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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2007-1082
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 9 3436-3440
Copyright © 2007 by The Endocrine Society

Iron Deficiency Predicts Poor Maternal Thyroid Status during Pregnancy

Michael B. Zimmermann, Hans Burgi and Richard F. Hurrell

Laboratory for Human Nutrition (M.B.Z., R.F.H.), Swiss Federal Institute of Technology (Eidgenössische Technische Hochschule), CH-8092 Zürich, Switzerland; and Committee for Fluoride-Iodine Fortification of Salt (M.B.Z., H.B.), Swiss Academy of Medical Science, CH-3007 Bern, Switzerland; Division of Human Nutrition (M.B.Z.), Wageningen University, 6700 Wageningen, The Netherlands

Address all correspondence and requests for reprints to: Michael B. Zimmermann, M.D., Laboratory for Human Nutrition, Swiss Federal Institute of Technology (Eidgenössische Technische Hochschule) Zürich, Schmelzbergstrasse 7, LFV E 19, CH-8092 Zürich, Switzerland. E-mail: michael.zimmermann{at}ilw.agrl.ethz.ch.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Pregnant women are often iron deficient, and iron deficiency has adverse effects on thyroid metabolism. Impaired maternal thyroid function during pregnancy may cause neurodevelopmental delays in the offspring.

Objective: Our objective was to investigate whether maternal iron status is a determinant of TSH and/or total T4 (TT4) concentrations during pregnancy.

Design and Outcome Measures: In a representative national sample of Swiss pregnant women (n = 365) in the second and third trimester, samples of urine and blood were collected, and data on maternal characteristics and supplement use were recorded. Concentrations of TSH, TT4, hemoglobin, mean corpuscular volume, serum ferritin, transferrin receptor, and urinary iodine were measured. Body iron stores were calculated and stepwise regressions performed to look for associations.

Results: Median urinary iodine was 139 µg/liter (range 30–433). In the third trimester, nearly 40% of women had negative body iron stores, 16% had a TT4 less than 100 nmol/liter, and 6% had a TSH more than 4.0 mU/liter. Compared with the women with positive body iron stores, the relative risk of a TT4 less than 100 nmol/liter in the group with negative body iron stores was 7.8 (95% confidence interval 4.1; 14.9). Of the 12 women with TSH more than 4.0 mU/liter, 10 had negative body iron stores. Serum ferritin, transferrin receptor, and body iron stores were highly significant predictors of TSH (standardized ß: –0.506, 0.602, and –0.589, respectively; all P < 0.0001) and TT4 (standardized ß: 0.679, –0.589, and 0.659, respectively; all P < 0.0001).

Conclusion: Poor maternal iron status predicts both higher TSH and lower TT4 concentrations during pregnancy in an area of borderline iodine deficiency.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
DURING THE SECOND and third trimester, pregnant women are highly vulnerable to iron deficiency (ID) anemia because their increased iron needs are rarely met by dietary sources (1, 2). In industrialized countries, the prevalences of anemia and ID during pregnancy range from 6–28% and 24–44%, respectively (1, 2, 3, 4). In developing countries, the majority of women are anemic in the second half of pregnancy (5, 6). Requirements for thyroid hormone during pregnancy also sharply increase to maintain maternal euthyroidism and transfer thyroid hormone to the fetus (7). To support this, the iodine requirement in pregnancy increases from 150–250 µg/d (8), making maternal thyroid function particularly vulnerable in regions of marginal iodine intake.

ID has multiple adverse effects on thyroid metabolism (9, 10). It decreases circulating thyroid hormone concentrations, likely through impairment of the heme-dependent thyroid peroxidase (TPO) enzyme (11). ID blunts the efficacy of iodine prophylaxis (12), and iron repletion improves the efficacy of iodized salt in goitrous children with ID (13).

