Isolated Hypothyroxinemia in Iranian Pregnant Women,the Role of Iodine Deficiency: A Population-Based Cross-Sectional Study

Abstract

Background:

Thyroid disorders such as subclinical hypothyroidism and isolated maternal hypothyroxinemia are understudied in pregnant women, despite their possible adverse effects on the health of mother and child. Also, the role of iodine deficiency in developing such disorders has not yet been fully understood.

Methods:

The present national population-based cross-sectional study was conducted on 1080 randomly recruited pregnant women, aged 20–40 from 12 provinces of Iran from 2013 to 2014. Serum concentrations of thyrotropin, T4, thyroid peroxidase antibody (TPOAb), and triiodothyronine (T3) resin uptake values were measured in fasting blood samples, and urinary iodine concentration (UIC) was measured in three separate urine samples. Multinomial logistic regression was run to analyze the possible risk factors regarding thyroid disorders. To clarify the role of iodine in thyroid status specifically, the determinants of UIC and its correlations with thyroid function tests were investigated independently and through subgroup analysis.

Results:

Isolated hypothyroxinemia was the most common thyroid disorder (9.9%), followed by subclinical hypothyroidism (8%). In comparison to euthyroid pregnant women, isolated hypothyroxinemia was more likely in pregnant women older than 30 years (odds ratio [OR] = 1.6), in the second and the third trimesters (OR = 2.62 and 2.12 respectively), with history of multiparity (OR = 1.72), residing in rural areas (OR = 1.57) and in the capital province of the country (OR = 3.3). Subclinical hypothyroidism was more likely in TPOAb positive pregnant women (OR = 2.56). All the mentioned ORs were statistically significant (p < 0.05). The UIC did not correlate significantly with any of the thyroid function tests in the study population. Subgroup analysis showed a significant correlation between UIC and T4 in pregnant women with subclinical hypothyroidism (p < 0.05).

Conclusion:

Isolated maternal hypothyroxinemia was the most prevalent thyroid disorder in Iranian pregnant women and its associated risk factors were identified. Although the calculated prevalence of thyroid disorders was expected in a moderately iodine deficient setting, no correlations between UICs and thyroid function tests were found at the individual level. The contribution of iodine deficiency to thyroid condition for each pregnant woman may be more evident in pregnant women with certain thyroid disorders or those with long-term iodine deficiency.

Introduction

Pregnant women are more likely to develop thyroid disorders, which is probably a result of poor adaptation to changes in the physiology of the thyroid gland during pregnancy, including increased iodine demands (1,2). Adaptation of the pregnant body is dependent on many factors, but iodine intake levels, pre-existing thyroid conditions, pregnancy status, and demographic factors are currently recognized as the main contributors (3,4). As the mentioned factors are not similar in different regions, the prevalence of thyroid disorders varies worldwide and does not follow the frequencies of nonpregnant populations. Considering the vital role of thyroid hormones for fetal growth and the overall health of pregnant women, disruption in their function can have a significant impact on the health of the entire population.

A few studies have been focused on the prevalence of thyroid disorders and identifying the associated risk factors in pregnancy, especially in the Middle East and Northern Africa; and certain thyroid disorders such as isolated maternal hypothyroxinemia, which may result in adverse pregnancy outcomes, are even less studied (5). Also, due to differences in the baseline characteristics of study populations, laboratory measurement methods for thyroid hormones, reference ranges for thyroid function tests, and definitions of thyroid disorders in the reported studies, the obtained results cannot be simply generalized to other regions (6).

This national cross-sectional survey was conducted to evaluate the prevalence of isolated hypothyroxinemia and other thyroid disorders during pregnancy in Iran, and to identify the associated risk factors. Also, to clarify the role of iodine deficiency in thyroid function, the determinants of urinary iodine concentration (UIC) levels and its correlation with thyroid function tests were investigated.

Materials and Methods

In this multicenter population-based cross-sectional survey, a total of 1080 pregnant women, 20–40 years old in all 3 trimesters, were randomly recruited from 12 provinces between October 2013 and February 2014.

