Iron Deficiency May Predict Greater Risk for Hypothyroxinemia: A Retrospective Cohort Study of Pregnant Women in China

Abstract

Background:

Pregnant women are highly vulnerable to iron deficiency (ID) due to the increased iron needs during pregnancy. ID decreases circulating thyroid hormone concentrations likely through impairment of iron-dependent thyroid peroxidase. The present study aimed to explore the association between ID and hypothyroxinemia in a retrospective cohort of pregnant women in China.

Methods:

To investigate the relationship between ID and hypothyroxinemia, 723 pregnant women were retrospectively analyzed, including 675 and 309 women in the second and third trimesters, respectively. Trimester-specific hypothyroxinemia was defined as free thyroxine (fT4) levels below the 2.5th percentile of the reference range with normal serum thyrotropin (TSH) or TSH higher than the 97.5th percentile of the reference range in each trimester of pregnancy. Serum TSH, fT4, thyroid peroxidase antibodies, thyroglobulin antibodies, serum ferritin, soluble transferrin receptor, and urinary iodine concentrations were measured. Serum ferritin, soluble transferrin receptor, and total body iron were used to indicate the nutritional iron status.

Results:

Cross-sectional multiple linear regression analysis showed that iron status was positively associated with serum fT4 levels in the first and second trimesters of pregnancy, but not in the third trimester. Logistic regression analysis showed that ID was an independent risk factor for hypothyroxinemia (odds ratio = 14.86 [confidence interval 2.31–95.81], p = 0.005 in the first trimester and odds ratio = 3.36 [confidence interval 1.01–11.21], p = 0.048 in the second trimester). The prospective analysis showed that pregnant women with ID during the first trimester of pregnancy had lower serum fT4 levels and a higher rate of hypothyroxinemia in the second or third trimester than those without ID.

Conclusions:

ID appears to be a risk factor to predict hypothyroxinemia in the first and second trimesters of pregnancy, but not in the third trimester. Pregnant women with ID in the first and second trimesters should be regarded as a high-risk group for maternal hypothyroxinemia.

Introduction

Iron deficiency (ID) is the most common nutritional deficiency worldwide and the leading cause of anemia (1). The World Health Organization (WHO) estimates that 23% of pregnant women in industrialized countries and 52% in non-industrialized nations suffer from anemia, mostly due to ID, indicating that pregnant women are particularly vulnerable to ID (2,3).

In recent years, the impact of thyroid hormone deficiency on pregnancy outcomes and offspring intelligence has developed into an important and controversial area in the field of endocrinology (4). Both perinatal thyroid insufficiency and ID are associated with an increased risk of adverse pregnancy complications and impaired fetal neurocognitive development (5 –7). Many studies have shown that ID can reduce thyroid hormone synthesis by having a negative impact on the iron-dependent thyroid peroxidase (TPO), an essential enzyme in the biosynthesis of thyroid hormones (8). In addition to that, ID was suspected to modulate thyroid metabolism by attenuating oxygen transport, a similar result in hypoxia (9,10). In 2007, Zimmermann et al. first reported that ID was related to lower thyroxine (T4) during pregnancy in a cross-sectional study of women living in an area with borderline iodine deficiency (11).

The Subclinical Hypothyroid in Early Pregnancy (SHEP) Study, aiming to evaluate thyroid insufficiency on maternal health or infant outcomes, was conducted in Liaoning Province of China between 2012 and 2015. Nineteen hospitals were involved in this study, including the Department of Obstetrics and Gynecology, and the Department of Endocrinology (5,12). A total of 12,236 women were enrolled in the SHEP study until September 2015, including 9964 pregnant women in the first trimester and 2272 non-pregnant women of childbearing age. Among the 9964 pregnant women, 1834 were followed in the second trimester (between 13 and 28 weeks of gestation) and/or the third trimester (between 29 and 40 weeks of gestation) of pregnancy. A previous cross-sectional study found a positive relationship between ID and hypothyroxinemia in pregnant women during their first trimester and non-pregnant women of childbearing age (13). However, no causality between ID and hypothyroxinemia was demonstrated. To address the effects of ID on thyroid hormone levels during pregnancy, a study was conducted that used surplus sera to measure soluble transferrin receptor (sTfR), serum ferritin (SF), and total body iron (TBI) in pregnant women who were included in the SHEP study. The present study aimed to investigate whether ID during an earlier trimester of pregnancy is associated with lower serum free T4 (fT4) levels and an increased risk for hypothyroxinemia in a later trimester of pregnancy.