Two prospective studies, using two different measures of impaired thyroid function in pregnancy (an increased TSH in the second trimester and hypothyroxinemia at 12 wk gestation) reported that even mild maternal thyroid dysfunction may impair neurodevelopment in the offspring (14, 15). Therefore, analyzing data from a national survey performed when pregnant women in Switzerland were mildly iodine deficient (16), our objective was to investigate whether maternal iron status is a determinant of TSH and/or total T4 (TT4) concentrations during pregnancy in an area of borderline iodine deficiency.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Using current census data, a two-stage probability proportionate to size cluster sampling method was used to obtain a representative national sample of women in the second and third trimester of pregnancy. A sample size of 400 was estimated based on a 40% prevalence of urinary iodine concentrations (UICs) less than 100 µg/liter, a 95% confidence interval for the true prevalence of UICs less than 100 µg/liter, a design effect of 2 and 15% relative precision. In stage 1, 25 obstetric clinics were recruited using stratified random selection; if a clinic declined participation, a replacement was randomly selected from the same stratum. In stage 2, the clinic physician randomly selected approximately 20 pregnant women in their second or third trimester. The exclusion criteria were a history of a thyroid disorder and/or current use of thyroid medication. In stage 2, seven women were excluded because of thyroid disease. All other women who were asked to participate consented. The study period was February to July 1999. Ethical approval for the study was obtained from the Eidgenössische Technische Hochschule Zürich, and informed written consent was obtained from the pregnant women.

For each subject, maternal age, gestational age, parity, and use of iodized salt and/or vitamin and mineral supplements were recorded. A spot urine sample was collected, and approximately 7 ml whole blood was collected by venipuncture into a heparinized tube. These were sent on the same day to the Eidgenössische Technische Hochschule Zürich. Hemoglobin (Hb) and mean corpuscular volume (MCV) were measured using a Beckman Coulter ACT8 Hematology Analyzer (Beckman Coulter, Inc., Miami, FL). Serum aliquots were then stored at –25 C for further analysis. Serum ferritin (SF) and serum transferrin receptor (TfR) concentrations were measured by immunoassay (RAMCO, Houston, TX). Serum folate was measured by chemoluminescence-immunoassay using the Access Immunoassay System (Beckman Coulter, Inc., Fullerton, CA). TT4 and TSH were measured using immunoassay (17). Spot urine samples were stored at –25 C until analysis, and UIC was measured using a modification of the Sandell-Kolthoff reaction (18).

Body iron stores were calculated from the ratio of the TfR to SF; positive values indicate the amount of iron in stores, and negative values indicate the deficit in tissue iron (19, 20). Women were classified as anemic if Hb was less than 105 g/liter in the second trimester or less than 110 g/liter in the third trimester (21). There is no consensus on reference values for TSH and TT4 during pregnancy; because our subjects were in the second and third trimester, we used the cutoffs of TSH more than 4.0 mIU/liter as indicating mild subclinical hypothyroidism and a TT4 less than 100 nmol/liter as indicating hypothyroxinemia (22, 23). ID was defined as SF less than 15 µg/liter or TfR more than 8.5 mg/liter (4, 5). The reference range for serum folate in our laboratory is 2.5–9.0 µg/liter. A median UIC of 150–250 µg/liter indicates adequate iodine intake in pregnancy (8).

Data processing and statistics were performed using SPSS 13.0 for Windows (SPSS, Inc., Chicago, IL), and Excel (Microsoft Corp., Redmond, WA). Normally distributed data were expressed as means ± SD values; nonnormally distributed data were expressed as medians (ranges). Differences between groups for normally and nonnormally distributed data were tested using unpaired t and Mann-Whitney U tests, respectively. Multiple regression and analysis of covariance were used to test for associations. P values < 0.05 were considered significant.


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The characteristics of the sample, which included 365 women from 23 obstetric clinics, are shown in Table 1Go. The age range was 16–42 yr, and the range in parity was 1–8. Median (range) serum folate in the second and third trimesters, and overall, were 6.9 (2.2–58.0), 7.9 (1.8–63.5), and 7.6 µg/liter (1.8–63.5), respectively. Only 3% of women had a serum folate concentration less than 2.5 µg/liter. Mean ages (±SD) of women in the second and third trimester, and overall, were 29.6 ± 4.2, 29.9 ± 5.2, and 29.8 ± 4.8 yr, respectively. Mean gestation ages (±SD) of women in the second and third trimester, and overall, were 18.6 ± 3.6, 31.9 ± 4.4, and 26.7 ± 7.7 wk, respectively. Mean parities (±SD) of women in the second and third trimester, and overall, were 2.0 ± 1.1, 1.8 ± 1.0, and 1.9 ± 1.0, respectively. Only 6% of women were anemic; the range of Hb was 92–157 g/liter. However, ID was common, particularly in the third trimester, as indicated by the high prevalence of abnormal iron status indices and microcytosis, and nearly 40% of women had negative body iron stores. Compared with the second trimester, SF concentrations were significantly lower (P < 0.01) and TfR concentrations significantly higher (P < 0.05) in the third trimester, indicating a decline in iron status in the later part of pregnancy. Folate status was generally adequate, with only 3% of women having low serum folate concentrations.