Since primary school enrolment rate in Iran is sufficiently high, median UIC value of school age children can represent iodine intake status of the community (7). Using data from the national survey of students in 2013, each province of the country was categorized into one of the following groups based on their median UIC: <100, 100–150, and >150 μg/L. Four provinces were randomly chosen from each group (8). Using linear systematic random sampling, one rural and one urban health center were chosen from the list of existing hospitals and maternity clinics. Sixty and 30 pregnant women were randomly recruited from urban and rural health centers, respectively, while attending their antenatal appointments. As a result, 90 pregnant women from each of the 12 randomly selected provinces were included in the study population. After excluding 8 individuals with missing data on all variables relevant to this study, 1072 pregnant women were included in the initial analysis. Pregnant women with partial missing data were excluded only in the analysis of the relevant variable.

Venous blood samples were drawn from the participants by using anticoagulant-free tubes. After centrifugation, samples were kept at −80° until further analyses. Levels of thyrotropin (TSH), total thyroxine (TT4), triiodothyronine resin uptake (T3Up), and thyroid peroxidase antibodies (TPOAb) were assessed in all serum samples. To reduce day-to-day variations of UIC, three morning samples were obtained, kept in ideal conditions, and assayed at the end of the study. The mean of these three samples was reported for each participant. Written informed consent was obtained from all participants.

Laboratory measurements

Laboratory measurements have been explained in detail elsewhere (8), but a brief description is presented here. The UIC was measured by a manual method based on the Sandell-Kolthoff technique and expressed as μg/L. Analytical sensitivity was 1.39 μg/L. TSH and TT4 were measured by using an electrochemiluminescence immunoassay (Roche Diagnostics kits, Roche/Hitachi Cobas e-411 analyzer; GmbH, Mannheim, Germany). TPOAb was measured through an immunoenzymometric assay, by using a commercial kit (Monobind, Costa Mesa, CA). T3 resin uptake (T3up) test was performed by an enzyme immunoassay (DiaPlus kits, San Francisco, CA). Intra- and inter-assay coefficients of variation were 4.4% and 3.9% for UIC, 2.7% and 4.7% for TT4, 2.1% and 3.3% for TSH, 2.5% and 5.3% for TPOAb, and, finally, 2.3% and 3.8% for T3up test, respectively.

Due to increased thyroxine binding globulin and decreased albumin during pregnancy, current free thyroxine (fT4) immunoassays are influenced by the method applied and are not reliable (9,10). Calculating free thyroxine index (fT4I) has been reported to be a better estimate of fT4 during pregnancy and can ultimately provide a better estimate of the true prevalence of isolated hypothyroxinemia (8,11,12); consequently, fT4 was not measured in our study.

Definition

We used local reference ranges for TT4, fT4I, and TSH in each trimester (10,13). fT4I was calculated as [TT4 × (T3up)]/(Mean of the T3up reference range). Local trimester specific mean of T3up reference range (0.25 for the first and 0.22 for second and third trimesters) was used for the calculation of fT4I (10). Local reference ranges used for TSH in the first, second, and third trimesters of pregnancy were 0.2 to 3.9, 0.5 to 4.1, and 0.6 to 4.1 mIU/L, respectively. Similarly, for TT4 they were 8.2 to 18.5, 10.1 to 20.6, and 9 to 19.4 μg/dL; and for fT4I the values were 8.5 to 19, 9.7 to 21, and 8.7 to 20.4 in each trimester, respectively. Subclinical hypothyroidism was defined as a TSH level of more than 3.9 mIU/L and less than 10 mIU/L in the first trimester and more than 4.1 and less than 10 mIU/L in both the second and third trimesters with normal fT4I levels. Overt hypothyroidism was defined as a TSH level above 10 mIU/L or higher than normal reference ranges in each trimester and fT4I values below trimester-specific normal range. Isolated hypothyroxinemia was defined as lower than normal fT4I values with normal TSH levels. Subclinical hyperthyroidism was defined as having lower than normal TSH and normal fT4I values in each trimester, respectively. Fourteen individuals did not meet any of the mentioned diagnostic criteria in the definition section. Pregnant women with gestational ages below 15 weeks, between 15 and 29 weeks, and more than 29 weeks were categorized in the first, second, and third trimesters, respectively. Participants with TPOAb values >35 IU/mL were considered as TPOAb positive, considering local reference intervals (14). None of the individuals with abnormal thyroid function tests was aware of their condition before this study and they were subsequently informed.

