Review Article
Mariacarla Moleti, MD, PhD; Francesco Trimarchi, MD; Francesco Vermiglio, MD
ABSTRACT Objective: Various physiological changes occur in maternal thyroid economy during pregnancy. This review focuses on the events taking place during gestation that together strongly influence maternal thyroid function. Methods: Scientific reports on maternal thyroid physiology in pregnancy. Results: During the 1st trimester, human chorionic gonadotropin (hCG) induces a transient increase in free thyroxine (FT4) levels, which is mirrored by a lowering of thyroid-stimulating hormone (TSH) concentrations. Following this period, serum FT4 concentrations decrease of approximately 10 to 15%, and serum TSH values steadily return to normal. Also starting in early gestation, there is a marked increase in serum thyroxine-binding globulin (TBG) concentrations, which peak around midgestation and are maintained thereafter. This event, in turn, is responsible for a significant rise in total T4 and triiodothyronine (T3). Finally, significant modifications in the peripheral metabolism of maternal thyroid hormones occur, due to the expression and activity of placental types 2 and 3 iodothyronine deiodinases (D2 and D3, respectively). Conclusion: In line with these variations, both free thyroid hormone and TSH reference intervals change
Submitted for publication August 15, 2013 Accepted for publication December 19, 2013 From the Dipartimento di Medicina Clinica e Sperimentale, University of Messina, Messina, Italy. Address correspondence to Dr. Francesco Vermiglio, Azienda Ospedaliera Universitaria “G. Martino,” Via Consolare Valeria, 1 98125, Messina, Italy. E-mail: [email protected] Published as a Rapid Electronic Article in Press at http://www.endocrine practice.org on January 21, 2014. DOI:10.4158/EP13341.RA To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright © 2014 AACE.
throughout pregnancy, and most scientific societies now recommend that method- and gestation-specific reference ranges be used for interpreting results in pregnancy. The maternal iodide pool reduces during pregnancy because of increased renal clearance of iodine and transfer of iodine to the feto-placental unit. This results in an additional requirement of iodine during pregnancy of ~100% as compared to nonpregnant adults. In accordance, the recommended iodine intake in pregnancy is 250 mg/day. A daily iodine intake below this threshold poses risks of various degrees of thyroid insufficiency for both the mother and the fetus. (Endocr Pract. 2014;20:589-596) Abbreviations: D2 = type 2 iodothyronine deiodinase; D3 = type 3 iodothyronine deiodinase; FSH = follicle-stimulating hormone; hCG = human chorionic gonadotropin; ID = iodine deficiency; LH = luteinizing hormone; T3 = triiodothyronine; T4 = thyroxine; TBG = thyroxinebinding globulin; TSH = thyroid-stimulating hormone; UIE = urinary excretion of iodine INTRODUCTION As soon as pregnancy is established, various physiological changes occur in maternal thyroid economy, ultimately aimed at ensuring the regular outcome of pregnancy and normal offspring development (1,2). In fact, several lines of evidence have accumulated over the past 20 years, and they collectively demonstrate the importance of thyroid hormone in regulating both placentation and fetal neurodevelopment (2,3). Advances in this field have revealed that both maternal and fetal thyroid function play an essential role in pregnancy, the mother being more important in early developmental events, and the fetus gradually increasing its contribution in later stages. However, the relative contributions of maternal and fetal thyroid in achieving the complete fetal maturation remain to be definitively established, although the role of the fetal
ENDOCRINE PRACTICE Vol 20 No. 6 June 2014 589
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thyroid might actually be more relevant than previously assumed (4,5). This review will focus on events that take place during gestation and strongly influence maternal thyroid economy. The importance of normative gestational-related reference ranges for thyroid hormones and the role of an adequate iodine supply in pregnancy will be also discussed. THYROID PHYSIOLOGY IN NORMAL PREGNANCY Pregnancy is accompanied by complex alterations in thyroid economy, resulting from several hormonal and metabolic changes specifically related to the pregnant state. These changes are summarized in Table 1 and discussed below. Maternal Thyroid Stimulation by Human Chorionic Gonadotropin Human chorionic gonadotropin (hCG) is a 37-kDa glycoprotein that is structurally similar to follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH) and is secreted by the syncytiotrophoblasts of the placenta into both the fetal and maternal circulation. From the very first weeks of gestation, the thyroid gland is directly stimulated by hCG, the concentration of which peaks in the first 8 to 11 weeks of pregnancy, decreases thereafter, and remains in plateau up to pregnancy term (6,7). The structural homology between hCG and TSH molecules and their receptors provides the basis for the thyrotropic action of hCG (8). During normal pregnancy, hCG-induced thyroid stimulation is responsible for a sharp augmentation in thyroxine (T4) production by maternal thyroid gland, which is paralleled, near the end