Methods

Subjects

The SHEP study, aiming to evaluate the impact of thyroid insufficiency on maternal health or infant outcomes, was conducted between 2012 and 2015 in Liaoning Province of China, a region where iodine status was adequate (12). Nineteen hospitals were involved in this study, including the Department of Obstetrics and Gynecology, and the Department of Endocrinology. To be enrolled in the SHEP study, women had to be residents in the local area for >10 years, be aged 19–40 years, be planning to become pregnant or have a singleton pregnancy at 4–12 weeks of gestation, have no history of thyroid disease or any other chronic diseases, and not be taking any oral contraceptives or medical regimen that may affect thyroid function, such as glucocorticoids, dopamine, or antiepileptic drugs (12). Basic clinical information was obtained from all the participants, including personal information, personal and family history of thyroid diseases, parity, smoking or drinking, chronic diseases, and multiple-micronutrient supplementation. The height and weight of each participant were measured, their thyroid was palpated, and fasting serum and urine samples were collected. By 2015, 9964 pregnant women were recruited and had blood drawn to test their thyroid function, but only 1834 of them participated in a follow-up study during pregnancy. The present study retrospectively analyzed the data from these 1834 pregnant women, as well as 2272 non-pregnant women of childbearing age from the SHEP study. After excluding the participants with self-reported blood diseases, infections, fever, drug treatments, supplementation treatments (iron, iodine, levothyroxine [LT4], or antithyroid medication), as well as positive thyroid autoantibodies (thyroid peroxidase antibodies [TPOAb] and thyroglobulin antibodies [TgAb]), a total of 723 pregnant women and 1645 non-pregnant women were selected. These final participants had blood drawn to measure their levels of SF and sTfR. Among the 723 pregnant women, 675 and 309 women participated in the second trimester and third trimesters, respectively, and 261 pregnant women followed in both the second and third trimesters. The flow diagram for the selected subjects is shown in Figure 1.

FIG. 1.

The flow diagram for the procedure of the subjects selected. ^aExcluding the subjects with self-reported blood diseases, infection or fever history on collecting vein blood, positive thyroid autoantibodies, drug treatment, or supplementation containing iron or iodine, and levothyroxine or antithyroid drug treatment during both the registration and pregnancy.

Methods

Samples of urine and blood were obtained from each participant after an overnight fast. All specimens were frozen at −20°C until shipment, transferred on dry ice to the Endocrinology Institute of China Medical University, and assayed within one week.

Serum TSH, fT4, TPOAb, TgAb, and SF were measured using electrochemiluminescence immunoassays with a Cobas Elecsys 601 platform (Roche Diagnostics, Basel, Switzerland). The intra-assay coefficients of variation for serum TSH, fT4, TPOAb, TgAb, and SF were 1.57–4.12%, 2.24–6.33%, 2.42–5.63%, 1.3–4.9%, and 1.43–4.52%, respectively. The inter-assay coefficients of variation were 1.26–5.76%, 4.53–8.23%, 5.23–8.16%, 2.1–6.9%, and 3.52–7.91%, respectively (12,13). Serum sTfR was measured using the immunoturbidimetric assay on a Cobas C501 analyzer (Roche Diagnostics). The intra- and inter-assay coefficients of variation for sTfR were 2.26–5.46% and 3.57–6.24%, respectively (13). Urinary iodine concentrations (UIC) were determined by the ammonium persulfate method based on the Sandell–Kolthoff reaction. The intra-and inter-assay coefficients of variation for the UIC were 3–4% and 4–6% at 66 μg/L and 2–5% and 3–6% at 230 μg/L, respectively (13).

Diagnostic criteria for ID were defined as SF <12 μg/L (14,15) or sTfR >4.4 mg/L (14) or TBI <0 mg/kg (13,14). TBI was calculated from sTfR and SF concentrations with a formula from Cook et al. (16 –18), as previously described by Yu et al. (13). Positive values of TBI indicated adequacy of iron storage, and negative values indicated ID (11,13,17).

TSH and fT4 were 0.27–4.2 IU/mL and 12–22 pmol/L, respectively, according to the manufacturer's reference ranges. In the present study, hypothyroxinemia included both isolated hypothyroxinemia (IH) and overt hypothyroidism (OH). The trimester-specific IH was defined as fT4 levels below the 2.5th percentile of the reference range with normal TSH levels (P2.5th–P97.5th percentiles) in each trimester of pregnancy. The trimester-specific OH was defined as fT4 levels below the 2.5th percentile with TSH levels higher than the 97.5th percentile of the reference range in each trimester of pregnancy, and subclinical hypothyroidism as TSH levels higher than the 97.5th percentile of the reference range with normal fT4 levels (P2.5th– P97.5th percentiles) in each trimester of pregnancy. The first trimester-specific reference ranges for TSH and fT4 were 0.14–4.87 mIU/L and 12.35–20.71 pmol/L, respectively, as previously described by Li et al. (12). The reference population, including 986 pregnant women in the second trimester and 469 pregnant women in the third trimester, of the second and third trimester-specific reference ranges for serum fT4 and TSH was selected according to Guideline 22 developed by the National Academy of Clinical Biochemistry (19). Thus, the second trimester-specific reference ranges for TSH and fT4 were 0.36–4.42 mIU/L and 9.08–16.89 pmol/L, respectively. Also, the third trimester-specific reference ranges for TSH and fT4 were 0.51–3.79 mIU/L and 8.40–13.81 pmol/L, respectively. The manufacturer's reference ranges for SF, TPOAb, TgAb, and sTfR were 15–150 μg/L, 0–34 IU/mL, 0–115 IU/mL, and 1.9–4.4 mg/L, respectively.

