Maternal hypothyroxinemia in the first trimester of gestation and association with obstetric and neonatal outcomes and iron deficiency: a prospective Brazilian study

Pedro Weslley Rosario Luis Fernando Faria Oliveira Maria Regina Calsolari About the authors

ABSTRACT

Objective:

To evaluate the association of isolated hypothyroxinemia in the first trimester with obstetric and neonatal outcomes and iron deficiency.

Subjects and methods:

The study was prospective. Women who had become pregnant spontaneously were initially selected. Next, anti-thyroid peroxidase antibodies (TPOAb), free T4 (FT4), total T4 (TT4), TSH, and ferritin were measured. TPOAb-positive women were excluded. The final sample consisted of 596 women with serum TSH between 0.1 and 2.5 mIU/l. Hypothyroxinemia was defined as FT4 < 0.86 ng/dL and < 0.92 ng/dL, corresponding to the 5th and 10th percentiles, respectively, and TT4 < 7.8 ng/dL. None of the pregnant women was treated with levothyroxine until the end of pregnancy.

Results:

The women ranged in age from 18 to 36 years, with a median gestation of 9 weeks. T4 levels were not correlated with BMI or maternal TSH. Isolated hypothyroxinemia was observed in 4.3% (FT4 < 0.86 ng/dL), 9% (FT4 < 0.92 ng/dL), and 7% (TT4 < 7.8 ng/dL) of the pregnant women. The frequencies of obstetric and neonatal outcomes were similar in women with versus without hypothyroxinemia. In women without iron deficiency, 8.4%, 3.9%, and 6.5% had FT4 < 0.92 ng/dl, FT4 < 0.86 ng/dL and TT4 < 7.8 ng/dL, respectively. These frequencies of hypothyroxinemia were significantly higher among women with iron deficiency (20.7%, 14.8% and 17.2%, respectively).

Conclusions:

This prospective Brazilian study found no association between isolated hypothyroxinemia in the first trimester of gestation and obstetric or neonatal outcomes, but an association was demonstrated with iron deficiency.

Keywords
Pregnancy; first trimester; hypothyroxinemia; iron deficiency; obstetric and neonatal outcomes

INTRODUCTION

When screening for thyroid dysfunction in pregnancy is indicated, it should be performed in the first prenatal visit, which usually occurs in the first trimester. Possible consequences of subclinical hypothyroidism and isolated maternal hypothyroxinemia also appear to be more worrisome when they occur in the first trimester of gestation, a period when the fetus still does not produce thyroid hormone and depends on maternal thyroxine (T4) (11. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med. 1999;341(8):549-55.). It is therefore more important to know the impact of these conditions when diagnosed in the early stages of pregnancy (11. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med. 1999;341(8):549-55.,22. Lazarus J, Brown RS, Daumerie C3 Hubalewska-Dydejczyk A, Negro R, Vaidya B. 2014 European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J. 2014;3(2):76-94.).