of the first trimester, by a transient increase in free thyroid hormone levels. These changes are responsible, in turn, for a decrease in TSH concentration (Fig. 1), with thyrotropin levels in this stage of pregnancy being suppressed in about 20% of pregnancies (9,10). In twin pregnancies, hCG elevations are particularly pronounced and are responsible for increased thyroidal stimulation, leading more frequently to increased free T4 and suppressed TSH levels (11). The activation of the negative feedback on the pituitary gland, which is associated with an increased hCGrelated hormonal output by the thyroid gland, is only transient. Starting from the early second trimester, a slight but definite trend towards an increase in TSH concentrations occurs. This change reflects the opposite trend in free thyroid hormone levels resulting from the increased hormonebinding capacity of the serum, due to the rise in thyroxinebinding globulin (TBG) concentrations (9). Changes in Thyroid Hormone Transport Proteins Pregnancy is associated with a physiological increase in serum TBG and a lowering in serum albumin concentrations. TBG is a 54-kDa glycoprotein synthesized in the liver as a single polypeptide chain of 415 amino acids. It has a single iodothyronine-binding site with affinity slightly higher for T4 than for T3. Under the effect of high concentrations of circulating estrogens, serum TBG increases a few weeks after conception and reaches a plateau during midgestation (Fig. 2). The mechanism for this increase is related to both an increased TBG production rate by hepatocytes and a reduced clearance of the protein from plasma (12,13). The progressive expansion of the TBG extracellular pool, the magnitude of which is estimated in 2.5- to 3-fold of basal levels (9), is responsible for a progressive
Table 1 Physiologic Changes Affecting Maternal Thyroid Function during Pregnancy Physiologic change Thyroid stimulation by hCG produced by the trophoblastic cells of the conceptus Estrogen-induced increase in serum TBG Placental expression of D2 and D3 deiodinases Increased renal I- clearance I- diversion to the feto-placental unit Increased iodide consumption for thyroid hormone synthesis
Timing From very early pregnancy up to the end of the 1st trimester
Effect Transiently increased free T4 and T3 and decreased TSH levels
Progressively increasing from early pregnancy up to midgestation; plateau thereafter Higher expression and activity at early gestation; trend to decrease as gestation progresses From early pregnancy up to term
Increased total T4 and T3 Increased peripheral iodothyronine metabolism Reduced maternal iodide pool
Abbreviations: D2 = type 2 iodothyronine deiodinase; D3 = type 3 iodothyronine deiodinase; hCG = human chorionic gonadotropin; T3 = triiodothyronine; T4 = thyroxine; TBG = thyroxine-binding globulin; TSH = thyroid-stimulating hormone
591
Fig. 1. Serum TSH and hCG as a function of gestational age. Serum hCG was determined at initial evaluation, and TSH at initial evaluation and during late gestation. The symbols give the mean value (±SE) for samples pooled for 2 weeks of gestation. Each point corresponds to the average of 33 determinations for hCG and 49 for TSH. Reproduced with permission from (9).
increase in total hormone fractions (which reach their plateau values by 20 weeks of gestation), and a trend towards a reduction in free thyroid hormone levels (free T4 and free T3). The latter event results in an increase in serum TSH secretion (observed from the second trimester and up to pregnancy term) aimed at enhancing the overall production rate of thyroid hormone by the maternal thyroid gland, finally designed to achieve the new equilibrium state and ensure the homeostasis of the free hormone concentrations during pregnancy. Nonetheless, in physiological conditions (i.e., preserved thyroid function and adequate iodine availability), the increase in TBG concentrations almost doubles the magnitude of the increase in maternal thyroxine. This discrepancy (i.e, a greater increase in TBG than in T4 levels) results in a progressively decreasing T4/TBG ratio, ultimately leading to progressive (physiological) decrease of about 10 to 15% in free T4 and free T3 concentrations (9,14). Modifications in the Peripheral Metabolism of Thyroid Hormones Another important event that affects maternal thyroid economy during pregnancy is related to changes in the peripheral metabolism of thyroid hormones. These variations occur throughout gestation due to elevated deiodination activity in the placenta. The iodothyronine deiodinases expressed by human placenta are the types 2 (D2) and 3 (D3), the activity levels of which decline with pregnancy progression (15). The predominant iodothyronine deiodinase expressed in human placenta is D3, which catalyzes removal of an inner ring iodine atom from T4 to generate rT3 and from
Fig. 2. Serum T4 (top), T3 (middle), and TBG (bottom) as a function of gestational age. Each point gives the mean value (±1 SD) of determinations performed at the initial presentation, pooled for 3 weeks, between 5 and 28 weeks (n = 510) and again for samples obtained between 28 and 39 weeks (n = 355). The latter samples include both late initial evaluations and the second series of determinations at 30-33 weeks. Each point represents an average of 72 individual determinations. The dashed lines illustrate the theoretical curves of T3 and T4 concentrations required to yield the average molar ratios of T4/TBG and T3/ TBG that correspond to nonpregnant reference subjects (0.37 for T4/TBG and 0.0089 for T3/TBG, using a molecular weight of 57 kDa for TBG). Reproduced with permission from (9).