Statistical analysis

All statistical analyses were performed using IBM SPSS Statistics for Windows v21.0 software (IBM Corp, Armonk, NY). The Kolmogorov–Smirnov method was used to test the data distribution. The data following normal distribution are presented as means ± standard deviations (SD), and an independent sample t-test was used to assess the difference between two groups. The other data are presented as medians, and the Kruskal–Wallis H test of ranked groups was utilized. Categorical data are presented as percentages (cases), evaluated using the chi-square test. Spearman's rank correlation analysis was used to examine the correlation between fT4 and age, body mass index (BMI), TSH, UIC, SF, sTfR, and TBI. Multiple linear regression analysis was used to test the association between fT4 and its related risk factors. Multiple logistic regression analysis was used to analyze the risk factors of hypothyroxinemia further. p-Values <0.05 were considered statistically significant.

Ethics committee approval

The experimental procedure described was approved by the Ethics Committee of China Medical University ([2012]2011-32-4), and was congruent with the Declaration of Helsinki. Written informed consent was obtained from every participant.

Results

Both iron indicators and thyroid hormone levels show a similar tendency during different trimesters of pregnancy

The non-pregnant women of childbearing age were of a similar age and BMI as the pregnant women in the first trimester (Table 1). The serum levels of iron indicators (SF, sTfR, and TBI) and fT4 were compared between the non-pregnant women and pregnant women in the different trimesters of pregnancy (Table 1). In the first trimester, pregnant women had lower sTfR levels and higher TBI, SF, and fT4 levels compared to non-pregnant women. As the pregnancy progressed, serum TBI, SF, and fT4 decreased, while sTfR increased, indicating a gradual decline of iron and thyroid hormone levels during pregnancy.

Table 1.

Demographic Characteristics and Thyroid and Iron Indicators in Non-Pregnant Women of Childbearing Age and Pregnant Women in Different Trimesters of Pregnancy

	Non-pregnancy (n = 1645)	First trimester (n = 723)	Second trimester (n = 675)	Third trimester (n = 309)	p
General characteristics
Age (years)	29.05 ± 3.75	29.29 ± 3.49
BMI (kg/m²)	21.86 ± 3.48	21.96 ± 3.15
Smoking (%)	1.03 (17/1645)	0.69 (5/723)
Drinking (%)	2.31 (38/1645)	2.62 (19/723)
GW (weeks)		8.02 ± 1.16	20.21 ± 2.96	30.16 ± 0.98
Laboratory tests
TSH (mIU/L)	2.07 (1.51–2.86)^a	1.50 (1.02–2.25)^b	1.62 (1.16–2.32)^b	1.68 (1.17–2.24)^b	<0.001
fT4 (pmol/L)	15.69 ± 2.40^a	16.25 ± 1.96^b	12.50 ± 2.17^c	11.00 ± 1.57^d	<0.001
SF (μg/L)	51.27 (29.15–80.22)^a	66.53 (41.18–100.80)^b	41.34 (24.90–67.24)^c	14.26 (9.29–26.16)^d	<0.001
sTfR (mg/L)	3.11 (2.60–3.75)^a	2.58 (2.19–3.13)^b	2.44 (2.08–2.86)^c	3.60 (2.99–4.44)^d	<0.001
TBI (mg/kg)	6.81 (4.63–8.66)^a	8.51 (6.39–10.28)^b	6.97 (4.73–8.92)^a	1.65 (−0.27 to 4.54)^c	<0.001
UIC (μg/L)	164.30 (100.09–250.75)^a	170.22 (124.57–225.49)^b	138.33 (89.58–204.38)^c	130.46 (85.08–198.19)^c	<0.001
Prevalence of thyroid diseases
Overt hypothyroidism, % (n)	0.12% (2)	0%	0.74% (5)	0	0.05
Isolated hypothyroxinemia, % (n)	0	1.80% (13)	2.22% (15)	2.91% (9)	0.42
Subclinical hypothyroidism, % (n)	7.47% (123)	1.60% (6)^*	2.22% (15)^*	2.27% (7)^*	<0.001

Age, BMI, GW and fT4 were expressed as means ± SD. TSH, SF, sTfR, TBI, and UIC are expressed as median (interquartile range). Categorical data are presented as percentage (cases).

p < 0.001, a statistically significant difference between the four groups.

a,b,c,d

A statistically significant difference between the four groups using Kruskal–Wallis H test of ranked groups, p < 0.05.

Compared to the non-pregnant women, p < 0.01.

BMI, body mass index; GW, gestational week; TSH, thyrotropin; fT4, free thyroxine; SF, serum ferritin; sTfR, soluble transferrin receptor; TBI, total body iron; UIC, urinary iodine concentration.

