Iron deficiency, an independent risk factor for isolated hypothyroxinemia in pregnant and nonpregnant women of childbearing age in China.

ORIGINAL

ARTICLE

Iron Deficiency, an Independent Risk Factor for Isolated Hypothyroxinemia in Pregnant and Nonpregnant Women of Childbearing age in China Xiaohui Yu 1, Zhongyan Shan 1, Chenyan Li 1, Jinyuan Mao 1, Weiwei Wang 1, Xiaochen Xie 1, Aihua Liu1, Xiaochun Teng 1, Weiwei Zhou 2, Chenyang Li 2, Bin Xu 3, Lihua Bi 4, Tao Meng 5, Jianling Du6, Shaowei Zhang 7, Zhengnan Gao 8, Xiaomei Zhang 9, Liu Yang 10, Chenling Fan 1, and Weiping Teng 1 1 Endocrine Institute and Liaoning Provincial Key Laboratory of Endocrine Diseases, Department of Endocrinology and Metabolism, The First Hospital of China Medical University, Shenyang, China; 2 Shenyang Women’s and Children’s Hospital, Shenyang, China; 3 Department of Obstetrics and Gynecology, No. 202 Hospital of People’s Liberation Army, Shenyang, China; 4 Dalian Obstetrics and Gynecology Hospital, Dalian, China; 5 Department of Obstetrics and Gynecology, The First Hospital of China Medical University, Shenyang, China; 6 Department of Endocrinology, The First Affiliated Hospital of Dalian Medical University, Dalian, China; 7 Department of Endocrinology, No. 202 Hospital of People’s Liberation Army, Shenyang, China; 8 Department of Endocrinology, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, China; 9 Department of Endocrinology, The First Hospital of Dandong, Dandong, China; 10 Shenyang Women and Children Health Care Center, Shenyang, China

CONTEXT: Isolated hypothyroxinemia during early pregnancy may irreversibly damage offspring’s neurodevelopment. However, the causes are not well clarified. OBJECTIVE: To explore the association of iron deficiency (ID) with hypothyroid function in early pregnant and non-pregnant women. DESIGN: 7,953 pregnant women of ⱕ 12 weeks’ gestation and 2,000 childbearing-aged women were recruited. A subpopulation including 3,340 pregnant women and 1,052 non-pregnant women with sufficient iodine intake and negative TPOAb were studied. Mild and severe hypothyroxinemia were defined as FT4 levels below the 10th percentile and the fifth percentile with normal TSH. Total body iron (TBI), serum ferritin (SF) and serum transferrin receptor (sTfR) were used as indicators for iron nutrition. RESULTS: Serum FT4 levels were significantly lower in both pregnant and non-pregnant women with ID compared with the corresponding groups without ID (both p ⬍ 0.05). The prevalence of mild and severe hypothyroxinemia was markedly higher in women with ID than those without, in both pregnant and non-pregnant women (all p ⬍ 0.01). Logistic regression indicated that ID was an independent risk factor for both mild and severe hypothyroxinemia in pregnancy [OR ⫽ 2.440 (1.324 – 4.496), p ⫽ 0.004 and OR ⫽ 3.278 (1.443–7.446), p ⫽ 0.005, respectively] and non-pregnancy [OR ⫽ 2.662 (1.330 –5.329), p ⫽ 0.006 and OR ⫽ 3.254 (1.375–7.700), p ⫽ 0.007, respectively]. CONCLUSIONS: An association between ID and isolated hypothyroxinemia was found in both pregnant and childbearing-aged women independent of the effects of iodine and thyroid autoimmunity. We speculate that ID maybe a pathogenic factor for hypothyroxinemia, even in pregnant women during the first trimester.