T3 to form T2. Because D3 prevents T4 from being activated and inactivates T3, it protects the developing fetus from excessive exposure to maternal thyroid hormones. In addition, placental D3 activity is thought to represent an important source of iodine to be delivered to the fetus for the production of thyroid hormones by the fetal gland. In addition to D3, the human placenta also expresses D2, which catalyzes the removal of an outer ring iodine atom from T4 to generate T3. D2 is believed to be important,
592
mainly in the earlier stages of gestation, in guaranteeing adequate intraplacental levels of T3 required for trophoblast development and differentiation (15). Overall, the increased degradation of the iodothyronines by placental deiodinases contributes, among other factors, to the increase in hormone demand. Changes in Maternal Iodide Pool During pregnancy there is a trend towards a reduction in the maternal iodide pool, mainly because of 3 events: 1) an increased iodide consumption needed for the increased synthesis of thyroxine by the maternal gland, 2) an increased renal clearance of iodide, and 3) transfers of iodine from the mother to the fetus. Attempts to roughly quantify the losses of iodine due to these factors have been made (16,17). Increased Iodide Consumption for Thyroid Hormone Synthesis The increased iodide consumption is due to the increased organification of this micronutrient in 2 tyrosines, monoiodotyrosine (MIT) and diiodiotyrosine (DIT), the coupling of which generates thyroid hormones. The increase in maternal T4 production is roughly estimated to exceed by 50% the normal hormone synthesis in the nonpregnant population (9). Consequently, additional 50 to 100 mg of iodine/day are needed to guarantee this increased output of thyroxine in pregnant women. This value has been estimated on the basis of the 50% increase in the dose of levothyroxine (LT4) to be administered to maintain euthyroidism in hypothyroid women during gestation. Increased Iodine Loss through the Kidney Early in pregnancy, the renal clearance of iodide increases significantly because of an increase in renal blood flow and glomerular filtration. However, an increase in urinary excretion of iodine (UIE) in pregnancy is neither proven nor quantitatively assessed because the studies on this issue report no differences (18,19), increases (20-22), and even reductions (9,23,24) in UIE in pregnant women compared with nonpregnant women and the general population. Factors likely accounting for these variations may include differences in study design, timing of UIE evaluation (early versus mid- or late gestation), methods of urinary iodine assay, and, not least, iodine intake of populations under examination. Transfer of Iodine from Mother to Fetus The human fetal thyroid develops the ability to accumulate iodine by 10 to 12 weeks of gestation (25). The iodine needed for fetal thyroid function comes from deiodination of iodothyronines within the placenta. In addition, the placenta transfers iodine from the maternal circulation to the fetal placental unit (9). This transfer is ultimately regulated by hCG through the stimulation of both sodium
iodide symporter (NIS) mRNA and protein expression in the membrane of cytotrophoblast cells (26,27). This mechanism would be aimed at providing an early availability of substrate for the production of thyroid hormones by the fetal gland well before the onset of its function in the second half of gestation, thus suggesting a possible role for the placenta as an iodine storage organ (28). Overall, the transfer of iodine from the mother is estimated at about 50 to 75 mg/day toward the end of gestation, but it is likely more minimal in the first trimester. This value is derived from objective data and inferences, such as the measure of the iodide accumulated in the fetal thyroid over gestation, the proportion of iodide content in overall fetal hormone production, and the substitutive doses of LT4 to be administered to hypothyroid neonates (17). Whether placental iodine storage might actually act as a compensatory source of iodine to the fetus in the event of inadequate maternal iodine intake is an intriguing hypothesis that remains unsettled. Considering all these factors, the overall additional dose of iodine during gestation needed to provide an adequate substrate for both maternal and fetal needs is around 150 mg/day. This supplement must be added to the usual dietary dose, thus reaching an overall daily dietary intake of 250 to 300 mg/day. All the above-described events can properly take place provided that the thyroid gland is both anatomically and functionally intact and that iodine intake is adequate to the increased demands of pregnancy. THYROID FUNCTION TESTING IN PREGNANCY Due to gestational-induced changes in thyroid physiology, the reference limits of thyroid parameters used for the general population are no longer valid as a means to diagnose thyroid dysfunction during pregnancy (29,30). Given the serious impact of maternal thyroid dysfunction on pregnancy outcome and fetal health, this aspect is extremely important and deserves special attention. In accordance, many efforts have been made in recent years to establish gestational reference ranges for thyroid function tests (31-36). As previously stated, TSH concentrations are physiologically reduced during the first trimester of pregnancy. Thus, normal TSH values at early gestation are lower than those found in the general population, with some 20% of euthyroid pregnant women found to have suppressed thyrotropin levels. Conversely, the upper normal limit for TSH during this stage of pregnancy is significantly lower than those recorded in general population, and TSH values above 2.3 to 2.5 mU/L should be regarded as indicative of gestational thyroid insufficiency. As pregnancy progresses, there is a physiological trend of TSH towards an increase, and the upper normal gestational limits are