Statistical analysis

Multinomial logistic regression was used to evaluate the factors associated with thyroid function status. Due to the small sample size in subclinical and clinical hyperthyroidism and clinical hypothyroidism categories of the outcome variable, they were excluded from the outcomes of the regression model. In the first step toward building the regression model, the correlation between thyroid status and possible predictors was investigated through independent bivariate analysis. After bivariate analysis, correlations with α < 0.1 and those clinically relevant were selected as potential predictors in the regression model. Age group (>30, <30), number of prior pregnancies (first pregnancy, second pregnancy, or more), pregnancy trimester (first, second, or third), TPOAb levels (<35 IU/mL, >35 IU/mL), area (rural or urban), UIC levels (≥150 μg/L, ≤150 μg/L), and the respective province of each pregnant woman (Tehran or the rest of the country) were the variables included as the initial predictor variables. Variables that did not explain any of the variation were dropped from the final regression model. The final model was then adjusted for smoking, history of thyroid disorders, and taking thyroid related drugs. No significant multicollinearity or interaction was found among the final predictor variables. To clarify the role of iodine in thyroid status specifically, the determinants of UIC and its correlations with thyroid function tests were investigated independently. In addition, the correlations between serum levels of thyroid function tests and UIC were investigated through defined thyroid status and pregnancy trimester subgroups as well.

The Shapiro–Wilk test was used for testing the normality of data distribution. As none of the thyroid function test variables (fT4I, TT4, and TSH) and UIC had a normal distribution (p < 0.001), Spearman's correlation test was used to assess the correlation between them. Spearman's rank-order correlation was run to determine the relationship between UIC and fT4I, TT4 and TSH in subgroups defined by thyroid status. The monotonic relationship between variables was confirmed with scatter plots. Kruskal–Wallis H-test was used to compare median UICs and TPOAb between defined thyroid status subgroups. Pearson's chi-squared test was used to compare differences in categorical variables. The homogeneity of variance between the mentioned subgroups was confirmed by Levene's test. p Values below 0.05 were considered significant. SPSS version 15.0 and R version 3.4.1 were used for data analysis.

The study was approved by the Human Research Committee of the Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences.

Results

Baseline characteristics of the study population are summarized in Table 1. The study population consisted of pregnant women with a mean age of 27.1 ± 7.1 years and their respective mean gestational age was 20.7 ± 10 weeks. The median UIC value of the study population was 87.3 μg/L, and its distribution exhibited substantial positive skewness. Prevalence of thyroid conditions in the study population and in each trimester is presented in Table 2. Isolated hypothyroxinemia was the most prevalent thyroid disorder (9.9%), followed by subclinical hypothyroidism (8%). Euthyroid pregnant women comprised 75.7% of the study population.

Table 1.