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2015 by the Endocrine Society Received October 23, 2014. Accepted January 9, 2015.

doi: 10.1210/jc.2014-3887

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Iron deficiency: a risk factor of hypothyroxinemia

n recent years, the impact of mild thyroid insufficiency on pregnant outcomes and offspring’s intelligence has been a focus of research. Several recent studies have indicated that mild thyroid insufficiency, such as isolated hypothyroxinemia and subclinical hypothyroidism during pregnancy, can increase the prevalence of spontaneous abortion, placental abruption, preterm birth, fetal distress, and preeclampsia (1–7), and contribute to impaired cognitive outcome of the offspring (8 –11). However, some other studies did not indicate the adverse impact on these outcomes from hypothyroxinemia (12–15). Although iodine deficiency and thyroid autoimmunity have been considered as the contributors for thyroid insufficiency, they can’t explain the whole etiology of thyroid insufficiency. So the potential etiology of mild thyroid insufficiency should be explored further. Iron deficiency (ID) is the most prevalent of all micronutrient deficiencies worldwide. Numerous studies have shown that ID can impair thyroid hormone synthesis and metabolism. It decreases plasma T4 and T3 concentrations by impairing two initial steps catalyzed by heme-dependent thyroid peroxidase (TPO) enzyme in thyroid hormones synthesis (16). And ID appears to decrease TSH response to TRH (17), reduce the peripheral conversion of T4 to T3 and increase circulating TSH (18, 19). Pregnant women are highly vulnerable to ID. They have an increased demand for iron to expand their erythrocyte mass and generate the iron supply to the growing fetus. However, studies on the effect of ID on thyroid function in an iodine-adequate population are scarce. To improve our understanding of the direct relationship between ID and thyroid function, studies are required where the effects of iodine malnutrition are eliminated. Therefore, the objective of this study was to investigate whether maternal iron nutrition deficiency can affect thyroid status of women in the first trimester of pregnancy and nonpregnant women of childbearing age in an iodine adequate area in China.

Subjects and Methods Subjects The subclinical hypothyroid in early pregnancy (SHEP) study started in June 2012 in Liaoning Province in northeast China, where iodine availability was adequate according to the median urinary iodine concentration (UIC) measured in 101 schoolchildren which was 191.2 ␮g/L, as described by Chenyan Li (20). Nineteen hospitals were involved in this study, and included the departments of obstetrics and gynecology, and departments of endocrinology. Recruitment criteria included residence in the city for more than 10 years; age between 19 and 40 years; and planning to become pregnant or having a singleton pregnancy at 4 to12 weeks of gestation. Exclusion criteria included multiple pregnancies; patients with history of thyroid diseases or any


other chronic diseases; patients on oral contraceptive (OC) regimens before pregnancy or any medical regimen that may affect thyroid function, such as glucocorticoids, dopamine, or antiepileptic drugs. Up to September 2013, a total of 9953 women participated in the initial stage of the study, including 7953 pregnant women in the first trimester and 2000 nonpregnant women of childbearing age. All the participants were asked to complete the questionnaires on the demographic data, history of thyroid diseases, parity, smoking and drinking, chronic diseases and medication use. Their fasting serum and urine samples were collected. Serum TSH, free T4 (FT4), TPO antibody (TPOAb), serum ferritin (SF), and UIC were measured. The median UIC in the whole population of pregnant and nonpregnant women was 162.3 ␮g/L and 164.6 ␮g/L, respectively. However, in order to eliminate the impact of iodine and thyroid autoimmunity, we selected a subpopulation with sufficient iodine intake according to the WHO Technical Consultation recommendation (21) [for pregnant women: UIC between 150 and 499 ␮g/L; and for nonpregnant women: UIC between 100 and 299 ␮g/L] and with negative TPOAb for further study. Thus, a final total of 4392 women, including 3340 pregnant women in the first trimester and 1052 nonpregnant women were selected. (Figure 1) Among these women serum transferrin receptor (sTfR) was also measured besides the above parameters.