Cross-sectional data analysis: ID during the first and second trimesters of pregnancy is associated with lower serum fT4 levels and an increased rate of hypothyroxinemia during this same period, but this association is not maintained during the third trimester

First trimester

According to the trimester-specific reference ranges for serum fT4 and TSH, 13 subjects were diagnosed with hypothyroxinemia in the first trimester. The pregnant women with ID had lower serum fT4 levels and a higher rate of hypothyroxinemia relative to those without ID in the first trimester (Table 2). The cross-sectional correlation analysis showed a correlation between some independent variables and serum fT4. SF (r = 0.12, p = 0.001) and TBI (r = 0.129, p < 0.001) were positively associated with serum fT4 levels. BMI (r = −0.211, p < 0.001), sTfR (r = −0.076, p = 0.04), and urinary iodine (r = −0.077, p = 0.04) were negatively associated with serum fT4 levels. Further, multiple linear regression analysis showed that serum TBI, BMI, and urinary iodine were associated with serum fT4 levels (Table 3). To analyze the risk factors for hypothyroxinemia, multiple logistic regression analysis was applied using maternal age, gestational week, ID, BMI, and urinary iodine as independent variables and hypothyroxinemia as the dependent variable. It was found that ID was an independent risk factor for hypothyroxinemia (odds ratio [OR] = 14.86 [confidence interval (CI) 2.31–95.81], p = 0.005; Table 4).

Table 2.

Comparison of Serum fT4 Levels and Rate of Hypothyroxinemia Between Pregnant Women With or Without ID in the Different Trimesters of Pregnancy

	Serum fT4		Rate of hypothyroxinemia
Stage	ID	Iron adequacy	ID	Iron adequacy
T1, n = 723	15.00 ± 1.99^** (n = 34)	16.35 ± 1.95 (n = 689)	8.82%^* (n = 34)	1.45% (n = 689)
T2, n = 645	11.30 ± 3.02^** (n = 42)	12.58 ± 2.08 (n = 633)	11.90%^** (n = 42)	2.37% (n = 633)
T3, n = 309	10.87 ± 1.49 (n = 144)	11.12 ± 1.66 (n = 165)	2.08% (n = 144)	3.64% (n = 165)

Trimester-specific hypothyroxinemia was defined as fT4 levels below the 2.5th percentile of the reference range with TSH levels in the normal reference range (P2.5th–P97.5th percentiles) or higher than the 97.5th percentile of the reference range in each trimester of pregnancy.

ID was defined as SF <12 μg/L or sTfR >4.4 mg/L or TBI <0 mg/kg.

p < 0.01 compared to iron adequacy; ^* p < 0.05 compared to iron adequacy.

ID, iron deficiency; T1, first trimester; T2, second trimester; T3, third trimester.

Table 3.

Multiple Linear Regression Analysis of fT4 and Related Risk Factors in Different Trimesters of Pregnancy

		β	p
First trimester (n = 723)	Constant	18.93	<0.001
	TBI	0.082	0.001
	BMI	–0.145	<0.001
	Gestational week	–0.046	0.498
	Iodine	–0.001	0.011
	Age	0.013	0.555
Second trimester (n = 675)	Constant	20.17	<0.001
	TBI	0.067	0.005
	Gestational week	–0.345	<0.001
	Iodine	0.000	0.755
	Age	–0.060	0.003
Third trimester (n = 309)	Constant	11.64	<0.001
	TBI	0.029	0.400
	Gestational week	–0.018	0.862
	Iodine	–0.002	0.015
	Age	0.006	0.855

Table 4.

Evaluation of the Risk Factors for Hypothyroxinemia in Different Trimesters of Pregnancy Using Multiple Logistic Regression Analysis

	First trimester		Second trimester		Third trimester
	OR [CI]	p	OR [CI]	p	OR [CI]	p
Maternal age	0.84 [0.71–0.99]	0.042	1.15 [1.03–1.29]	0.015	1.10 [0.91–1.34]	0.317
Gestational week	1.08 [0.53–2.23]	0.827	1.53 [1.19–1.96]	0.001	0.75 [0.33–1.67]	0.476
ID	14.86 [2.31–95.81]	0.005	3.36 [1.01–11.21]	0.048	0.59 [0.14–2.53]	0.484
Increased BMI	14.50 [2.65–79.32]	0.002
Excessive iodine	9.77 [1.35–70.95]	0.024	0.95 [0.28–3.22]	0.94	11.05 [0.5–250.06]	0.107

ID was defined as SF <12 μg/L or sTfR >4.4 mg/L or TBI <0 mg/kg.

Increased BMI: BMI ≥25 kg/m² vs. BMI <25 kg/m².

Excessive iodine: urinary iodine >500 μg/L vs. urinary iodine 150–250 μg/L.

First trimester: maternal age, gestational week, ID, BMI, and urinary iodine were used as independent variables in the logistic regression model.

Second and third trimesters: maternal age, gestational week, and ID were used as independent variables in the logistic regression model. BMI was not available for the second and third trimesters, and thus is not included in Table 4.

Trimester-specific hypothyroxinemia was defined as fT4 levels below the 2.5th percentile of the reference range with TSH levels in the normal reference range (P2.5th– P97.5th percentiles) or higher than the 97.5th percentile of the reference range in each trimester of pregnancy.