Isolated hypothyroxinemia is diagnosed in the presence of serum TSH within the normal range associated with T4 concentrations below the 2.5th, 5th or 10th percentile (22. Lazarus J, Brown RS, Daumerie C3 Hubalewska-Dydejczyk A, Negro R, Vaidya B. 2014 European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J. 2014;3(2):76-94.44. Dosiou C, Medici M. Management of Endocrine Disease: Isolated maternal hypothyroxinemia during pregnancy: knowns and unknowns. Eur J Endocrinol. 2017;176(1):R21-R38.). Regarding TSH, except when the assay- and population-specific references values are available, the range of 0.1 to 2.5 mIU/l has been accepted for the definition of maternal euthyroidism in the first trimester (22. Lazarus J, Brown RS, Daumerie C3 Hubalewska-Dydejczyk A, Negro R, Vaidya B. 2014 European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J. 2014;3(2):76-94.,33. Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017;27(3):315-89.,55. De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, et al. Management of Thyroid Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2012;97(8):2543-65.77. Sgarbi JA, Teixeira PF, Maciel LM, Mazeto GM, Vaisman M, Montenegro Junior RM, et al.; Brazilian Society of Endocrinology and Metabolism. The Brazilian consensus for the clinical approach and treatment of subclinical hypothyroidism in adults: recommendations of the thyroid Department of the Brazilian Society of Endocrinology and Metabolism. Arq Bras Endocrinol Metabol. 2013;57(3):166-83.). It is worth noting that this range does also seem to be adequate for our population (88. Rosario PW, Carvalho M, Calsolari MR. TSH reference values in the first trimester of gestation and correlation between maternal TSH and obstetric and neonatal outcomes: a prospective Brazilian study. Arch Endocrinol Metab. 2016;60(4):314-8.). Iodine deficiency appears to the most important factor in the etiology of isolated hypothyroxinemia, but other factors have also been implicated, such as environmental disruptors, obesity, and iron deficiency (44. Dosiou C, Medici M. Management of Endocrine Disease: Isolated maternal hypothyroxinemia during pregnancy: knowns and unknowns. Eur J Endocrinol. 2017;176(1):R21-R38.). No consensus exists regarding the consequences and need for levothyroxine (L-T4) replacement therapy in isolated hypothyroxinemia (44. Dosiou C, Medici M. Management of Endocrine Disease: Isolated maternal hypothyroxinemia during pregnancy: knowns and unknowns. Eur J Endocrinol. 2017;176(1):R21-R38.). The American College of Obstetricians and Gynecologists (ACOG) does not consider this condition in its guidelines (99. American College of Obstetricians and Gynecologists. Practice Bulletin No. 148: Thyroid disease in pregnancy. Obstet Gynecol. 2015;125(4):996-1005.). The American Thyroid Association (ATA) does not recommend its treatment (33. Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017;27(3):315-89.), while the Endocrine Society proposes partial replacement therapy (55. De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, et al. Management of Thyroid Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2012;97(8):2543-65.). According to the European Thyroid Association (ETA), treatment can be considered when hypothyroxinemia is detected in the first trimester, but not when it is detected in the second or third trimester (22. Lazarus J, Brown RS, Daumerie C3 Hubalewska-Dydejczyk A, Negro R, Vaidya B. 2014 European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J. 2014;3(2):76-94.). A large recent study found no benefit of L-T4 replacement therapy in isolated hypothyroxinemia, but one limitation of that study is that this therapy was generally initiated only in the 18th week of gestation (1010. Casey BM, Thom EA, Peaceman AM, Varner MW, Sorokin Y, Hirtz DG, et al.; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy. N Engl J Med. 2017;376(9):815-25.,1111. Cooper DS, Pearce EM. Subclinical Hypothyroidism and Hypothyroxinemia in Pregnancy – Still No Answers. N Engl J Med. 2017;376(9):876-7.).

In view of the lack of consensus regarding the management of isolated hypothyroxinemia, notably when detected in the first trimester, the objective of this study was to evaluate the association of this condition with obstetric and neonatal outcomes. The association with iron deficiency was also explored. To our knowledge, no Brazilian study has so far evaluated these associations.

SUBJECTS AND METHODS

The study was prospective and was approved by the local Research Ethics Committee (88. Rosario PW, Carvalho M, Calsolari MR. TSH reference values in the first trimester of gestation and correlation between maternal TSH and obstetric and neonatal outcomes: a prospective Brazilian study. Arch Endocrinol Metab. 2016;60(4):314-8.).

Selection

The population studied was from the metropolitan region of Belo Horizonte (Minas Gerais, Brazil). One thousand and eighty two pregnant women who underwent prenatal exams at a clinical analysis laboratory and who had become pregnant spontaneously were initially interviewed and examined (88. Rosario PW, Carvalho M, Calsolari MR. TSH reference values in the first trimester of gestation and correlation between maternal TSH and obstetric and neonatal outcomes: a prospective Brazilian study. Arch Endocrinol Metab. 2016;60(4):314-8.). Women who met the clinical criteria shown in Table 1 (n = 748) were first selected. Next, anti-thyroid peroxidase antibodies (TPOAb), free T4 (FT4), total T4 (TT4), TSH, and ferritin were measured. TPOAb-positive pregnant women (n = 38) were excluded. Women with hyperemesis gravidarum, twin pregnancy or trophoblastic disease (n = 50) were also excluded. The sample consisted of 660 women and 596 with serum TSH between 0.1 and 2.5 mIU/l (2,3,5-7,8) were selected.