Methods Samples of fasting blood and spot urine were obtained from each participant in the morning. All specimens were frozen at –20°C until shipment, and assayed in one week. Serum TSH, FT4, TPOAb, and SF were measured using the electrochemiluminescence immunoassay on a Cobas Elesys 601 (Roche Diagnostics, Swiss). The intra-assay coefficients of variation (CV) of TSH, FT4, TPOAb, and SF were 1.57% to 4.12%, 2.24% to 6.33%, 2.42% to 5.63%, and 1.43% to 4.52%, respectively. The interassay CVs were 1.26% to 5.76%, 4.53% to 8.23%, 5.23% to 8.16%, and 3.52% to 7.91%, respectively. sTfR was measured using the immunoturbidimetric assay on Cobas c 501 (Roche Diagnostics, Swiss). The intra- and interassay CVs of sTfR were 2.26% to 5.46% and 3.57% to 6.24%, respectively. UIC was determined by the ammonium persulfate method based on the Sandell-Kolthoff reaction. The intra- and interassay CVs of UIC were 3% to 4% and 4% to 6% at 66 ␮g/L, respectively; 2% to 5% and 3% to 6% at 230 ␮g/L, respectively. The reference intervals of serum TSH and FT4 for pregnant (4 to 12 weeks of gestation) and nonpregnant women were acquired from our previous study (20). The reference intervals of TSH were 0.14 to 4.87 mIU/L and 0.69 to 5.64 mIU/L, respectively, for pregnant and nonpregnant women. The reference intervals of FT4 were 12.35 to 20.71 pmol/L and 12.27 to 19.10 pmol/L, respectively. The manufacturer-specified reference interval was 0 to 34 IU/mL for TPOAb. Diagnostic criteria for thyroid disorders: (i) overt hypothyroidism: elevated TSH levels combined with decreased FT4 levels; (ii) overt hyperthyroidism: decreased TSH levels combined with elevated FT4 levels; (iii) subclinical hypothyroidism: elevated TSH levels combined with normal FT4 levels; (iv) subclinical hyperthyroidism: decreased TSH levels combined with normal FT4 levels; (v) isolated hypothyroxinemia: mild and severe hypothyroxinemia were defined as FT4 levels below the 10th percentile (FT4 ⬍ 13.72 pmol/L in pregnancy and FT4 ⬍ 13.48


doi: 10.1210/jc.2014-3887


Pregnant women enrolled: N = 7953 ( Jun 2012-Sep 2013)

Non-pregnant women enrolled: N = 2000 ( Jun 2012-Sep 2013)

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Bonferroni correction. A ‘p’ value less than 0.05 was considered to be statistically significant.

Ethics committee approval Excluding UIC < 150 μg/L: N = 3916

Excluding UIC ≥ 500 μg/L: N = 375

Excluding ones with positive TPOAb: N = 322

Left for analysis: N = 4037






Excluding UIC < 100 μg/L: N = 495

Excluding UIC ≥ 300 μg/L: N = 317

Excluding ones with positive TPOAb: N = 136

The experimental procedure described here was approved by the Ethics Committee of China Medical University and is congruent with the Declaration of Helsinki. Written informed consents were obtained from all the participants, and there were no stipends provided to them.

Results

Characteristics of the subjects Table 1 shows the general characteristics, thyroid function parameters and iron nutrition status of the subjects. The mean gestational age was 6.5 ⫾ 1.2 weeks for pregnant women. In pregnant women, the mean FT4 level was higher (16.50 ⫾ 3.02 vs. 15.71 ⫾ 2.02 pmol/L, P ⬍ .001), and the median TSH level was lower (1.79 vs. 2.06 mIU/L, P ⬍ .001). The median SF level and mean TBI level of pregnant women were higher than those of nonpregnant women (64.76 vs. 51.27 ␮g/L, P ⬍ .001 and 7.92 ⫾ 3.22 vs. 6.35 ⫾ 3.43 mg/kg, P ⬍ .001, respectively), and the median sTfR level was lower in pregnant women (2.67 vs. 3.11 mg/L, P ⬍ .001). The prevalence of ID during early pregnancy and nonpregnancy was, respectively, 3.0% and 7.5% based on low SF, 5.2% and 11.7% based on high sTfR, and 2.6% and 5.4% based on negative TBI. The prevalence of ID on the basis of high sTfR was higher than that on the basis of low SF or negative TBI, whether in pregnant or nonpregnant women (all P ⬍ .01). The prevalence of ID based on low SF was similar to that based on negative TBI in both pregnant and nonpregnant women. 94.2% of ID from negative TBI coincided with that from low SF in pregnancy. And the rate was 86.0% in nonpregnancy.