OR, odds ratio; CI, confidence interval.

Second trimester

Twenty subjects were diagnosed with hypothyroxinemia in the second trimester according to the trimester-specific reference ranges for serum fT4 and TSH. Similar to the first trimester, the pregnant women with ID had lower serum fT4 levels and a higher rate of hypothyroxinemia compared to those without ID in the second trimester (Table 2). Serum fT4 levels were positively correlated with serum SF (r = 0.211, p < 0.001) and TBI (r = 0.255, p < 0.001), but negatively associated with maternal age (r = −0.176, p < 0.001), gestational week (r = −0.52, p < 0.001), and sTfR (r = −0.258, p < 0.001). Further, the association of serum fT4 levels with serum TBI, gestational week, and maternal age was revealed by multiple linear regression analysis (Table 3). Multiple logistic regression analysis was performed to analyze the risk factors for hypothyroxinemia using maternal age, gestational week, and ID as independent variables, and hypothyroxinemia as the dependent variable. This analysis also found that ID was an independent risk factor for hypothyroxinemia (OR = 3.36 [CI 1.01–11.21], p = 0.048; Table 4).

Third trimester

According to the trimester-specific reference ranges for serum fT4 and TSH, nine subjects were diagnosed with hypothyroxinemia in the third trimester. There was no significant difference in either serum fT4 levels or the rate of hypothyroxinemia between the pregnant women with or without ID in the third trimester (Table 2). Univariate analysis showed that urinary iodine was negatively associated with serum fT4 levels (r = −0.077, p = 0.04). Multiple linear regression analysis also showed that urinary iodine was negatively associated with serum fT4 levels (Table 3). However, no risk factor for hypothyroxinemia was apparent (Table 4).

Prospective data analysis: ID during the first trimester of pregnancy is associated with lower serum fT4 levels and an increased rate of hypothyroxinemia in the second or third trimester of pregnancy

The cross-sectional data from both first and second trimesters in the pregnant women showed that iron stores were positively correlated with maternal serum fT4 levels. The study further investigated prospectively whether the iron status in an earlier trimester of pregnancy would affect serum fT4 levels or the rate of hypothyroxinemia in a later trimester of pregnancy.

First, the serum fT4 levels of the second or third trimester were compared between women with or without ID in the previous trimester (Supplementary Tables S1–S3; Supplementary Data are available online at www.liebertpub.com/thy). Compared to the women without ID, the women with ID in the first trimester had lower serum fT4 levels in both the second (Supplementary Table S1) and third (Supplementary Table S2) trimesters. However, no significant difference was found in serum fT4 levels of the third trimester between the pregnant women previously diagnosed with or without ID in the second trimester (Supplementary Table S3).

Second, the rate of hypothyroxinemia of the second or third trimester was analyzed in pregnant women who were diagnosed with or without ID in their previous trimester. The results showed that the pregnant women diagnosed with ID in the first trimester had a higher rate of hypothyroxinemia in the second and third trimesters compared to those without ID. However, the difference was not statistically significant, which might be mainly due to the limited numbers of participants with ID in the first trimester (Supplementary Tables S1–S3).

Discussion

The association between iron stores and thyroid hormone has been recently identified. A previous study reported a positive correlation between ID and hypothyroxinemia during the first trimester of pregnancy (13). This study retrospectively examined 723 pregnant women from the SHEP study throughout their entire pregnancies, providing the opportunity to analyze the association of ID with hypothyroxinemia within each trimester of pregnancy. The data revealed that in an area without iodine deficiency, iron status was positively associated with serum fT4 levels in the first and second trimesters of pregnancy, but not in the third trimester. In addition to this, the study also showed that pregnant women with ID in the first trimester had lower serum fT4 levels and a higher rate of hypothyroxinemia in the second or third trimester compared to those without ID.

OH and IH in pregnancy have been shown to be associated with an increased risk of both adverse pregnancy complications and poor fetal neurocognitive development (20 –23). Currently, a case-finding approach to identify women at high risk of thyroid dysfunction during pregnancy is recommended. Based on the findings of this study, pregnant women with ID in the first and second trimesters should be regarded as a high-risk group for maternal hypothyroxinemia.