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  		TABLE 1. Characteristics of a cross-sectional national sample of Swiss pregnant women, by trimester

 
TT4 concentrations were significantly lower in the third compared with the second trimester (P < 0.05), with 16% of women having a TT4 less than 100 nmol/liter in the third trimester. Only one woman had both a TT4 less than 100 nmol/liter and a TSH more than 4.0 mU/liter. The population was mildly iodine deficient. The median UIC of 139 µg/liter was slightly lower than that indicating iodine sufficiency in pregnancy (150 µg/liter), and 59% of women had a UIC less than 150 µg/liter. Of women, 81% reported using iodized salt at home; 11% were using noniodized salt, and 8% were uncertain. Of subjects, 71% were taking a daily multivitamin-mineral supplement: 65% were taking a supplement, including iron (range 5–160 mg/d); 63% were taking a supplement, including folate (range 100-1800 µg/d); but only 13% were taking a supplement containing iodine (150 µg/d).

Figure 1Go shows the relationships between body iron stores and TT4 or TSH. Compared with the women with positive body iron stores, the relative risk of having a TT4 concentration less than 100 nmol/liter in the group with negative body iron stores was 7.8 (95% confidence interval 4.1; 14.9). Of the 12 women with TSH concentrations more than 4.0 mU/liter, 10 of them had negative body iron stores.


Figure 1
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  		FIG. 1. The relationship between body iron stores and serum TSH and TT4 in mildly iodine-deficient pregnant women (n = 365) in the second and third trimester.

 
Table 2Go shows the results of the stepwise regressions with TSH as the dependent variable, including as covariates maternal age, week of gestation, parity, Hb, MCV, serum folate, UIC, iron supplementation, and, separately, the three indicators of iron status. In the model including body iron, but not TfR or SF, only body iron and MCV were significant predictors, with week of gestation showing a trend toward an association (P = 0.086). In the model including TfR, only TfR, MCV, and week of gestation were significant predictors. In the model including SF, only SF and MCV were significant predictors.


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  		TABLE 2. Results of the regressions with TSH as the dependent variable, including as covariates maternal age, week of gestation, parity, Hb, MCV, serum folate, urinary iodine, iron supplement use, and body iron stores, TfR, or SF

 
Table 3Go shows the results of the regressions with TT4 as the dependent variable, including the same covariates described previously for TSH. In the model including body iron, but not TfR or SF, only body iron and week of gestation were significant predictors, with MCV showing a trend toward an association (P = 0.81). In the model including TfR, only TfR, week of gestation, and MCV were significant predictors, with serum folate showing a trend toward an association (P = 0.70). In the model including SF, only SF and MCV were significant predictors.


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  		TABLE 3. Results of the regressions with total T4 as the dependent variable, including as covariates maternal age, week of gestation, parity, Hb, MCV, serum folate, urinary iodine, iron supplement use, and body iron stores, TfR, or SF

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our findings suggest that poor maternal iron status predicts both higher TSH and lower TT4 concentrations during pregnancy in an area of borderline iodine deficiency. Although the cross-sectional design of our study does not establish causation, an effect of iron status on thyroid function is plausible. ID blunts the thyrotropic response to TRH, decreases serum T3 and T4 levels, slows turnover of T3, and may reduce T3 nuclear binding (9). A central mechanism in this effect is impairment of the heme-dependent enzyme TPO, limiting synthesis of thyroid hormone, and reducing circulating TT3 and TT4 (11). ID reduces the efficacy of iodine prophylaxis (12), and iron repletion enhances it (13). In young anemic women, treatment with iron may increase circulating thyroid hormone concentrations (24, 25). In patients with subclinical hypothyroidism, iron repletion modestly increases circulating thyroid hormone and lowers TSH (26).