Table 1
Inclusion criteria

Protocol

At the time of the study, and still today, T4 measurement is not necessary in women with TSH ≤ 2.5 mIU/L without TPOAb. There was also, and continues to be, no consensus recommendation regarding the treatment of hypothyroxinemia. Hence, in order to avoid interference with the results, the protocol was approved foreseeing the non-repetition of thyroid function tests during pregnancy and was thus executed. None of the pregnant women was treated with L-T4 until the end of pregnancy. Regarding iron supplementation, the women only received the recommended daily doses in all pregnant women without additional supplementation in those with iron deficiency.

Outcomes

Obstetric and neonatal outcomes were compared between women with FT4 < 0.86 ng/dL and < 0.92 ng/dL and those with FT4 ≥ 0.92 ng/dL. These values correspond, respectively, to the 5th and 10th percentiles of FT4 concentrations obtained for the initially selected 660 TPOAb-negative women (88. Rosario PW, Carvalho M, Calsolari MR. TSH reference values in the first trimester of gestation and correlation between maternal TSH and obstetric and neonatal outcomes: a prospective Brazilian study. Arch Endocrinol Metab. 2016;60(4):314-8.). We also compared women with TT4 < 7.8 ng/dL and ≥ 7.8 ng/dL. This value is provided by the assay as the lower limit of normal for the first trimester of gestation and corresponds exactly to 1.5 times the lower limit of the reference range for non-pregnant healthy adults (1212. IMULITE® and IMMULITE® 2000 Reference Range Compendium.). The outcomes (reported in Table 2) were predefined before the start of the study based on those used in the largest series that evaluated the association between hypothyroxinemia and pregnancy outcomes (1313. Casey BM, Dashe JS, Spong CY, McIntire DD, Leveno KJ, Cunningham GF. Perinatal significance of isolated maternal hypothyroxinemia identified in the first half of pregnancy. Obstet Gynecol. 2007;109(5):1129-35.). The definitions of hypothyroxinemia were also pre-established.

Table 2
Obstetric outcomes

Laboratory

Iron deficiency was defined as a ferritin concentration < 15 ng/mL (1414. Daru J, Allotey J, Peña-Rosas JP, Khan KS. Serum ferritin thresholds for the diagnosis of iron deficiency in pregnancy: a systematic review. Transfus Med. 2017;27(3):167-74.). TSH, FT4, TT4 and TPOAb were measured with a chemiluminescent assay (Diagnostic Products Corporation, Los Angeles, CA). Serum samples were obtained from the women in the morning (at about 8 a.m.) after an 8- to 10-h fast (88. Rosario PW, Carvalho M, Calsolari MR. TSH reference values in the first trimester of gestation and correlation between maternal TSH and obstetric and neonatal outcomes: a prospective Brazilian study. Arch Endocrinol Metab. 2016;60(4):314-8.).

Statistical

The Spearman or Pearson correlation test was used to analyze the correlation between T4 and body mass index (BMI) and TSH. The t-test or Mann-Whitney test and Fisher's exact test or the χ2 test were used for comparison between groups. A P value < 0.05 was considered statistically significant.

RESULTS

The characteristics of the 596 patients are shown in Table 3.

Table 3
Characteristics of the 596 patients

FT4 levels were not correlated with BMI (p = 0.6) or maternal TSH (p = 0.1). TT4 levels were also not correlated with BMI (p = 0.7) or maternal TSH (p = 0.15).

Tables 2 and 4 show the obstetric and neonatal outcomes, respectively, according to maternal T4 concentrations in the first trimester of gestation. The groups were similar in terms of age, BMI and maternal TSH levels. No difference in the frequencies of obstetric or neonatal outcomes was observed, regardless of the definition of isolated hypothyroxinemia.