593
mostly reported to fall below 3.0 mU/L and 3.5 mU/L in the second and third trimester, respectively. Being aware of the above changes in TSH levels over gestation is of relevance in clinical practice, as the utilization of nonpregnant reference intervals to interpret thyroid function tests in pregnant women carries the risk of misdiagnosis (37). Unlike gestational TSH values, for which there is substantial agreement among researchers, normative thyroid hormone values for pregnancy are still far from being established. This is mainly due to the fact that direct analog FT4 immunoassays currently used to estimate FT4 concentrations are variously biased by either endogenous or in vitro factors. In particular, these assays are known to be affected to variable degrees by the physiological changes in TBG and albumin occurring during gestation (38, 39), and the same specimens analyzed by different immunoassay platforms may provide remarkably different results (40). Conversely, methods of analysis based on the physical separation of the free from the protein-bound T4 fraction by equilibrium dialysis (ED) or ultrafiltration (UF) before direct quantification of the hormone content in the dialysate/ultrafiltrate, are generally regarded as reference methods (41,42). Recently, an International Federation of Clinical Chemistry (IFCC) working group proposed FT4 measurement by ED combined with isotope dilution-liquid chromatography/tandem mass spectrometry (ED ID-LC/ tandem MS) as the reference measurement procedure (RMP) to measure serum FT4 (43). In general, most of current routine immunoassays provide lower FT4 values than the RMP, even if divergences seem to be greater for high values rather than for values in the low range (28-30). Because of these methodological difficulties, establishing normative values of FT4 for pregnancy is challenging and, whatever the method, it is recommended that method- and gestation-specific reference ranges are used for interpreting results in pregnancy (47). Alternatively, the FT4 index or the total T4 adjusted for pregnancy (i.e., total T4 nonpregnant reference range multiplied by 1.5) have been proposed as reliable methods of estimating FT4 status in pregnancy (29,48), although the reliability of these methods in the evaluation of maternal thyroid function during pregnancy is disputed (49). THE IMPORTANCE OF IODINE NUTRITION DURING PREGNANCY Iodine is an essential constituent of thyroid hormones, which, in turn, are essential for normal progression of pregnancy and the neuro-intellectual development of the fetus. At present, no other use apart from thyroid hormone synthesis is known in human biology. Iodine deficiency (ID) affects almost 2 billion people worldwide. Based on the latest evaluation of ID disorders (IDDs), 111 countries are considered iodine sufficient and 30 are still mildly to moderately iodine deficient
(50). Pregnant women from populations exposed to ID are potentially at risk of suffering major iodine disorders (51). Also, pregnant women living in regions where iodine intake is considered sufficient for the general population may theoretically be at risk of suffering from the consequences of ID (only transient and limited to gestational period) because of iodine intake that is not adequate to meet the increasing needs imposed by pregnancy (52). The recommended iodine intake in pregnancy based on a technical consultation on behalf of the World Health Organization (WHO) is 250 mg/day, roughly corresponding to a UIE of 185 mg/L. This goal is supposedly achievable through universal salt iodization (USI), provided that this measure has been in effect for at least 2 years and that iodized salt is consumed by >90% of households. Conversely, in countries where a USI program is lacking and/or the percentage of households consuming iodized salt is
Mariacarla Moleti, MD, PhD; Francesco Trimarchi, MD; Francesco Vermiglio, MD