Although it is plausible that poor iron status impaired thyroid function in our sample, there are other potential explanations for our findings. One is that iron status is a surrogate for another, unmeasured confounder. Alternatively, poor thyroid function could lower iron status. In hypothyroidism, ID may occur due to poor iron absorption secondary to achlorhydria (27, 28). And although anemia is common in hypothyroidism, affecting 25–50% of adult patients (29, 30), it is typically normocytic or slightly macrocytic, and patients typically have normal iron stores. Our data do not suggest anemia secondary to hypothyroidism because only 6% of our sample was anemic, all of the anemia was microcytic, ID was common, and no subject was clearly hypothyroid.

A strength of the study was that iron status was defined using both SF and TfR, allowing calculation of body iron stores. Using SF alone to assess iron status during pregnancy is of limited value because of potential dilution effects secondary to the expansion of blood volume; mean values during pregnancy are similar to the nonpregnant, iron-deficient state (3, 4). The ability to recognize ID during pregnancy can be improved by using TfR measurements because the circulating TfR concentration is increased during pregnancy only if ID is present (3, 4). Moreover, calculation of body iron stores allows characterization of the entire range of iron status in pregnancy, from depletion of iron stores through ineffective erythropoiesis (19, 20). This may have increased our ability to detect associations between iron status and thyroid function.

The prevalence of anemia and ID in our sample (6 and 28%, respectively) is generally lower than that reported in pregnant women from most other industrialized countries of Europe and North America (1, 2, 3, 4, 5, 6). Because younger maternal age and lower socioeconomic level are risk factors for anemia (31), the older age and higher socioeconomic level of our sample compared with other countries, as well as widespread use of iron- and folate-containing supplements, may explain the lower anemia prevalence. If poor iron status impairs thyroid function in pregnancy, then the effect seen in our sample may be accentuated in other countries, particularly in the developing world, where iron status (and iodine status) is often even more compromised.

We examined the effect of iron status on both TSH and T4 concentrations because prospective case-control studies, using either an increased TSH in the second trimester (15) or a low free T4 at 12 wk gestation (14), have demonstrated adverse effects on infant and child development. A limitation of our study is that our sample did not include women earlier in pregnancy. Decreased availability of maternal thyroid hormone may be a critical factor impairing fetal development in the early stages of gestation, before the fetal thyroid gland becomes active (32). Early identification and treatment of subclinical hypothyroidism may prevent adverse effects on the psychomotor and auditory systems of the newborn (33). In addition, we did not measure antithyroid antibodies; high titers of maternal TPO antibodies may increase the risk of having a developmentally impaired child (34). Finally, we found a relationship between ID and thyroid function in an area of marginal iodine supply; this may not occur when iodine intakes are adequate in pregnant women, either from iodized salt or supplemental iodine (35, 36). If confirmed, these findings argue for the early detection and treatment of ID in pregnancy, not only to combat anemia but also to avoid its adverse effects on maternal thyroid function and fetal development.


   Acknowledgments
 
We thank the participating women and the medical staff of the obstetric centers for their participation in the study. We also thank S. Hess (Eidgenössische Technische Hochschule, Zürich, Switzerland) and T. Torresani (Children’s Hospital, Zürich, Switzerland) for data collection and analyses; S. Brogli (University Hospital Zürich), S. Kollaart, and C. Ammann (Eidgenössische Technische Hochschule, Zürich, Switzerland) for assistance in the laboratory; and I. Aeberli (Eidgenössische Technische Hochschule Zürich) for assistance with the statistical analyses.


   Footnotes
 
This study was supported by the Swiss Foundation for Nutrition Research (Zürich, Switzerland) and the Swiss Federal Institute of Technology (Eidgenössische Technische Hochschule) (Zürich, Switzerland).

All authors made substantial contributions to the study design, data collection, and data analyses, as well as to the writing and/or editing of the paper. No author has a personal or financial interest in the companies or organizations sponsoring this research, including advisory board affiliations.

Disclosure Statement: The authors have nothing to disclose.

First Published Online June 12, 2007

Abbreviations: Hb, Hemoglobin; ID, iron deficiency; MCV, mean corpuscular volume; SF, serum ferritin; TfR, transferrin receptor; TPO, thyroid peroxidase; TT4, total T4; UIC, urinary iodine concentration.

Received May 15, 2007.

Accepted June 4, 2007.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Zimmermann MB, Hurrell RF, Nutritional iron deficiency. Lancet, in press
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mean corpuscular hemoglobin is the red blood cell index which might have been more indicative than m
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