Figure 1. The flow diagram for the procedure of the subjects selected. The left part is for pregnant women, and the right part is for nonpregnant women. Abbreviations: UIC, urinary iodine concentration.

pmol/L in nonpregnancy, respectively) and the fifth percentile (both FT4 ⬍ 12.87 pmol/L) with normal TSH levels. Total body iron (TBI) was calculated, as previously described in detail from sTfR and SF concentrations by using a formula from Cook et al (22–24) after converting Roche sTfR concentrations to those equivalent to the Flowers assay (25) used in the development of the TBI model (23, 24). The formula used is as follows:

TBI共mg/kg兲 ⫽ ⫺ 关log10共sTfR ⫻ 1000/SF兲 ⫺ 2.8229兴/0.1207 To convert the Roche sTfR concentrations to that equivalent to the Flowers assay, we applied a conversion equation derived from a previous comparison of the 2 assays (n ⫽ 40) (26):

FlowerssTfR ⫽ 1.5 ⫻ RochesTfR ⫹ 0.35mg/L. We used the original Roche SF concentrations for the TBI calculation because a previous comparison of the Roche assay with the enzyme-linked immunosorbent assay (ELISA) method used to develop the TBI model indicated that these two methods generated similar values (23, 24). Positive values of TBI indicate the amount of iron in stores, and negative values indicate the deficit in tissue iron (23, 27). We used the manufacturer-specified reference interval of 1.9 to 4.4 mg/L for sTfR, and a value of sTfR ⬎ 4.4 mg/L to indicate ID. An abnormal value for SF was defined as less than 12 ␮g/L (22, 28).

Statistical analysis Data processing and statistics were performed using SPSS 16.0 software (SPSS, Inc., Chicago, IL). The mean ⫾ SD were calculated for normally distributed variables, while values of the median (interquartile range) were determined for data with skewed distributions. Independent sample t tests were used in two-group comparisons. We log transformed TSH, SF and sTfR to normalize the distributions before analysis because TSH, SF and sTfR concentrations were positively skewed (28). Multiple linear regression was used to test the association. Logistic regression was used to evaluate the risk factors for thyroid disorders. The level of significance for multiple tests was adjusted by

Relationship between iron status and thyroid function in early pregnancy and nonpregnancy On the basis of TBI concentration, we assigned pregnant and nonpregnant women into two groups each: those with ID and those without (Table 2). In both pregnant and nonpregnant women, the age, BMI, median UIC and parity in the women with ID were similar to those in the women without. The median TSH levels and the prevalence of hypothyroidism and of hyperthyroidism were also similar in the women with ID and in those without. There is a significant difference in serum FT4 levels, which were


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Table 1. women


Demographic data, thyroid function test and iron nutrition indexes for early pregnant and non-pregnant Pregnant women (n ⴝ 3340)

General characteristics Age (y)a BMI (kg/m2) a Smoking (%) Drinking (%) Laboratory tests TSH (mIU/liter) c FT4 (pmol/liter) a TPOAb (IU/mL) c SF (␮g/liter) c sTfR (mg/liter) c TBI (mg/kg) a Prevalence of ID (%) based on low SF based on high sTfR based on negative TBI Median UIC (␮g/liter) c

Non-pregnant women (n ⴝ 1052)

28.8 ⫾ 3.4 21.7 ⫾ 3.2b 1.1 (37/3340) 3.1 (103/3340)

29.0 ⫾ 3.8 22.2 ⫾ 4.2 0.8 (8/1052) 2.1 (22/1052)

1.79 (1.12–2.61) b 16.50 ⫾ 3.02 b 7.23 (5.00 –10.58) 64.76 (40.01–97.56) b 2.67 (2.24 –3.23) b 7.92 ⫾ 3.22 b

2.06 (1.49 –2.83) 15.71 ⫾ 2.02 8.68 (6.15–12.14) 51.27 (29.15– 80.22) 3.11 (2.60 –3.75) 6.35 ⫾ 3.43

3.0 (101/3340) d 5.2 (175/3340) b 2.6 (86/3340) b 206.2 (174.0 –263.0) b

7.5 (79/1052) 11.7 (123/1052) 5.4 (57/1052) 175.4 (136.8 –225.2)

Abbreviations: BMI, body mass index; TSH, thyrotropin; FT4, free thyroxine; TPOAb, thyroid peroxidase antibody; SF, serum ferritin; sTfR, serum transferrin receptor; TBI, total body iron; ID, iron deficiency; UIC, urinary iodine concentration. a

Means ⫾ SD

b

P ⬍ 0.01 compared with non-pregnant women

c

Median (interquartile range)

d

P ⬍ 0.05 compared with non-pregnant women.

Table 2.