ABSTRACT Objective: Various physiological changes occur in maternal thyroid economy during pregnancy. This review focuses on the events taking place during gestation that together strongly influence maternal thyroid function. Methods: Scientific reports on maternal thyroid physiology in pregnancy. Results: During the 1st trimester, human chorionic gonadotropin (hCG) induces a transient increase in free thyroxine (FT4) levels, which is mirrored by a lowering of thyroid-stimulating hormone (TSH) concentrations. Following this period, serum FT4 concentrations decrease of approximately 10 to 15%, and serum TSH values steadily return to normal. Also starting in early gestation, there is a marked increase in serum thyroxine-binding globulin (TBG) concentrations, which peak around midgestation and are maintained thereafter. This event, in turn, is responsible for a significant rise in total T4 and triiodothyronine (T3). Finally, significant modifications in the peripheral metabolism of maternal thyroid hormones occur, due to the expression and activity of placental types 2 and 3 iodothyronine deiodinases (D2 and D3, respectively). Conclusion: In line with these variations, both free thyroid hormone and TSH reference intervals change
Submitted for publication August 15, 2013 Accepted for publication December 19, 2013 From the Dipartimento di Medicina Clinica e Sperimentale, University of Messina, Messina, Italy. Address correspondence to Dr. Francesco Vermiglio, Azienda Ospedaliera Universitaria “G. Martino,” Via Consolare Valeria, 1 98125, Messina, Italy. E-mail: [email protected] Published as a Rapid Electronic Article in Press at http://www.endocrine practice.org on January 21, 2014. DOI:10.4158/EP13341.RA To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright © 2014 AACE.
throughout pregnancy, and most scientific societies now recommend that method- and gestation-specific reference ranges be used for interpreting results in pregnancy. The maternal iodide pool reduces during pregnancy because of increased renal clearance of iodine and transfer of iodine to the feto-placental unit. This results in an additional requirement of iodine during pregnancy of ~100% as compared to nonpregnant adults. In accordance, the recommended iodine intake in pregnancy is 250 mg/day. A daily iodine intake below this threshold poses risks of various degrees of thyroid insufficiency for both the mother and the fetus. (Endocr Pract. 2014;20:589-596) Abbreviations: D2 = type 2 iodothyronine deiodinase; D3 = type 3 iodothyronine deiodinase; FSH = follicle-stimulating hormone; hCG = human chorionic gonadotropin; ID = iodine deficiency; LH = luteinizing hormone; T3 = triiodothyronine; T4 = thyroxine; TBG = thyroxinebinding globulin; TSH = thyroid-stimulating hormone; UIE = urinary excretion of iodine INTRODUCTION As soon as pregnancy is established, various physiological changes occur in maternal thyroid economy, ultimately aimed at ensuring the regular outcome of pregnancy and normal offspring development (1,2). In fact, several lines of evidence have accumulated over the past 20 years, and they collectively demonstrate the importance of thyroid hormone in regulating both placentation and fetal neurodevelopment (2,3). Advances in this field have revealed that both maternal and fetal thyroid function play an essential role in pregnancy, the mother being more important in early developmental events, and the fetus gradually increasing its contribution in later stages. However, the relative contributions of maternal and fetal thyroid in achieving the complete fetal maturation remain to be definitively established, although the role of the fetal
ENDOCRINE PRACTICE Vol 20 No. 6 June 2014 589
590
thyroid might actually be more relevant than previously assumed (4,5). This review will focus on events that take place during gestation and strongly influence maternal thyroid economy. The importance of normative gestational-related reference ranges for thyroid hormones and the role of an adequate iodine supply in pregnancy will be also discussed. THYROID PHYSIOLOGY IN NORMAL PREGNANCY Pregnancy is accompanied by complex alterations in thyroid economy, resulting from several hormonal and metabolic changes specifically related to the pregnant state. These changes are summarized in Table 1 and discussed below. Maternal Thyroid Stimulation by Human Chorionic Gonadotropin Human chorionic gonadotropin (hCG) is a 37-kDa glycoprotein that is structurally similar to follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH) and is secreted by the syncytiotrophoblasts of the placenta into both the fetal and maternal circulation. From the very first weeks of gestation, the thyroid gland is directly stimulated by hCG, the concentration of which peaks in the first 8 to 11 weeks of pregnancy, decreases thereafter, and remains in plateau up to pregnancy term (6,7). The structural homology between hCG and TSH molecules and their receptors provides the basis for the thyrotropic action of hCG (8). During normal pregnancy, hCG-induced thyroid stimulation is responsible for a sharp augmentation in thyroxine (T4) production by maternal thyroid gland, which is paralleled, near the end