ID is the most prevalent micronutrient deficiency worldwide and is a public health problem in both industrialized and non-industrialized countries. Pregnant women and women of childbearing age are at high risk of ID (1). It is estimated that almost 50% of women do not have adequate iron stores for pregnancy (24,25). Even in Europe, nearly 20% of women of childbearing age do not have adequate iron reserves (26). However, it is still controversial whether physicians should recommend universal screening for ID anemia in pregnant women to prevent adverse maternal health and birth outcomes (27 –30). Pregnant women are usually advised to take iron supplements to avoid ID anemia during the second half of pregnancy, which is a period of rapid fetal growth and development (1,27,30). Maternal thyroid hormones play an essential role in the neurologic development of the fetus during the first half of pregnancy because the fetus itself does not produce thyroid hormones until 18–20 weeks of gestation (31,32). Prospective studies have also shown that thyroid deficiency in the first half of pregnancy can adversely affect the neurodevelopment of the offspring (21,22,33). Previous work has indicated that ID first impairs the iron-dependent TPO activity, an essential enzyme in thyroid hormone synthesis, followed by decreasing the iron content in the fetal brain, as maternal iron is more critical for fetal brain development (34). Therefore, perinatal ID can lead to maternal and neonatal hypothyroxinemia, which impairs early brain development before the perinatal brain iron depletion, indicating that hypothyroxinemia, instead of perinatal brain iron depletion, might be a primary mechanism underlying the impairment of brain development (35). However, until now, there has been no evidence that treatment of ID reverses hypothyroxinemia in the first or second trimester of pregnancy.

An unusual finding of this study was that ID was associated with an increased risk for hypothyroxinemia in both the first and second trimesters of pregnancy, but not in the third trimester. Two possible explanations are proposed for this finding. First, the decrease in fT4 levels due to the poor performance of immunoassays in the third trimester may cause the change in an association with ID (36). Second, physiologic hemodilution during the third trimester may also contribute to the lower fT4 levels (37). During the second half of pregnancy or the third trimester of pregnancy, it is estimated that the total blood volume increases by almost 45%, with an increase of nearly 50% in plasma volume and an increase of nearly 35% in red blood cell mass (31,38). The disproportionate increase between plasma volume and red blood cell mass during pregnancy leads to decreases in hemoglobin and SF concentrations, making it difficult to distinguish physiologic hemodilution from ID during the third trimester (24). Scholl et al. previously reported that ID anemia during the first two trimesters of pregnancy was associated with a twofold increased risk for preterm delivery and a threefold increased risk for delivering a baby with low birth weight (39). However, it has been reported that ID anemia during the third trimester was associated with a reduced risk for preterm delivery and low birth weight. Some studies have even demonstrated an absent correlation between ID anemia in the third trimester and preterm birth (40,41). In the present study, as the pregnancy progressed, SF and TBI gradually decreased, suggesting the occurrence of both hemodilution and iron mobilization from body stores to meet the increased demands associated with pregnancy (31). In contrast, sTfR concentrations were reduced in the first two trimesters of pregnancy and increased in the third trimester, consistent with the increased erythropoiesis observed in the third trimester (42,43).

The present study focused on investigating the effect of ID on hypothyroxinemia. However, there has been only limited evidence about the relationship between thyroid function and iron metabolism. Hepcidin, a liver-derived peptide hormone, is one of the most important regulators of iron homeostasis. Recently, Fischli et al. reported that hepcidin and SF levels were higher in patients with Graves' hyperthyroidism when compared to patients with euthyroidism (44). Subsequent experiments demonstrated that triiodothyronine (T3) increased hepcidin mRNA expression in HepG2 cells (44). T3 was also found to upregulate ferritin gene expression through the modulation of iron regulatory proteins (IRPs) binding activities and enhancement of IRE-dependent translation (45). Unfortunately, fT3 and hepcidin levels were not measured in the present study. Further evidence is required to elucidate whether maternal hypothyroxinemia leads to decreased levels of hepcidin or SF that results in the reduction of iron reserves.

In order to examine whether ID is a risk factor for hypothyroxinemia, analyses in this study were carefully designed. First, to reduce the interference in studying the association between iron and thyroid hormone, this study excluded pregnant women who had taken any drug or supplements containing iron or iodine during pregnancy, as well as women who had received LT4 treatment or antithyroid drugs. Second, the present study also excluded pregnant women with positive thyroid autoantibodies, as they are known to have an increased risk of hypothyroxinemia.

It should be mentioned that there are several limitations in the present study. First, pregnant women in the first trimester with a history of chronic diseases, including ID anemia, were excluded, likely underestimating the effects of ID on thyroid hormone levels during the period of pregnancy. Second, the 723 pregnant women analyzed in the present study were not randomly enrolled, resulting in fewer cases of subclinical hypothyroidism and IH in the first trimester, possibly introducing selection bias. Third, the sample size in the present study was relatively small. Thus, the relationship between ID and IH or OH could not be analyzed separately. Therefore, larger prospective trials to replicate these findings are needed in the future.

In conclusion, for the first time, it is reported that ID is associated with an increased rate of hypothyroxinemia during the first and second trimesters of pregnancy. Pregnant women with ID in the first and second trimesters should be regarded as a high-risk group for maternal hypothyroxinemia.

Footnotes

Acknowledgments

This project has been registered in the World Health Organization's International Clinical Trial Registry Platform (registration number: ChiCTR-TRC-13003805). This study was supported by grants from the 973 Science and Technology Research Foundation, Ministry of Science and Technology of China (Grant 2011CB512112); the Chinese National Natural Science Foundation (Grant 81170730); the Health and Medicine Research Foundation, Ministry of Health in China (Grant 201002002); and the Key Platform Foundation of Science and Technology for the Universities in Liaoning Province (16010). We gratefully acknowledge the invaluable contribution of doctors from the gynecology and obstetrics clinics in the 13 hospitals and six prenatal clinics in Liaoning Province, and are indebted to the residents who participated in this study.