Comparison of thyroid function between women with iron deficiency (ID) and those without Pregnant women Women with ID (n ⫽ 86)

Thyroid parameters TSH (mIU/liter) a FT4 (pmol/liter) b Prevalence of thyroid diseases Overt hypothyroidism, %(n) Overt hyperthyroidism, %(n) Subclinical hypothyroidism, %(n) Subclinical hyperthyroidism, %(n) Isolated hypothyroxinemia Mild hypothyroxinemia, %(n) Severe hypothyroxinemia, %(n)

Women without ID (n ⫽ 3254)

Non-pregnant women Women with ID (n ⫽ 57)

Women without ID (n ⫽ 995)

1.82 (1.20 –2.73) 15.37 ⫾ 1.81 c

1.79 (1.12–2.61) 16.38 ⫾ 3.04

2.06 (1.49 –2.54) 15.08 ⫾ 3.41 d

2.06 (1.49 –2.85) 15.75 ⫾ 1.90

1.16 (1) 0 2.33 (2) 2.33 (2)

0.31 (10) 1.08 (35) 3.10 (101) 0.58 (19)

0 1.75 (1) 0 1.75 (1)

0.3 (3) 0.9 (9) 2.41 (24) 1.91 (19)

18.60 (16) c 9.30 (8) c

7.96 (259) 2.67 (87)

24.56 (14) c 14.03 (8) c

9.85 (98) 4.82 (48)

Abbreviations: TSH, thyrotropin; FT4, free thyroxine; ID, iron deficiency. a

Median (interquartile range)

b

Mean ⫾ SD

c

P ⬍ 0.01 compared with the women without ID

d

P ⬍ 0.05 compared with the women without ID.

significantly lower in the women with ID than in those without (15.37 ⫾ 1.81 vs. 16.38 ⫾ 3.04 pmol/L, P ⫽ .004 in pregnancy and 15.08 ⫾ 3.41 vs. 15.75 ⫾ 1.90 pmol/L, P ⫽ .028 in nonpregnancy, respectively). The most striking difference between the groups is the prevalence of mild and severe hypothyroxinemia, which is markedly higher in the women with ID than in those without [in pregnancy:

18.60% vs. 7.96%, ␹2 ⫽ 12.566, P ⫽ .001, OR ⫽ 2.643 (1.513– 4.617) and 9.30% vs. 2.67%, ␹2 ⫽ 13.322, P ⫽ .001, OR ⫽ 3.734 (1.749 –7.969), respectively; in nonpregnancy: 24.56% vs. 9.85%, ␹2 ⫽ 12.266, P ⫽ .001, OR ⫽ 2.980 (1.574 –5.641) and 14.03% vs. 4.82%, ␹2 ⫽ 9.076, P ⫽ .005, OR ⫽ 3.221 (1.445–7.181), respectively]. (Table 2)


doi: 10.1210/jc.2014-3887


The dramatic difference in the prevalence of hypothyroxinemia between the women with and without ID warranted a closer look for any features that may correspond with the occurrence of this condition. No differences were found in age, parity, maternal educational level and family income between the women with hypothyroxinemia and those without, whether during pregnancy or nonpregnancy. However, mean TBI concentration in the women with mild and severe hypothyroxinemia was significantly lower than that in those without in pregnancy (7.20 ⫾ 3.64 vs. 7.96 ⫾ 3.18 mg/kg, P ⫽ .003 and 6.72 ⫾ 4.02 vs. 7.93 ⫾ 3.20 mg/kg, P ⫽ .005, respectively) and was slightly lower in nonpregnancy (5.16 ⫾ 4.29 vs. 6.40 ⫾ 3.30 mg/kg, P ⫽ .052 and 4.93 ⫾ 4.39 vs. 6.34 ⫾ 3.37 mg/kg, P ⫽ .044, respectively). The prevalence of ID was considerably higher in the women with mild and severe hypothyroxinemia than in those without, for both pregnant [5.82% vs. 2.30%, ␹2 ⫽ 12.204, P ⫽ .007, OR ⫽ 2.625 (1.497– 4.603) and 8.42% vs. 2.43%, ␹2 ⫽ 13.008, P ⫽ .005, OR ⫽ 3.696 (1.728 –7.906), respectively] and nonpregnant women [12.50% vs. 4.82%, ␹2 ⫽ 10.818, P ⫽ .015, OR ⫽ 2.819 (1.484 –5.356) and 14.29% vs. 5.19%, ␹2 ⫽ 8.099, P ⫽ .066, OR ⫽ 3.046 (1.363– 6.806), respectively]. With regards to subclinical hypothyroidism, the TBI concentrations and the prevalence of ID were similar in the women with this condition and in those without, both in pregnancy and nonpregnancy. The results of bivariate correlation showed that the TBI concentrations were positively correlated with serum FT4 levels (r ⫽ 0.126, P ⬍ .001 in pregnancy and r ⫽ 0.144, P ⬍ .001 in nonpregnancy, respectively). While the TBI concentrations were negatively correlated with serum TSH levels for pregnant women (r ⫽ – 0.105, P ⬍ .001), no association was shown between the TBI concentrations and serum TSH levels for nonpregnant women. Multivariate analysis Linear regression showed that serum FT4 levels were correlated with TBI, when FT4 acted as the dependent variable and the covariates included TBI, maternal age, BMI, and gestational age (in pregnancy) (Table 3). Serum Table 3.