Table 4
Neonatal outcomes

Iron deficiency was diagnosed in 29 (4.8%) pregnant women. This frequency was 4.2% in women with FT4 ≥ 0.92 ng/dL. The frequencies of iron deficiency were significantly higher in women with FT4 < 0.86 ng/dL and < 0.92 ng/dL (hypothyroxinemia), 15.4% (p = 0.03) and 11.1% (p = 0.04), respectively. Women with TT4 < 7.8 ng/dL (hypothyroxinemia) also exhibited a higher frequency of iron deficiency than women with TT4 ≥ 7.8 ng/dL (12% versus 4.3%, p = 0.045). In women without iron deficiency, 8.4%, 3.9% and 6.5% had FT4 < 0.92 ng/dL, FT4 < 0.86 ng/dL and TT4 < 7.8 ng/dL respectively. These frequencies of hypothyroxinemia were significantly higher among women with iron deficiency, 20.7% (p = 0.038), 14.8% (p = 0.032) and 17.2% (p = 0.045), respectively.

DISCUSSION

Some characteristics of the present study should be highlighted. This was a prospective study. Hypothyroxinemia was defined using three different criteria of T4 concentration. Regarding TSH, a cutoff of 2.5 mIU/l was used since it is still the most accepted value for the first trimester of gestation (22. Lazarus J, Brown RS, Daumerie C3 Hubalewska-Dydejczyk A, Negro R, Vaidya B. 2014 European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J. 2014;3(2):76-94.,33. Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017;27(3):315-89.,55. De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, et al. Management of Thyroid Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2012;97(8):2543-65.77. Sgarbi JA, Teixeira PF, Maciel LM, Mazeto GM, Vaisman M, Montenegro Junior RM, et al.; Brazilian Society of Endocrinology and Metabolism. The Brazilian consensus for the clinical approach and treatment of subclinical hypothyroidism in adults: recommendations of the thyroid Department of the Brazilian Society of Endocrinology and Metabolism. Arq Bras Endocrinol Metabol. 2013;57(3):166-83.) and is compatible with the normal range for our population (88. Rosario PW, Carvalho M, Calsolari MR. TSH reference values in the first trimester of gestation and correlation between maternal TSH and obstetric and neonatal outcomes: a prospective Brazilian study. Arch Endocrinol Metab. 2016;60(4):314-8.). In addition, an overestimated TSH cutoff may compromise the conclusions because of the inclusion of women with subclinical hypothyroidism. Women with TPOAb were excluded to rule out the possible interference of thyroid autoimmunity with the outcomes. The women were evaluated in the first trimester since eventual repercussions of isolated hypothyroxinemia would be greater during this period (11. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med. 1999;341(8):549-55.,22. Lazarus J, Brown RS, Daumerie C3 Hubalewska-Dydejczyk A, Negro R, Vaidya B. 2014 European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J. 2014;3(2):76-94.,1111. Cooper DS, Pearce EM. Subclinical Hypothyroidism and Hypothyroxinemia in Pregnancy – Still No Answers. N Engl J Med. 2017;376(9):876-7.) and treatment is particularly considered in this stage of pregnancy (22. Lazarus J, Brown RS, Daumerie C3 Hubalewska-Dydejczyk A, Negro R, Vaidya B. 2014 European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J. 2014;3(2):76-94.). None of the women was treated with L-T4 during pregnancy. Finally, few studies have investigated the relationship between hypothyroxinemia and iron deficiency. To our knowledge, this is the first Brazilian study analyzing the association of hypothyroxinemia with obstetric and neonatal outcomes and iron deficiency.