Author Disclosure Statement

The authors declare no competing or financial interests.

References

World Health Organization. 2001. Iron Deficiency Anaemia Assessment, Prevention, and Control: A Guide for Programme Managers. World Health Organization, Geneva, Switzerland.

De Benoist

, Egli

, Cogswell

. 2008. Worldwide Prevalence of Anaemia 1993–2005. World Health Organization, Geneva, Switzerland.

Lopez

, Cacoub

, Macdougall

, Peyrin-Biroulet

. 2016. Iron deficiency anaemia. Lancet, 387:907–916.

Alexander

, Pearce

, Brent

, Brown

, Chen

, Dosiou

, Grobman

, Laurberg

, Lazarus

, Mandel

, Peeters

, Sullivan

. 2017. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid, 27:315–389.

Teng

, Shan

, Patil-Sisodia

, Cooper

. 2013. Hypothyroidism in pregnancy. Lancet Diabetes Endocrinol, 1:228–237.

McCann

, Ames

. 2007. An overview of evidence for a causal relation between iron deficiency during development and deficits in cognitive or behavioral function. Am J Clin Nutr, 85:931–945.

Radlowski

, Johnson

. 2013. Perinatal iron deficiency and neurocognitive development. Front Hum Neurosci, 7:585.

Hess

, Zimmermann

, Arnold

, Langhans

, Hurrell

. 2002. Iron deficiency anemia reduces thyroid peroxidase activity in rats. J Nutr, 132:1951–1955.

Galton

. 1972. Some effects of altitude on thyroid function. Endocrinology, 91:1393–1403.

10.

Surks

. 1969. Effect of thyrotropin on thyroidal iodine metabolism during hypoxia. Am J Physiol, 216:436–439.

11.

Zimmermann

, Burgi

, Hurrell

. 2007. Iron deficiency predicts poor maternal thyroid status during pregnancy. J Clin Endocrinol Metab, 92:3436–3440.

12.

, Shan

, Mao

, Wang

, Xie

, Zhou

, Li

, Xu

, Bi

, Meng

, Du

, Zhang

, Gao

, Zhang

, Yang

, Fan

, Teng

. 2014. Assessment of thyroid function during first-trimester pregnancy: what is the rational upper limit of serum TSH during the first trimester in Chinese pregnant women?. J Clin Endocrinol Metab, 99:73–79.

13.

, Shan

, Li

, Mao

, Wang

, Xie

, Liu

, Teng

, Zhou

, Li

, Xu

, Bi

, Meng

, Du

, Zhang

, Gao

, Zhang

, Yang

, Fan

, Teng

. 2015. Iron deficiency, an independent risk factor for isolated hypothyroxinemia in pregnant and nonpregnant women of childbearing age in China. J Clin Endocrinol Metab, 100:1594–1601.

14.

Mei

, Cogswell

, Looker

, Pfeiffer

, Cusick

, Lacher

, Grummer-Strawn

. 2011. Assessment of iron status in US pregnant women from the National Health and Nutrition Examination Survey (NHANES), 1999–2006. Am J Clin Nutr, 93:1312–1320.

15.

Cook

, Baynes

, Skikne

. 1992. Iron deficiency and the measurement of iron status. Nutr Res Rev, 5:198–202.

16.

Cogswell

, Looker

, Pfeiffer

, Cook

, Lacher

, Beard

, Lynch

, Grummer-Strawn

. 2009. Assessment of iron deficiency in US preschool children and nonpregnant females of childbearing age: National Health and Nutrition Examination Survey 2003–2006. Am J Clin Nutr, 89:1334–1342.

17.

Cook

, Flowers

, Skikne

. 2003. The quantitative assessment of body iron. Blood, 101:3359–3364.

18.

Skikne

, Flowers

, Cook

. 1990. Serum transferrin receptor: a quantitative measure of tissue iron deficiency. Blood, 75:1870–1876.

19.

Baloch

, Carayon

, Conte-Devolx

, Demers

, Feldt-Rasmussen

, Henry

, LiVosli

, Niccoli-Sire

, John

, Ruf

, Smyth

, Spencer

, Stockigt

. 2003. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid, 13:3–126.

20.

Pop

, Brouwers

, Vader

, Vulsma

, van Baar

, de Vijlder

. 2003. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol (Oxf), 59:282–288.

21.

Korevaar

, Muetzel

, Medici

, Chaker

, Jaddoe

, de Rijke

, Steegers

, Visser

, White

, Tiemeier

, Peeters

. 2016. Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: a population-based prospective cohort study. Lancet Diabetes Endocrinol, 4:35–43.

22.

Henrichs

, Bongers-Schokking

, Schenk

, Ghassabian

, Schmidt

, Visser

, Hooijkaas

, de Muinck

, Hofman

, Jaddoe

, Visser

, Steegers

, Verhulst

, de Rijke

, Tiemeier

. 2010. Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study. J Clin Endocrinol Metab, 95:4227–4234.