TSH levels were negatively correlated with the TBI levels in early pregnancy (standardized ␤ ⫽ – 0.055, p ⫽ 0.002), but not in nonpregnancy. We analyzed the risk factors for isolated hypothyroxinemia using the logistic regression with mild and severe hypothyroxinemia as the dependent variables and the covariates including ID based on negative TBI, maternal age, increased BMI (BMI ⬎ 24 kg/m2) and gestational age (in pregnancy) (Table 4). We found that ID was an independent risk factor for mild (OR ⫽ 2.440, 95% CI: 1.324 – 4.496, P ⫽ .004) and severe hypothyroxinemia (OR ⫽ 3.278, 95% CI: 1.443–7.446, P ⫽ .005) in early pregnancy. And there are the similar results in nonpregnant women (OR ⫽ 2.662, 95% CI: 1.330 –5.329, P ⫽ .006 for mild hypothyroxinemia and OR ⫽ 3.254, 95% CI: 1.375– 7.700, P ⫽ .007 for severe hypothyroxinemia, respectively). However, whether in early pregnancy or in nonpregnancy ID was not a risk factor for subclinical hypothyroidism. DISSCUSION ID is the most common nutritional disorder worldwide and its prevention has been a public health goal. Hypothyroxinemia during early pregnancy have become a focus in the field of maternal thyroid disorders, because of its probable detrimental effects on neuropsychological development of the offspring (8, 10, 11), while some other studies showed the inconsistent results (12–15). However, the causes of hypothyroxinemia have not been clarified yet. To our knowledge, the current study is the first population-based survey on association of iron deficiency with thyroid function during the first trimester of pregnancy in an iodine adequate area. In this study, although the median UIC in the whole population of pregnant women was 162.3 ␮g/L, 49.2% of pregnant women still had UIC ⬍ 150 ␮g/L which was defined as iodine deficiency by WHO. Iodine deficiency and iodine excess have been proved to increase the occurrence of thyroid diseases. In order to eliminate these conditions, we selected a subpopulation in which UICs were between 150 ␮g/L and 499 ␮g/L in pregnant women and between 100 ␮g/L and 299 ␮g/L in nonpregnant women,

Linear regression for serum FT4 and relating risk factors Pregnant women

TBI Age BMI Gestational days

5

Non-pregnant women

␤

t

p

␤

t

0.188 0.007 ⫺ 0.133 0.020

4.933 0.403 ⫺ 7.402 1.129

0.000 0.687 0.000 0.259

0.134 ⫺ 0.061 ⫺ 0.094 N/A

4.120 ⫺ 1.887 ⫺ 2.893 N/A

p 0.000 0.059 0.004 N/A

Multivariable linear regression model adjusted for maternal age, BMI and gestational days (in pregnancy). Abbreviations: TBI, total body iron; BMI, body mass index; N/A, not applicable.


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Table 4.