Regarding the association of hypothyroxinemia with iron deficiency, our results confirm the data of a Chinese observational study, which also evaluated women in the first trimester of gestation from an iodine-sufficient area (1515. Yu X, Shan Z, Li C, Mao J, Wang W, Xie X, et al. Iron deficiency, an independent risk factor for isolated hypothyroxinemia in pregnant and nonpregnant women of childbearing age in China. J Clin Endocrinol Metab. 2015;100(4):1594-601.). Since it would be more than a coincidence that iron and iodine deficiencies are the consequence of broad nutritional deficiency or that isolated hypothyroxinemia (in the absence of hypothyroidism) causes iron deficiency, iron deficiency is more likely to contribute to hypothyroxinemia (1515. Yu X, Shan Z, Li C, Mao J, Wang W, Xie X, et al. Iron deficiency, an independent risk factor for isolated hypothyroxinemia in pregnant and nonpregnant women of childbearing age in China. J Clin Endocrinol Metab. 2015;100(4):1594-601.). It is possible that iodine sufficiency influences the consequence of iron deficiency in terms of thyroid dysfunction, whether it is predominantly hypothyroxinemia (without TSH elevation) in an iodine-sufficient population (1515. Yu X, Shan Z, Li C, Mao J, Wang W, Xie X, et al. Iron deficiency, an independent risk factor for isolated hypothyroxinemia in pregnant and nonpregnant women of childbearing age in China. J Clin Endocrinol Metab. 2015;100(4):1594-601.) like ours, or subclinical hypothyroidism in an iodine-deficient population (1616. Zimmermann MB, Burgi H, Hurrell RF. Iron deficiency predicts poor maternal thyroid status during pregnancy. J Clin Endocrinol Metab. 2007;92(9):3436-40.). However, further clinical studies involving pregnant women are necessary to consistently confirm this association.

We found no association between isolated hypothyroxinemia in the first trimester of gestation and obstetric or neonatal outcomes. Casey and cols., comparing 16,011 women with normal TSH and T4 and 233 with hypothyroxinemia before 20 weeks of gestation, also observed no association between this alteration and any of the obstetric or neonatal outcomes analyzed (1313. Casey BM, Dashe JS, Spong CY, McIntire DD, Leveno KJ, Cunningham GF. Perinatal significance of isolated maternal hypothyroxinemia identified in the first half of pregnancy. Obstet Gynecol. 2007;109(5):1129-35.). Cleary-Goldman and cols. evaluated 10,021 pregnant women with normal TSH and T4 and 232 with hypothyroxinemia (1717. Cleary-Goldman J, Malone FD, Lambert-Messerlian G, Sullivan L, Canick J, Porter TF, et al. Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol. 2008;112(1):85-92.). In the first trimester, hypothyroxinemia was associated with preterm labor (adjusted odds ratio [aOR] 1.62; 95% confidence interval [CI] 1.00-2.62) and macrosomia (aOR 1.97; 95% CI 1.37-2.83) (1717. Cleary-Goldman J, Malone FD, Lambert-Messerlian G, Sullivan L, Canick J, Porter TF, et al. Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol. 2008;112(1):85-92.). In the second trimester, it was associated with gestational diabetes (aOR 1.7; 95% CI 1.02-2.84) (1717. Cleary-Goldman J, Malone FD, Lambert-Messerlian G, Sullivan L, Canick J, Porter TF, et al. Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol. 2008;112(1):85-92.). Finally, a third study involving more than 5,000 women revealed an association of hypothyroxinemia with preterm labor (1818. Korevaar TI, Schalekamp-Timmermans S, de Rijke YB, Visser WE, Visser W, de Muinck Keizer-Schrama SM, et al. Hypothyroxinemia and TPO-antibody positivity are risk factors for premature delivery: the generation R study. J Clin Endocrinol Metab. 2013;98(11):4382-90.), but not with hypertensive disease in pregnancy (1919. Medici M, Korevaar TI, Schalekamp-Timmermans S, Gaillard R, de Rijke YB, Visser WE, et al. Maternal early-pregnancy thyroid function is associated with subsequent hypertensive disorders of pregnancy: the generation R study. J Clin Endocrinol Metab. 2014;99(12):E2591-8.). A meta-analysis that included these and other smaller studies found only a statistically significant increased risk of placental abruption (OR 2.3; 95% CI: 1.1–4.8) compared to euthyroid controls (2020. Chan S, Boelaert K. Optimal management of hypothyroidism, hypothyroxinaemia and euthyroid TPO antibody positivity preconception and in pregnancy. Clin Endocrinol (Oxf). 2015;82(3):313-26.). Taken together, these findings show that the association of hypothyroxinemia with obstetric and neonatal outcomes is still inconsistent (44. Dosiou C, Medici M. Management of Endocrine Disease: Isolated maternal hypothyroxinemia during pregnancy: knowns and unknowns. Eur J Endocrinol. 2017;176(1):R21-R38.). In fact, there is no reproducibility of the results in the different studies and no cause-effect relationship could be established.