23.

Haddow

, Palomaki

, Allan

, Williams

, Knight

, Gagnon

, O'Heir

, Mitchell

, Hermos

, Waisbren

, Faix

, Klein

. 1999. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med, 341:549–555.

24.

Scholl

. 2005. Iron status during pregnancy: setting the stage for mother and infant. Am J Clin Nutr, 81:1218S–1222S.

25.

Perry

, Yip

, Zyrkowski

. 1995. Nutritional risk factors among low-income pregnant US women: the Centers for Disease Control and Prevention (CDC) Pregnancy Nutrition Surveillance System, 1979 through 1993. Semin Perinatol, 19:211–221.

26.

Hallberg

. 1995. Results of surveys to assess iron status in Europe. Nutr Rev, 53:314–322.

27.

Siu

. 2015. Screening for iron deficiency anemia and iron supplementation in pregnant women to improve maternal health and birth outcomes: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med, 163:529–536.

28.

Bothwell

. 2000. Iron requirements in pregnancy and strategies to meet them. Am J Clin Nutr, 72:257S–264S.

29.

Cantor

, Bougatsos

, Dana

, Blazina

, McDonagh

. 2015. Routine iron supplementation and screening for iron deficiency anemia in pregnancy: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med, 162:566–576.

30.

Recommendations to prevent and control iron deficiency in the United States. 1998. Centers for Disease Control and Prevention. MMWR Recomm Rep, 47:1–29.

31.

Vulsma

, Gons

, de Vijlder

. 1989. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med, 321:13–16.

32.

De Zegher

, Pernasetti

, Vanhole

, Devlieger

, Van den Berghe

, Martial

. 1995. The prenatal role of thyroid hormone evidenced by fetomaternal Pit-1 deficiency. J Clin Endocrinol Metab, 80:3127–3130.

33.

Finken

, van Eijsden

, Loomans

, Vrijkotte

, Rotteveel

. 2013. Maternal hypothyroxinemia in early pregnancy predicts reduced performance in reaction time tests in 5- to 6-year-old offspring. J Clin Endocrinol Metab, 98:1417–1426.

34.

, Teng

, Zheng

, Shan

, Li

, Jin

, Xiong

, Zhang

, Fan

, Teng

. 2014. Iron deficiency without anemia causes maternal hypothyroxinemia in pregnant rats. Nutr Res, 34:604–612.

35.

, Wang

, Shan

, Dong

, Zheng

, Jesse

, Rao

, Takahashi

, Li

, Teng

. 2016. Perinatal iron deficiency-induced hypothyroxinemia impairs early brain development regardless of normal iron levels in the neonatal brain. Thyroid, 26:891–900.

36.

Korevaar

, Chaker

, Medici

, de Rijke

, Jaddoe

, Steegers

, Tiemeier

, Visser

, Peeters

. 2016. Maternal total T4 during the first half of pregnancy: physiologic aspects and the risk of adverse outcomes in comparison with free T4. Clin Endocrinol (Oxf), 85:757–763.

37.

Lee

, Spencer

, Mestman

, Miller

, Petrovic

, Braverman

, Goodwin

. 2009. Free T4 immunoassays are flawed during pregnancy. Am J Obstet Gynecol, 200:260–261.

38.

Bothwell

, Charlton

, Cook

, Finch

. 1979. Iron Metabolism in Man. Blackwell Scientific Publications, Oxford.

39.

Scholl

, Hediger

, Fischer

, Shearer

. 1992. Anemia vs iron deficiency: increased risk of preterm delivery in a prospective study. Am J Clin Nutr, 55:985–988.

40.

Lieberman

, Ryan

, Monson

, Schoenbaum

. 1990. Facts and artifacts about anemia and preterm delivery. JAMA, 263:1200–1202.

41.

Zhou

, Yang

, Hua

, Deng

, Tao

, Stoltzfus

. 1998. Relation of hemoglobin measured at different times in pregnancy to preterm birth and low birth weight in Shanghai, China. Am J Epidemiol, 148:998–1006.

42.

Choi

, Im

, Pai

. 2000. Serum transferrin receptor concentrations during normal pregnancy. Clin Chem, 46:725–727.

43.

Akesson

, Bjellerup

, Berglund

, Bremme

, Vahter

. 1998. Serum transferrin receptor: a specific marker of iron deficiency in pregnancy. Am J Clin Nutr, 68:1241–1246.

44.

Fischli

, von Wyl

, Trummler

, Konrad

, Wueest

, Ruefer

, Heering

, Streuli

, Steuer

, Bernasconi

, Recher

, Henzen

. 2017. Iron metabolism in patients with Graves' hyperthyroidism. Clin Endocrinol (Oxf), 87:609–616.

45.

Leedman

, Stein

, Chin

, Rogers

. 1996. Thyroid hormone modulates the interaction between iron regulatory proteins and the ferritin mRNA iron-responsive element. J Biol Chem, 271:12017–12023.