Logistic regression evaluating the risk factors for mild and severe hypothyroxinemia Mild hypothyroxinemia

Pregnant women ID Increased BMI Non-pregnant women ID Age

Severe hypothyroxinemia

OR (95% CI)

p

OR (95% CI)

p

2.440 (1.324 – 4.496) 2.425 (1.845–3.186)

0.004 0.000

3.278 (1.443–7.446) 2.884 (1.877– 4.430)

0.005 0.000

2.662 (1.330 –5.329) 1.056 (1.001–1.114)

0.006 0.046

3.254 (1.375–7.700) 1.051 (0.976 –1.132)

0.007 0.188

Multivariable model adjusted for maternal age, body mass index (BMI) and gestational days (in pregnancy). “Enter” method was used. Abbreviations: ID, iron deficiency; BMI, body mass index; CI: confidence interval.

and also negative TPOAb because of its impact on thyroid function. Single urine iodine may incompletely assess individual’s iodine status. However, iodine concentrations of spot urine samples were usually used to assess iodine status in epidemiological survey. Anderson’s study found that the number of spot urine samples needed to estimate the iodine level in a population with 95% confidence within a precision range of ⫾ 5% was about 500 (29). In this study, the numbers of pregnant and nonpregnant women in the subpopulation were more than 500. The median UICs of pregnant and nonpregnant women in the subpopulation were 206.2 ␮g/L and 175.4 ␮g/L, respectively. According to WHO Technical Consultation recommendation (21), the subpopulations of pregnant women and nonpregnant women were both iodine sufficient. In this study, the results demonstrate that the women with ID have the dramatically increased risk for mild and severe hypothyroxinemia in both early pregnancy and nonpregnancy. However, there was no association between ID and subclinical hypothyroidism. Zimmermann’s study indicates that poor maternal iron status predicts both higher TSH and lower TT4 concentrations in an area of borderline iodine deficiency (27). Our findings were similar to Zimmermann’s with regards to changes of T4 levels, but different with regards to changes of TSH levels. The diversity may be explained by the difference of iodine status and different stage of pregnancy. The association of ID and isolated hypothyroxinemia was distinct in the present study, which confirmed the findings of Zimmermann (27). However, the design of the present study is a cross-sectional investigation, which couldn’t define causation. Does ID cause hypothyroxinemia, or vise versa, or are both ID and hypothyroxinemia caused by another yet unidentified agent? Previous studies have shown that ID can adversely influence thyroid hormone metabolism by altering control of the central nervous system (CNS) (30), decreasing the binding of T3 to

hepatic nuclear receptors (31) and reducing thyroid peroxidase activity (16), an enzyme essential for thyroid hormone synthesis. ID could also impair thyroid metabolism through lowered oxygen transport (32). It is likely that these mechanisms jointly contribute to the impairment of thyroid function. In our group, Hu et al found that serum TT4 levels positively related to liver iron, SF, serum iron, and hemoglobin concentrations and negatively related to sTfR concentrations in iron-deficient dams on the delivery day (33). Bastian et al studied the 12-day-old offspring of iron-deficient mice and found that serum T4 and T3levels were reduced by 67% and 43%, respectively, and that T3 in brain tissue was reduced by 25%, compared with healthy control animals (34). These findings suggest that ID affects thyroid hormone levels. In contrast, in 2012, Tong et al found that infants with congenital hypothyroidism did not show laboratory signs of ID (35). Thus, we speculate that ID may be a pathogenic factor for isolated hypothyroxinemia. There are several advantages afforded by the procedures used in the current study. First, iron status was defined using TBI calculated from SF and sTfR. This may correct the potential dilution effects secondary to the expansion of blood volume and thus provide a more accurate reflection of iron status during pregnancy. Second, since iodine malnutrition and thyroid autoimmunity can influence thyroid function, we performed the study in an iodine-adequate area, and furthermore selected a subpopulation with sufficient iodine and without thyroid autoimmunity. In this way, we better focused our analysis on the effects of ID. Third, pregnant women of the first trimester were recruited in this study. Maternal thyroid hormones play a critical role in the neurological development of the fetus, especially during the first trimester, since the fetus does not produce thyroid hormone itself until 16 –20 weeks gestation (36, 37). Prospective clinical trials have shown that mild thyroid insufficiency such as an increased TSH level or a decreased FT4 level in the first