We recognize some limitations of the study. First, the number of women with hypothyroxinemia may have been insufficient to obtain statistical significance of small differences compared to euthyroid women. Second, since this was not an intervention study, the objective was limited to demonstrating the association between iron deficiency and hypothyroxinemia, but we did not evaluate the effect of iron supplementation on T4 concentrations. Finally, we analyzed obstetric and neonatal outcomes but not parameters of fetal brain development, which could also be compromised by isolated hypothyroxinemia (33. Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017;27(3):315-89.). Although an association between hypothyroxinemia at the beginning of pregnancy and some impairment of fetal brain development has been reported in some series (33. Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017;27(3):315-89.,2020. Chan S, Boelaert K. Optimal management of hypothyroidism, hypothyroxinaemia and euthyroid TPO antibody positivity preconception and in pregnancy. Clin Endocrinol (Oxf). 2015;82(3):313-26.), two randomized studies found no beneficial effect of L-T4 therapy on this aspect (1010. Casey BM, Thom EA, Peaceman AM, Varner MW, Sorokin Y, Hirtz DG, et al.; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy. N Engl J Med. 2017;376(9):815-25.,2121. Lazarus JH, Bestwick JP, Channon S, Paradice R, Maina A, Rees R, et al. Antenatal thyroid screening and childhood cognitive function. N Engl J Med. 2012;366:493-501.).

In conclusion, this prospective Brazilian study found no association of isolated hypothyroxinemia in the first trimester of gestation with obstetric or neonatal outcomes. Despite the need for confirmation in larger series, this result weakens the concern regarding serum T4 in pregnant women with normal TSH, i.e., with isolated hypothyroxinemia. In contrast, an association was demonstrated between hypothyroxinemia and iron deficiency. This finding suggests the importance of iron and possible repercussions of its deficiency on thyroid function and the need for intervention studies evaluating the effects of iron supplementation on thyroid status in pregnant women.

  • Funding: this work was supported by “National Council for Scientific and Technological Development – CNPq”.

REFERENCES

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    Daru J, Allotey J, Peña-Rosas JP, Khan KS. Serum ferritin thresholds for the diagnosis of iron deficiency in pregnancy: a systematic review. Transfus Med. 2017;27(3):167-74.
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    Yu X, Shan Z, Li C, Mao J, Wang W, Xie X, et al. Iron deficiency, an independent risk factor for isolated hypothyroxinemia in pregnant and nonpregnant women of childbearing age in China. J Clin Endocrinol Metab. 2015;100(4):1594-601.
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    Zimmermann MB, Burgi H, Hurrell RF. Iron deficiency predicts poor maternal thyroid status during pregnancy. J Clin Endocrinol Metab. 2007;92(9):3436-40.
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    Cleary-Goldman J, Malone FD, Lambert-Messerlian G, Sullivan L, Canick J, Porter TF, et al. Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol. 2008;112(1):85-92.
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    Korevaar TI, Schalekamp-Timmermans S, de Rijke YB, Visser WE, Visser W, de Muinck Keizer-Schrama SM, et al. Hypothyroxinemia and TPO-antibody positivity are risk factors for premature delivery: the generation R study. J Clin Endocrinol Metab. 2013;98(11):4382-90.
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    Medici M, Korevaar TI, Schalekamp-Timmermans S, Gaillard R, de Rijke YB, Visser WE, et al. Maternal early-pregnancy thyroid function is associated with subsequent hypertensive disorders of pregnancy: the generation R study. J Clin Endocrinol Metab. 2014;99(12):E2591-8.
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    Lazarus JH, Bestwick JP, Channon S, Paradice R, Maina A, Rees R, et al. Antenatal thyroid screening and childhood cognitive function. N Engl J Med. 2012;366:493-501.

Publication Dates

  • Publication in this collection
    17 May 2018
  • Date of issue
    June 2018

History

  • Received
    14 Sept 2017
  • Accepted
    19 Jan 2018
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