of the first trimester, by a transient increase in free thyroid hormone levels. These changes are responsible, in turn, for a decrease in TSH concentration (Fig. 1), with thyrotropin levels in this stage of pregnancy being suppressed in about 20% of pregnancies (9,10). In twin pregnancies, hCG elevations are particularly pronounced and are responsible for increased thyroidal stimulation, leading more frequently to increased free T4 and suppressed TSH levels (11). The activation of the negative feedback on the pituitary gland, which is associated with an increased hCGrelated hormonal output by the thyroid gland, is only transient. Starting from the early second trimester, a slight but definite trend towards an increase in TSH concentrations occurs. This change reflects the opposite trend in free thyroid hormone levels resulting from the increased hormonebinding capacity of the serum, due to the rise in thyroxinebinding globulin (TBG) concentrations (9). Changes in Thyroid Hormone Transport Proteins Pregnancy is associated with a physiological increase in serum TBG and a lowering in serum albumin concentrations. TBG is a 54-kDa glycoprotein synthesized in the liver as a single polypeptide chain of 415 amino acids. It has a single iodothyronine-binding site with affinity slightly higher for T4 than for T3. Under the effect of high concentrations of circulating estrogens, serum TBG increases a few weeks after conception and reaches a plateau during midgestation (Fig. 2). The mechanism for this increase is related to both an increased TBG production rate by hepatocytes and a reduced clearance of the protein from plasma (12,13). The progressive expansion of the TBG extracellular pool, the magnitude of which is estimated in 2.5- to 3-fold of basal levels (9), is responsible for a progressive
Table 1 Physiologic Changes Affecting Maternal Thyroid Function during Pregnancy Physiologic change Thyroid stimulation by hCG produced by the trophoblastic cells of the conceptus Estrogen-induced increase in serum TBG Placental expression of D2 and D3 deiodinases Increased renal I- clearance I- diversion to the feto-placental unit Increased iodide consumption for thyroid hormone synthesis
Timing From very early pregnancy up to the end of the 1st trimester
Effect Transiently increased free T4 and T3 and decreased TSH levels
Progressively increasing from early pregnancy up to midgestation; plateau thereafter Higher expression and activity at early gestation; trend to decrease as gestation progresses From early pregnancy up to term
Increased total T4 and T3 Increased peripheral iodothyronine metabolism Reduced maternal iodide pool
Abbreviations: D2 = type 2 iodothyronine deiodinase; D3 = type 3 iodothyronine deiodinase; hCG = human chorionic gonadotropin; T3 = triiodothyronine; T4 = thyroxine; TBG = thyroxine-binding globulin; TSH = thyroid-stimulating hormone
591
Fig. 1. Serum TSH and hCG as a function of gestational age. Serum hCG was determined at initial evaluation, and TSH at initial evaluation and during late gestation. The symbols give the mean value (±SE) for samples pooled for 2 weeks of gestation. Each point corresponds to the average of 33 determinations for hCG and 49 for TSH. Reproduced with permission from (9).
increase in total hormone fractions (which reach their plateau values by 20 weeks of gestation), and a trend towards a reduction in free thyroid hormone levels (free T4 and free T3). The latter event results in an increase in serum TSH secretion (observed from the second trimester and up to pregnancy term) aimed at enhancing the overall production rate of thyroid hormone by the maternal thyroid gland, finally designed to achieve the new equilibrium state and ensure the homeostasis of the free hormone concentrations during pregnancy. Nonetheless, in physiological conditions (i.e., preserved thyroid function and adequate iodine availability), the increase in TBG concentrations almost doubles the magnitude of the increase in maternal thyroxine. This discrepancy (i.e, a greater increase in TBG than in T4 levels) results in a progressively decreasing T4/TBG ratio, ultimately leading to progressive (physiological) decrease of about 10 to 15% in free T4 and free T3 concentrations (9,14). Modifications in the Peripheral Metabolism of Thyroid Hormones Another important event that affects maternal thyroid economy during pregnancy is related to changes in the peripheral metabolism of thyroid hormones. These variations occur throughout gestation due to elevated deiodination activity in the placenta. The iodothyronine deiodinases expressed by human placenta are the types 2 (D2) and 3 (D3), the activity levels of which decline with pregnancy progression (15). The predominant iodothyronine deiodinase expressed in human placenta is D3, which catalyzes removal of an inner ring iodine atom from T4 to generate rT3 and from
Fig. 2. Serum T4 (top), T3 (middle), and TBG (bottom) as a function of gestational age. Each point gives the mean value (±1 SD) of determinations performed at the initial presentation, pooled for 3 weeks, between 5 and 28 weeks (n = 510) and again for samples obtained between 28 and 39 weeks (n = 355). The latter samples include both late initial evaluations and the second series of determinations at 30-33 weeks. Each point represents an average of 72 individual determinations. The dashed lines illustrate the theoretical curves of T3 and T4 concentrations required to yield the average molar ratios of T4/TBG and T3/ TBG that correspond to nonpregnant reference subjects (0.37 for T4/TBG and 0.0089 for T3/TBG, using a molecular weight of 57 kDa for TBG). Reproduced with permission from (9).