doi: 10.1210/jc.2014-3887

trimester can adversely influence the outcomes of pregnancies, even irreversibly damage neurodevelopment of offspring (8 –11). We thus assessed the association between ID and thyroid function in early pregnancy to endeavor to understand the etiology of thyroid disorders and accumulate evidence for early intervention in case of ID. The limitations of our study are as follows. First, as mentioned above, the design of the present study is a crosssectional investigation, and we could not distinguish causation between ID and isolated hypothyroxinemia. Prospective randomized controlled trials are needed to clarify this. Second, the study should be extended to the population in iodine deficient or excessive area and pregnant women in the second and third trimester of pregnancy. Thus, we can completely evaluate the association of iron nutrition and thyroid function under different iodine nutrition and different phase of pregnancy. Third, we did not take inflammation into account, even though pregnancy itself is considered as an inflammatory state. Inflammation, however, may not be a significant problem in pregnancy. Mei et al reported the iron status in US pregnant women from NHANES, 1999 –2006, and their analysis suggested that the potential effect of inflammation on the results was small. They found that excluding the 43.9% of the samples that had elevated concentrations of CRP did not substantially affect the prevalence of ID (28). In conclusion, we have presented the first data on the association of iron nutrition with thyroid function in China. These data show a definite association between ID and isolated hypothyroxinemia in pregnant women during the first trimester and nonpregnant women of childbearing age. We speculate ID maybe a pathogenic factor for isolated hypothyroxinemia, even in women during the first trimester of pregnancy. However, further studies are needed to verify this.

Acknowledgments We gratefully acknowledge the invaluable contribution of doctors from the Gynecology and Obstetrics clinics in the 13 hospitals and 6 prenatal clinics in Liaoning Province, and are indebted to the residents who participated in this study.


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National Natural Science Foundation (grant 81 170 730); Health and Medicine Research Foundation, Ministry of Health in China (grant 201 002 002); Research Foundation of Department of Science and Technology of Liaoning Province government in China (Grants 2012225020 and 2011225023); Research Foundation of Innovative Team in Advanced Educational Institute (Grant LT2012015); Research Foundation of Key Laboratory of Endocrine Diseases in Shenyang City (Grant F11– 244 –1– 00); and Guanghua Science and Technology Foundation of China (grant 2007– 02). Cocorrespondence to: Zhongyan Shan, MD, PhD, Endocrine Institute and Liaoning Provincial Key Laboratory of Endocrine Diseases, Department of Endocrinology and Metabolism, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, P. R. China, Phone: ⫹86 24 83283298, Fax: ⫹86 24 83283294, e-mail: [email protected] Authors’ statement: The authors hereby confirm that neither the manuscript nor any part of it, except for abstracts of less than 400 words, has been published or is being considered for publication elsewhere. By signing this letter each of us acknowledges that he or she participated sufficiently in the work to take public responsibility for its content. Disclosure Summary: The authors have no potential conflict of interest to declare. Address all correspondence and requests for reprints to: Weiping Teng, M.D. or Zhongyan Shan, M.D., Ph.D., Endocrine Institute and Liaoning Provincial Key Laboratory of Endocrine Diseases, Department of Endocrinology and Metabolism, The First Hospital of China Medical University, Shenyang, Liaoning, 110 001, P. R. China. E-mail: [email protected] or [email protected]. This study was supported by 973 Science and Technology Research Foundation, Ministry of Science and Technology in China (Grant 2011CB512112); Twelve-Five Science and Technology Support Program (Grant 2014BAI06B02); Chinese National Natural Science Foundation (grant 81 170 730); Health and Medicine Research Foundation, Ministry of Health in China (grant 201 002 002); Research Foundation of Department of Science and Technology of Liaoning Province government in China (Grants 2012225020 and 2011225023); Research Foundation of Innovative Team in Advanced Educational Institute (Grant LT2012015); Research Foundation of Key Laboratory of Endocrine Diseases in Shenyang City (Grant F11–244 –1– 00); and Guanghua Science and Technology Foundation of China (grant 2007– 02). Disclosure Summary: The authors have no potential conflict of interest to declare.

References Address all correspondence and requests for reprints to: Weiping Teng, MD, Endocrine Institute and Liaoning Provincial Key Laboratory of Endocrine Diseases, Department of Endocrinology and Metabolism, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, P. R. China, Phone: ⫹86 24 83283298, Fax: ⫹86 24 83283294, e-mail: [email protected]. This work was supported by Funding: 973 Science and Technology Research Foundation, Ministry of Science and Technology in China (Grant 2011CB512112); Twelve-Five Science and Technology Support Program (Grant 2014BAI06B02); Chinese

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