Baseline Characteristics of the Study Population

Basic characteristics (mean ± SD)
Age (years)	27.1 ± 7.1
More than 30 years old, n (%)	282 (26.3)
Gestational age (weeks)	20.7 ± 10.0
Thyroid function tests (mean ± SD, median [IQR] for UIC, TSH, and TPOAb)
Total (first trimester/second trimester/third trimester)
TT4 (μg/dL)	11.2 ± 2.5 (11.0 ± 2.6/11.4 ± 2.4/11.0 ± 2.5)
fT4I	12.0 ± 3.1 (12.0 ± 3.1/12.5 ± 3.0/11.7 ± 3.0)
TSH (mIU/L)	1.9 [1.3–2.8] (1.6 [1.0–2.7]/2.0 [1.5–3.0]/2.0 [1.4–2.8])
UIC (μg/L)	87 [46–139] (92 [49–145]/86 [46–138]/77 [42–132])
TPOAb levels, n (%)
More than 35 IU/mL	90 (8.4)
Less than 35 IU/mL	982 (91.6)
Pregnancy trimesters, n (%)
First	389 (36.3)
Second	373 (34.8)
Third	310 (28.9)
Number of prior pregnancies, n (%)
One	430 (42.6)
More than one	580 (57.4)
Area of residence, n (%)
Urban	674 (62.8)
Rural	367 (34.2)
Location of residence, n (%)
Capital	91 (8.5)
Rest of the country	921 (85.9)

fT4I, free thyroxine index; IQR, interquartile range; TPOAb, thyroid peroxidase antibody; TSH, thyrotropin; TT4, total thyroxine; UIC, urinary iodine concentration.

Table 2.

Prevalence of Thyroid Disorders in the Study Population

Thyroid function status	n (%), [CI]	Prevalence in each trimester, n (%)
Thyroid function status	n (%), [CI]	First	Second	Third
Euthyroid	812 (75.7), [74–79.4]	293 (36)	280 (34)	239 (30)
Subclinical hypothyroidism	86 (8), [6.4–10]	34 (40)	26 (30)	26 (30)
Clinical hypothyroidism	18 (1.7), [0.9–2.6]	10 (56)	5 (28)	3 (16)
Isolated hypothyroxinemia	106 (9.9), [8.1–11.9]	20 (19)	52 (49)	34 (32)
Subclinical hyperthyroidism	27 (2.5), [1.6–3.5]	18 (67)	4 (15)	5 (18)
Clinical hyperthyroidism	9 (0.8), [0.4–1.4]	1 (11)	2 (22)	6 (67)
Total prevalence of thyroid disorders	246 (22.9)	88 (35)	89 (36)	69 (29)
Subjects not fitting in any of the defined criteria	14 (1.3)

CI, confidence interval.

Multinomial logistic regression was run to assess factors associated with thyroid status, consisting of euthyroid, subclinical hypothyroid, and pregnant women with isolated hypothyroxinemia, since the sample size of other defined categories (pregnant women with clinical or subclinical hyperthyroidism and those with clinical hypothyroidism) was not sufficient for this analysis. Euthyroid pregnant women were the reference category. Odds ratios (OR) and respective confidence intervals [CI] calculated for each risk factor included in the final model of the regression analysis are presented in Table 3. The Pearson and deviance goodness-of-fit statistics had insignificant p-values (p = 0.13 and p = 0.09, respectively), which can imply the adequate fit of the present model. In comparison to euthyroid women, pregnant women with isolated hypothyroxinemia are more likely to be older than 30 years (OR = 1.6 [CI 1–2.5]), more likely to be observed in the second and third trimesters (OR = 2.62 [CI 1.48–4.62] and OR = 2.12 [CI 1.22–3.8] respectively) than the first trimester; more likely to be observed in pregnant women with a history of multiparity (OR = 1.72 [CI 1.04–2.85]) in comparison to pregnant women in their first pregnancy; and more likely to be observed in rural regions (OR = 1.57 [CI 1.1–2.4]) or the capital province (OR = 3.3 [CI 1.8–6.2]) in comparison to urban regions and other provinces besides the capital province, respectively. On the other hand, in comparison to euthyroid pregnant women, pregnant women with subclinical hypothyroidism are more likely to have positive TPOAb levels more than 35 IU/mL (OR = 2.5 [CI 0.2–0.74]).

Table 3.