T3 to form T2. Because D3 prevents T4 from being activated and inactivates T3, it protects the developing fetus from excessive exposure to maternal thyroid hormones. In addition, placental D3 activity is thought to represent an important source of iodine to be delivered to the fetus for the production of thyroid hormones by the fetal gland. In addition to D3, the human placenta also expresses D2, which catalyzes the removal of an outer ring iodine atom from T4 to generate T3. D2 is believed to be important,
592
mainly in the earlier stages of gestation, in guaranteeing adequate intraplacental levels of T3 required for trophoblast development and differentiation (15). Overall, the increased degradation of the iodothyronines by placental deiodinases contributes, among other factors, to the increase in hormone demand. Changes in Maternal Iodide Pool During pregnancy there is a trend towards a reduction in the maternal iodide pool, mainly because of 3 events: 1) an increased iodide consumption needed for the increased synthesis of thyroxine by the maternal gland, 2) an increased renal clearance of iodide, and 3) transfers of iodine from the mother to the fetus. Attempts to roughly quantify the losses of iodine due to these factors have been made (16,17). Increased Iodide Consumption for Thyroid Hormone Synthesis The increased iodide consumption is due to the increased organification of this micronutrient in 2 tyrosines, monoiodotyrosine (MIT) and diiodiotyrosine (DIT), the coupling of which generates thyroid hormones. The increase in maternal T4 production is roughly estimated to exceed by 50% the normal hormone synthesis in the nonpregnant population (9). Consequently, additional 50 to 100 mg of iodine/day are needed to guarantee this increased output of thyroxine in pregnant women. This value has been estimated on the basis of the 50% increase in the dose of levothyroxine (LT4) to be administered to maintain euthyroidism in hypothyroid women during gestation. Increased Iodine Loss through the Kidney Early in pregnancy, the renal clearance of iodide increases significantly because of an increase in renal blood flow and glomerular filtration. However, an increase in urinary excretion of iodine (UIE) in pregnancy is neither proven nor quantitatively assessed because the studies on this issue report no differences (18,19), increases (20-22), and even reductions (9,23,24) in UIE in pregnant women compared with nonpregnant women and the general population. Factors likely accounting for these variations may include differences in study design, timing of UIE evaluation (early versus mid- or late gestation), methods of urinary iodine assay, and, not least, iodine intake of populations under examination. Transfer of Iodine from Mother to Fetus The human fetal thyroid develops the ability to accumulate iodine by 10 to 12 weeks of gestation (25). The iodine needed for fetal thyroid function comes from deiodination of iodothyronines within the placenta. In addition, the placenta transfers iodine from the maternal circulation to the fetal placental unit (9). This transfer is ultimately regulated by hCG through the stimulation of both sodium
iodide symporter (NIS) mRNA and protein expression in the membrane of cytotrophoblast cells (26,27). This mechanism would be aimed at providing an early availability of substrate for the production of thyroid hormones by the fetal gland well before the onset of its function in the second half of gestation, thus suggesting a possible role for the placenta as an iodine storage organ (28). Overall, the transfer of iodine from the mother is estimated at about 50 to 75 mg/day toward the end of gestation, but it is likely more minimal in the first trimester. This value is derived from objective data and inferences, such as the measure of the iodide accumulated in the fetal thyroid over gestation, the proportion of iodide content in overall fetal hormone production, and the substitutive doses of LT4 to be administered to hypothyroid neonates (17). Whether placental iodine storage might actually act as a compensatory source of iodine to the fetus in the event of inadequate maternal iodine intake is an intriguing hypothesis that remains unsettled. Considering all these factors, the overall additional dose of iodine during gestation needed to provide an adequate substrate for both maternal and fetal needs is around 150 mg/day. This supplement must be added to the usual dietary dose, thus reaching an overall daily dietary intake of 250 to 300 mg/day. All the above-described events can properly take place provided that the thyroid gland is both anatomically and functionally intact and that iodine intake is adequate to the increased demands of pregnancy. THYROID FUNCTION TESTING IN PREGNANCY Due to gestational-induced changes in thyroid physiology, the reference limits of thyroid parameters used for the general