment derived from the population-specific database. Our results on overt thyroid symptoms and pregnancy outcomes also support these reference intervals rather than that adopted from international guidelines.

In the current study, at 2.5–97.5 percentile approximately 1%–2% FT4 values were obtained in outliers and 98%–99% within lower limit FT4-cutoffs, i.e., 10.38pmol/L (1st trimester), 9.0 pmol/L (2nd trimester) and 8.20pmol/L (3rd trimester).

Although the literature is replete with reports on hormonal profiles our knowledge is limited as to how the thyroid in pregnant women from iodine-deficient areas handles the dual challenge. There have been 31 cross-sectional studies,[24],[25] 19 from Iodine-sufficient (IS zones, one from India[26] 12 from iodine-deficient zones ID), and 9 longitudinal studies (5 ID, 4 IS) to understand the dynamics of thyroid hormones in pregnancy, across trimesters, but clear-cut patterns are yet to emerge.

In cross-sectional studies, due to large inter-individual variations, the patterns tend to be masked unless the enormous sample size is available. Longitudinal self-sequential follow-up data afford more accurate interpretations. In longitudinal studies of iodine-deficient populations.[27],[28],[29],[30],[31] TSH shows increasing trends, both in upper and lower limits and FT4 invariably declines across the trimesters. In iodine-sufficient populations[32],[33],[34],[35] also, interestingly, in almost all, TSH shows a rising and FT4 a declining trend. However, iodine status, in all these studies is only presumed, not assessed, except in one.[33] The study, employing a somewhat larger sample size, affords inter-trimester comparisons of individual values indicating that the observed trends are indeed significant, i.e., rise in TSH (P < 0.0001 1st trimester vs. 2nd and 3rd) and decline in FT4 (P < 0.0001, 1st trimester vs. 2nd and 3rd) across the trimesters [Table 1] and [Figure 2]. Interestingly FT4 decline has been reported in iodine-supplemented pregnant women too,[36] although, using different FT4 assay method. The declining pattern, irrespective of iodine deficiency or sufficiency, may reflect attempt at euthyroidism. This, however, needs to be established using same FT4 protocols.

Examining the hormonal profiles individually, FT4 exhibited more or less stable pattern of decline from 1st to 3rd trimester, characterized by a gentle slope. In TSH profile, however, two patterns became evident. One, increasing with a very strong slope 77% of individuals (n = 236) and the other with a gentle to moderate slope 23% (n = 71), the former apparently a reflection of iodine deficiency challenge and suggestive of an active homeostatic mechanism as evident from the strong correlation observed between TSH and FT4 also [Figure 3].

Our observations on iodine-deficient populations of Himalayan habitats (mild iodine-deficient as per WHO) are also akin to that in pregnancy. Normal TSH, T4, T3, FT4 profiles in these populations were observed despite 70%–90% consumption of un-iodised salt, indicative of efficient hormonal adjustments (homeostasis) without iodine prophylaxis, reflected also in the low prevalence of iodine deficiency disorders in the area.[37]

Current survey revealed 1.1% nonvisible palpable Grade1 goiter, 0.4% miscarriages, 0.68% premature birth, 1.59% stillbirth. Data retrieved from past 10 years were comparable with these values, namely, miscarriage = 0.41%, premature birth = 0.41%, stillbirth = 0.76% [Table 2]. No data bases are available on these pregnancy outcomes for comparison, except for still birth. Present data on still birth are in harmony with that reported for different Indian States.[38] Pregnancy outcome in the follow-up longitudinal study population was 100% successful in all 340 pregnant women including the 8 that developed palpable goiter, with no incidence of miscarriage, preterm delivery and still birth. Despite iodine deficiency this particular rural segment of North-Indian population appears to be healthy as evident from BMI also (Pregnant group 19.50 ± 0.17, nonpregnant 20.01 ± 0.14 kg/m2).

A multi-centric study from the states of Bihar, Haryana, Uttarakhand, and Uttar Pradesh, is in progress, and would provide further insights into homeostasis as well as pave way for developing population specific guidelines for management of thyroid during pregnancy in the Indian subcontinent.


  Conclusion Top


Iodine deficiency appears to enhance the upper cut-offs of TSH. Thyroid function remains unimpaired in continued mild iodine deficiency during pregnancy as a result of efficient homeostasis. Study underscores the need for indigenous population-specific ranges to avoid misclassification errors.

Longitudinal trimester-specific normative reference ranges for thyroid hormones in iodine deficient pregnant women have been obtained for the first time in India. This paves way to adequate diagnosis of thyroid dysfunction and development of indigenous guidelines.

Normal hormonal ranges and normal pregnancy outcome despite iodine deficiency reflect a healthy life style in rural India.

Acknowledgment

We gratefully acknowledge Apeejay Education Society for providing Research Fellowship to 1st author. AK acknowledges Department of Science and Technology for Senior Research Fellowship. Help of Dr. Vineet Sharma is acknowledged in the standardization process of DBS extraction. We are grateful to Dr. Elizabeth Pearce, Medical Centre, Boston University, USA, for critical comments on the original version of the manuscript.

Financial support and sponsorship

Research facility (Lab Equipments, Reagents etc.,) was provided by Apeejay Stya University.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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