Factors Associated with Thyroid Status, the Multinomial Regression Model

Variable	Isolated hypothyroxinemia			Subclinical hypothyroidism
Variable	OR [CI]	SE	p	OR [CI]	SE	p
Age
<30 years old	1			1
≥30 years old	1.6 [1–2.5]	0.24	0.05	1.2 [0.7–2.12]	0.28	0.5
Pregnancy trimester
First	1			1
Second	2.62 [1.48–4.62]	0.29	0.001	0.82 [0.47–1.4]	0.28	0.48
Third	2.12 [1.22–3.8]	0.30	0.01	0.9 [0.5–1.7]	0.28	0.7
Number of pregnancy
One	1			1
More than one	1.72 [1.04–2.85]	0.22	0.03	0.9 [0.6–1.6]	0.25	0.7
Area of residence
Urban	1			1
Rural	1.57 [1.1–2.43]	0.22	0.04	0.93 [0.57–1.53]	0.25	0.8
Location of residence
Rest of the country	1			1
Capital province (Tehran)	3.3 [1.81–6.25]	0.3	0.001	1.7 [0.83–3.84]	0.38	0.13
TPOAb levels
≥35 IU/mL	1			1
<35 IU/mL	0.86 [0.35–2.13]	0.45	0.75	2.56 [1.34–4.86]	0.32	0.001

Euthyroid pregnant women are the reference category.

IU, international unit; OR, odds ratio; SE, standard error.

To clarify the role of iodine in thyroid function, the determinants of UIC and its correlation with serum levels of thyroid function tests were investigated. No significant correlation was observed between UIC and thyroid function tests (TSH, TT4, or fT4I in the total study population; [data not shown due to insignificant results]). However, further subgroup analyses on pregnancy trimesters and thyroid status yielded the following results. Weak correlations were found between UIC and TT4 in the first (r's = 0.1, p = 0.04) and third trimesters (r's = −0.13, p = 0.01). Except for a significant correlation between UIC and TT4 (r's = 0.25, p = 0.02 [CI 0.04–0.44]) in pregnant women with subclinical hypothyroidism, no other significant correlation was observed in any of the other defined thyroid function subgroups. Similar results were obtained by using international reference ranges of thyroid hormones. Kruskal–Wallis H-test revealed that the UIC level was significantly different between pregnancy trimesters (p = 0.05, chi-square = 5.8), with decreasing values from the first toward the third trimester. No statistically significant differences of median UIC values were found among the defined thyroid status subgroups. The UIC was negatively associated with age (r's = −0.07, p < 0.05) and was significantly lower in rural areas (median 77.6 μg/L) in comparison to urban regions (median 113.1, p < 0.05). Pregnant women with more than two prior pregnancies had significantly lower levels of UIC (75.1 μg/L) in comparison to the rest of the pregnant women (91.7 μg/L, p < 0.05). The prevalence of UIC levels lower than 150 or 100 μg/L was not different among pregnant women with different thyroid statuses (p > 0.05). The UIC values were not significantly different when comparing Tehran and other provinces. Multiparity was more frequent in rural areas (25.5% of the rural population of the study) in comparison to urban regions (20.8% of the urban population of the study, p < 0.05).

TPOAb levels were significantly different across the defined thyroid status subgroups. Highest levels of TPOAb were observed in pregnant women with clinical and subclinical hypothyroidism, and lowest levels were observed in pregnant women with clinical hyperthyroidism (p = 0.001, chi-square = 22). However, pregnant women with isolated hypothyroxinemia had TPOAb levels similar to those of euthyroid pregnant women (mean ranks 514 and 520 respectively, p > 0.05).

Discussion

The results of this study present the prevalence of thyroid disorders and their associated risk factors in Iran. Iranian pregnant women are mildly iodine deficient. One in every four pregnant women had some level of thyroid dysfunction. Isolated hypothyroxinemia was the most prevalent disorder, followed by subclinical hypothyroidism. Age, parity, pregnancy trimester, area of residence (urban or rural), place of residence (capital province vs. the rest of the country), and TPOAb levels were variably associated with the overall thyroid status. No strong significant correlation was observed between UIC and thyroid function tests in the total study population. A moderate significant correlation was observed between UIC and TT4 in pregnant women with subclinical hypothyroidism.