population are no longer valid as a means to diagnose thyroid dysfunction during pregnancy (29,30). Given the serious impact of maternal thyroid dysfunction on pregnancy outcome and fetal health, this aspect is extremely important and deserves special attention. In accordance, many efforts have been made in recent years to establish gestational reference ranges for thyroid function tests (31-36). As previously stated, TSH concentrations are physiologically reduced during the first trimester of pregnancy. Thus, normal TSH values at early gestation are lower than those found in the general population, with some 20% of euthyroid pregnant women found to have suppressed thyrotropin levels. Conversely, the upper normal limit for TSH during this stage of pregnancy is significantly lower than those recorded in general population, and TSH values above 2.3 to 2.5 mU/L should be regarded as indicative of gestational thyroid insufficiency. As pregnancy progresses, there is a physiological trend of TSH towards an increase, and the upper normal gestational limits are
593
mostly reported to fall below 3.0 mU/L and 3.5 mU/L in the second and third trimester, respectively. Being aware of the above changes in TSH levels over gestation is of relevance in clinical practice, as the utilization of nonpregnant reference intervals to interpret thyroid function tests in pregnant women carries the risk of misdiagnosis (37). Unlike gestational TSH values, for which there is substantial agreement among researchers, normative thyroid hormone values for pregnancy are still far from being established. This is mainly due to the fact that direct analog FT4 immunoassays currently used to estimate FT4 concentrations are variously biased by either endogenous or in vitro factors. In particular, these assays are known to be affected to variable degrees by the physiological changes in TBG and albumin occurring during gestation (38, 39), and the same specimens analyzed by different immunoassay platforms may provide remarkably different results (40). Conversely, methods of analysis based on the physical separation of the free from the protein-bound T4 fraction by equilibrium dialysis (ED) or ultrafiltration (UF) before direct quantification of the hormone content in the dialysate/ultrafiltrate, are generally regarded as reference methods (41,42). Recently, an International Federation of Clinical Chemistry (IFCC) working group proposed FT4 measurement by ED combined with isotope dilution-liquid chromatography/tandem mass spectrometry (ED ID-LC/ tandem MS) as the reference measurement procedure (RMP) to measure serum FT4 (43). In general, most of current routine immunoassays provide lower FT4 values than the RMP, even if divergences seem to be greater for high values rather than for values in the low range (28-30). Because of these methodological difficulties, establishing normative values of FT4 for pregnancy is challenging and, whatever the method, it is recommended that method- and gestation-specific reference ranges are used for interpreting results in pregnancy (47). Alternatively, the FT4 index or the total T4 adjusted for pregnancy (i.e., total T4 nonpregnant reference range multiplied by 1.5) have been proposed as reliable methods of estimating FT4 status in pregnancy (29,48), although the reliability of these methods in the evaluation of maternal thyroid function during pregnancy is disputed (49). THE IMPORTANCE OF IODINE NUTRITION DURING PREGNANCY Iodine is an essential constituent of thyroid hormones, which, in turn, are essential for normal progression of pregnancy and the neuro-intellectual development of the fetus. At present, no other use apart from thyroid hormone synthesis is known in human biology. Iodine deficiency (ID) affects almost 2 billion people worldwide. Based on the latest evaluation of ID disorders (IDDs), 111 countries are considered iodine sufficient and 30 are still mildly to moderately iodine deficient
(50). Pregnant women from populations exposed to ID are potentially at risk of suffering major iodine disorders (51). Also, pregnant women living in regions where iodine intake is considered sufficient for the general population may theoretically be at risk of suffering from the consequences of ID (only transient and limited to gestational period) because of iodine intake that is not adequate to meet the increasing needs imposed by pregnancy (52). The recommended iodine intake in pregnancy based on a technical consultation on behalf of the World Health Organization (WHO) is 250 mg/day, roughly corresponding to a UIE of 185 mg/L. This goal is supposedly achievable through universal salt iodization (USI), provided that this measure has been in effect for at least 2 years and that iodized salt is consumed by >90% of households. Conversely, in countries where a USI program is lacking and/or the percentage of households consuming iodized salt is