The prevalence of clinical and subclinical hypothyroidism and hyperthyroidism in the study population was higher than in previous reports (15 –17). The observed higher prevalence may be partly explained by mild iodine insufficiency in pregnant women (8). However, although recent studies have reported lower and higher prevalence of thyroid disorders in iodine-sufficient and iodine-insufficient settings, respectively, this has not always been the case and considerable heterogeneity exists in the currently available reports (18 –23), which may be due to lack of a general consensus on the reference ranges of the thyroid function tests, the exact definition of each thyroid disorder, laboratory measurement methods of iodine status and thyroid hormones, and the iodine status of the study population (24). In addition, there may be certain aspects in the history of pregnant women and their demographic characteristics that can play a prominent role as well. The prevalence of isolated hypothyroxinemia followed a similar pattern. A relatively high prevalence of isolated hypothyroxinemia has been reported earlier, especially in mildly and severely iodine-deficient regions (18,21,24). In contrast, a recent cross-sectional study conducted in Fars province, south of Iran, reported a considerably lower prevalence of isolated hypothyroxinemia (1.4%) (20); however, the median UIC of the study population was not reported, and relatively selective inclusion and exclusion criteria decreased the external validity of this study. Due to the possible lack of any clinical signs and symptoms, isolated hypothyroxinemia and subclinical hypothyroidism are often understudied, despite reports claiming significant implications on fetal growth and development (5,25). As a result, investigating the associated risk factors could be of clinical value.

Pregnant women older than 30 years were 1.6 times more likely to be diagnosed with isolated hypothyroxinemia in comparison to those younger than 30 years old. Also, pregnant women with multiple prior pregnancies (more than 1) were 1.72 times more likely to be diagnosed with isolated hypothyroxinemia in comparison to those with no prior pregnancies. It has been suggested that mild-to-moderate iodine deficiency may be a prominent factor in developing isolated hypothyroxinemia (26). Gradual decrease of iodine reserves with aging or after multiple pregnancies may explain the current findings. In this study, age was negatively associated with UIC levels, and pregnant women with two or more prior pregnancies had significantly lower iodine levels. Autoimmune mechanisms, as suggested by the current literature, had no roles in explaining these findings (26,27). Correcting for TPOAb in the final regression model did not change the calculated OR significantly. In addition, the respective mean rank of the TPOAb levels in the isolated hypothyroxinemia subgroup was not significantly different compared with euthyroid pregnant women.

The prevalence of isolated hypothyroxinemia was higher in the second (OR = 2.62) and third trimester (OR = 2.12) in comparison to the first trimester. This can be, in part, due to the negative correlation between gestational age and fT4 levels, as reported earlier (28). Also, iodine levels tend to decrease during pregnancy toward the third trimester, as reported in this study, which may result in mild iodine deficiency and further contribute to the increased prevalence of isolated hypothyroxinemia (29).

Isolated hypothyroxinemia was observed more frequently in rural than urban areas (OR = 1.57). The analysis was adjusted for UIC levels and multiparity to rule out potential confounders. Consequently, the increased prevalence of isolated hypothyroxinemia in rural areas may be due to iron insufficiency in rural regions (30), which can be considered an independent predictor for a higher prevalence of isolated hypothyroxinemia (31).

Pregnant women were 3.34 times more likely to be diagnosed with isolated hypothyroxinemia in Tehran, the capital province, in comparison to the rest of the country. Tehran has a high population density with considerable heterogeneity because of significant socioeconomic and ethnic differences across the province, which can affect the health of each individual. In addition, the quality and the storing condition of the consumed iodized salt is very variable, which may have an impact on the prevalence of iodine deficiency in specific regions (32). Consequently, there may be regions in Tehran with significantly higher or lower values of UIC in comparison to the median UIC of the entire Tehranian population, as has been reported earlier (32). As a result, the median UIC of the Tehran province may not be a reliable independent predictor of thyroid status and despite similar UIC values, a higher prevalence of thyroid disorders may be expected in Tehran when compared with the rest of the provinces.

Positivity for TPOAb was the only significant risk factor identified in this study to be associated with subclinical hypothyroidism. Pregnant women with TPOAb levels of more than 35 IU/mL were three times more likely to be diagnosed with subclinical hypothyroidism. Similar results were reported in studies conducted in different settings (33).

Interestingly, although the mild iodine deficiency found in this study is in line with the majority of our findings, UIC levels did not correlate directly with any of the thyroid indices in the general study population. In addition, due to the small effect sizes, the observed significant correlations between UIC and TT4 in the first and third trimesters can be considered negligible (34). Also, UIC levels did not vary across pregnant women with different thyroid statuses and did not explain any of the variation when introduced into the regression model; therefore, they were dropped from the final model. Other studies conducted in mild iodine-deficient settings are consistent with our findings (29,35 –37). Notably, a few studies have observed correlations with considerable effect sizes between UIC and thyroid indices using linear regression modeling (38); however, due to characteristic positive skewness of UIC distribution (39), linear regression modeling can result in misinterpretation. Apparently, at least in mild iodine-deficient settings, UIC is not an independent predictor of thyroid status. Subgroup analysis based on thyroid condition of pregnant women yielded only a considerable significant positive correlation between UIC and TT4 in pregnant women with subclinical hypothyroidism. Similar results were previously obtained in controlled interventions on nonpregnant individuals (40). However, the clinical implications of the current finding for pregnant women with subclinical hypothyroidism are unclear. Perhaps the trend of recent iodine consumption by the population, or more specifically, the thyroid reserves of each individual can be a more important predictor for the thyroid status than the UIC at the population level. In addition, direct correlation between UIC and thyroid function tests may be more evident in certain thyroid conditions, such as subclinical hypothyroidism.

There are certain limitations to this study. First, because of its cross-sectional nature, causality cannot be inferred. Second, the obtained results might not be generalizable to Iranian pregnant women without sufficient access to primary health care centers. However, according to UNICEF databases and a local study, more than 94% of Iranian pregnant women have more than four antenatal appointments (UNICEF data, accessed on October 13, 2017) (41,42). As a result, our study population can represent the Iranian pregnant population in this setting. Third, body mass index and laboratory results evaluating serum iron and ferritin levels of the participants, which can be potential confounders, were not measured. Fourth, the power to detect weak to moderate correlations between UIC and thyroid function tests in some categories of our subgroup analysis may have been insufficient. Finally, some of the defined subgroups of thyroid disorders were dropped from the final regression model due to small sample sizes (less than 10 samples in each category of the final regression model). Due to their low prevalence, further studies focusing specifically on these thyroid disorders are needed.

The strengths of this study include its large sample size that was collected in a population at the national scale. In addition, iodine was measured three times in each individual to reduce day-to-day variations of UIC. Also, fT4I was measured instead of fT4, which has proved to be the more accurate measure in pregnancy (13).

An increasing amount of evidence is currently being directed toward the thyroid health of pregnant women, because minor disturbances may have long-term implications for mother and child beyond the gestational period. A high prevalence of different forms of thyroid disorders can be observed in pregnant women. Isolated hypothyroxinemia is responsible for a considerable proportion of these disorders. However, despite the possible adverse effects of isolated hypothyroxinemia, only a few studies have been focused on its prevalence and associated risk factors. Cohort studies are required to investigate the possible adverse effects of isolated hypothyroxinemia on mother and child in the long term and to estimate the cost-effectiveness of managing and screening for it. Despite the evident correlation between the individual iodine status and thyroid function in the majority of pregnant women with severe iodine deficiency or excess, this is mostly not the case in mild iodine-deficient or iodine-sufficient settings. Apparently, in pregnant populations with mildly deficient or sufficient iodine reserves, the contribution of iodine deficiency at an individual level may be more evident in women with certain thyroid disorders, such as subclinical hypothyroidism.

Footnotes

Acknowledgment

The authors would like to thank Miss. Forough Ghanbari for her time spent editing this article and her comments in helping them improve this article.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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